Publications

@article{Koba2022,
title = {A brainstem monosynaptic excitatory pathway that drives locomotor activities and sympathetic cardiovascular responses},
author = {Satoshi Koba and Nao Kumada and Emi Narai and Naoya Kataoka and Kazuhiro Nakamura and Tatsuo Watanabe },
url = {https://doi.org/10.1038/s41467-022-32823-x},
doi = {10.1038/s41467-022-32823-x},
year = {2022},
date = {2022-08-29},
journal = {Nature Communications},
volume = {13},
number = {1},
abstract = {Exercise including locomotion requires appropriate autonomic cardiovascular adjustments to meet the metabolic demands of contracting muscles, yet the functional brain architecture underlying these adjustments remains unknown. Here, we demonstrate brainstem circuitry that plays an essential role in relaying volitional motor signals, i.e., central command, to drive locomotor activities and sympathetic cardiovascular responses. Mesencephalic locomotor neurons in rats transmit central command-driven excitatory signals onto the rostral ventrolateral medulla at least partially via glutamatergic processes, to activate both somatomotor and sympathetic nervous systems. Optogenetic excitation of this monosynaptic pathway elicits locomotor and cardiovascular responses as seen during running exercise, whereas pathway inhibition suppresses the locomotor activities and blood pressure elevation during voluntary running without affecting basal cardiovascular homeostasis. These results demonstrate an important subcortical pathway that transmits central command signals, providing a key insight into the central circuit mechanism required for the physiological conditioning essential to maximize exercise performance.},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Fong2021,
title = {A method to evaluate dynamic cerebral pressure-flow relationships in the conscious rat.},
author = {Debra Fong and Kelly Gradon and Carolyn J. Barrett and Sarah-Jane Guild and Yu-Chieh Tzeng and Julian F.R. Paton and Fiona D. McBryde},
url = {https://doi.org/10.1152/japplphysiol.00289.2021},
year = {2021},
date = {2021-09-09},
journal = {Journal of Applied Physiology},
abstract = {The classic dogma of cerebral autoregulation is that cerebral blood flow is steadily maintained across a wide range of perfusion pressures. This has been challenged by recent studies suggesting little to no 'autoregulatory plateau' in the relationship between cerebral blood flow and blood pressure (BP). Therefore, the mechanisms underlying the cerebral pressure-flow relationship still require further understanding. Here we present a novel approach to examine dynamic cerebral autoregulation in conscious Wistar rats (n=16) instrumented to measure BP and internal carotid blood flow (iCBF), as an indicator of cerebral blood flow. Transient reductions in BP were induced by occluding the vena cava via inflation of a chronically implanted intravascular silicone balloon. Falls in BP were paralleled by progressive decreases in iCBF, with no evidence of a steady state plateau. No significant changes in internal carotid vascular resistance (iCVR) were observed. In contrast, intravenous infusions of the vasoactive drug sodium nitroprusside (SNP) produced a similar fall in BP but increases in iCBF and decreases in iCVR. These data suggest a considerable confounding influence of vasodilatory drugs such as SNP on cerebrovascular tone in the rat, making them unsuitable to investigate cerebral autoregulation. We demonstrate that our technique of transient vena cava occlusion produced reliable and repeatable depressor responses, highlighting the potential for our approach to permit assessment of the dynamic cerebral pressure-flow relationship over time in conscious rats.},
keywords = {Blood Pressure, Rat, TRM56SP},
pubstate = {published},
tppubtype = {article}
}

@article{Sachdeva2021,
title = {Noninvasive Neuroprosthesis Promotes Cardiovascular Recovery After Spinal Cord Injury},
author = {Rahul Sachdeva and Tom E Nightingale and Kiran Pawar and Tamila Kalimullina and Adam Mesa and Arshdeep Marwaha and Alison M M Williams and Tania Lam and Andrei V Krassioukov },
url = {https://doi.org/10.1007/s13311-021-01034-5},
doi = {s13311-021-01034-5},
year = {2021},
date = {2021-03-31},
journal = {Neurotherapeutics},
volume = {Open Source},
abstract = {Spinal cord injury (SCI) leads to severe impairment in cardiovascular control, commonly manifested as a rapid, uncontrolled rise in blood pressure triggered by peripheral stimuli—a condition called autonomic dysreflexia. The objective was to demonstrate the translational potential of noninvasive transcutaneous stimulation (TCS) in mitigating autonomic dysreflexia following SCI, using pre-clinical evidence and a clinical case report. In rats with SCI, we show that TCS not only prevents the instigation of autonomic dysreflexia, but also mitigates its severity when delivered during an already-triggered episode. Furthermore, when TCS was delivered as a multisession therapy for 6 weeks post-SCI, the severity of autonomic dysreflexia was significantly reduced when tested in the absence of concurrent TCS. This treatment effect persisted for at least 1 week after the end of therapy. More importantly, we demonstrate the clinical applicability of TCS in treatment of autonomic dysreflexia in an individual with cervical, motor-complete, chronic SCI. We anticipate that TCS will offer significant therapeutic advantages, such as obviating the need for surgery resulting in reduced risk and medical expenses. Furthermore, this study provides a framework for testing the potential of TCS in improving recovery of other autonomic functions such lower urinary tract, bowel, and sexual dysfunction following SCI.},
keywords = {Blood Pressure, Mouse, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Squair2021,
title = {Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury},
author = {Squair, Jordan W and Gautier, Matthieu and Mahe, Lois and Soriano, Jan Elaine and Rowald, Andreas Bichat, Arnaud and Cho, Newton and Anderson, Mark A and James, Nicholas D and Gandar, Jerome and Incognito, Anthony V and Schiavone, Giuseppe and Sarafis, Zoe K and Laskaratos, Achilleas and Bartholdi, Kay and Demesmaeker, Robin and Komi, Salif and Moerman, Charlotte and Vaseghi, Bita and Scott, Berkeley and Rosentreter, Ryan and Kathe, Claudia and Ravier, Jimmy and McCracken, Laura and Kang, Xiaoyang and Vachicouras, Nicolas and Fallegger, Florian and Jelescu, Ileana and Cheng, YunLong and Li, Qin and Buschman, Rik; Buse, Nicolas and Denison, Tim and Dukelow, Sean and Charbonneau, Rebecca and Rigby, Ian and Boyd, Steven K and Millar, Philip J and Moraud, Eduardo Martin and Capogrosso, Marco and Wagner, Fabien B and Barraud, Quentin and Bezard, Erwan and Lacour, Stéphanie P and Bloch, Jocelyne and Courtine, Grégoire and and Phillips, Aaron A

},
editor = {A Abdelkader},
url = {https://doi.org/10.1038/s41586-020-03180-w},
year = {2021},
date = {2021-01-27},
journal = {Nature},
volume = {590},
pages = {308–314},
abstract = {Abstract
Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1,2,3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This ‘neuroprosthetic baroreflex’ controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.},
keywords = {autonomic nervous system, Blood Pressure, neural circuits, Rat, spinal cord injury, Sympathetic Nerve Activity, TRM56SP},
pubstate = {published},
tppubtype = {article}
}

@article{Chapman2020,
title = {Treprostinil palmitil, an inhaled long-acting pulmonary vasodilator, does not show tachyphylaxis with daily dosing in rats},
author = {Richard W Chapman and Zhili Li and Donald Chun and Helena Gauani and Vladimir Malinin and Adam J Plaunt and David Cipolla and Walter R Perkins and Michel R Corboz},
url = {https://doi.org/10.1016/j.pupt.2020.101983},
year = {2020},
date = {2020-12-17},
journal = {Pulm Pharmacol Ther },
volume = {Online ahead of print.},
abstract = {Background: Treprostinil palmitil (TP) is an inhaled long-acting pulmonary vasodilator prodrug of treprostinil (TRE) that has been formulated for delivery as a suspension (treprostinil palmitil inhalation suspension; TPIS) and as a dry powder (treprostinil palmitil inhalation powder; TPIP). In humans, tachyphylaxis is frequently observed with continuous intravenous (IV) or subcutaneous (SC) infusion of TRE and requires dosage escalation to maintain activity. The aim of the present study was to determine whether tachyphylaxis occurs with repeat daily administration of inhaled TPIS.

Methods: Experiments were performed in male Sprague-Dawley rats prepared with a telemetry probe implanted into the right ventricle to measure the change in right ventricular pulse pressure (ΔRVPP) induced by exposure to a 10% oxygen gas mixture. TPIS (6 mL) at concentrations of 0.25, 0.5, and 1 mM was given by nose-only inhalation using an Aeroneb Pro nebulizer, either as a single administration or daily for 16 or 32 consecutive days. In studies involving consecutive daily administrations of TPIS, the delivered TP dosage was 140.3 μg/kg at 1 mM and ranged from 40.2 to 72.2 μg/kg at 0.5 mM. A separate cohort of telemetered rats received continuous IV infusion of TRE via an Alzet mini-pump at a dosage rate of 250 ng/kg/min for 16 days. Blood and lung tissue samples were obtained, and the concentration of TRE in the plasma and TRE and TP in the lungs were measured approximately 1 hour after TPIS administration.

Results: Dose-response studies with TPIS administered as a single administration inhibited the hypoxia-induced increase in RVPP in both a concentration-dependent (0.25, 0.5, and 1 mM) and time-dependent (1 to 24 hours) manner. TPIS, given QD or BID at inhaled doses ranging from 40.2 to 140.3 μg/kg for 16 or 32 consecutive days, produced statistically significant (P < .05) inhibition of the increase of RVPP due to hypoxia over the full duration of the dosing periods. By contrast, the inhibition of the hypoxia-induced increase in RVPP observed with IV TRE infusion (250 ng/kg/min) disappeared after 16 days of infusion. The plasma concentrations of TRE were significantly higher after IV TRE (range, 2.85-13.35 ng/mL) compared to inhaled TPIS (range, 0.22-0.73 ng/mL). Conclusions: There was no evidence of tachyphylaxis with repeat daily dosing of TPIS for a period of up to 32 days. The absence of tachyphylaxis with TPIS is likely related to its local vasodilatory effects within the lungs, combined with an absence of sustained high plasma concentrations of TRE.},
keywords = {Rat, Right Ventricular Pressure, TRM54PP},
pubstate = {published},
tppubtype = {article}
}

@article{Ribeiro2020,
title = {Depletion of C1 Neurons Attenuates the Salt-Induced Hypertension in Unanesthetized Rats},
author = {Natalia Ribeiro and Renato W. Martins Sá and Vagner R. Antunes},
url = {https://doi.org/10.1016/j.brainres.2020.147107},
year = {2020},
date = {2020-12-01},
journal = {Brain Research},
volume = {1748},
abstract = {High salt intake is able to evoke neuroendocrine and autonomic responses that include vasopressin release and sympathoexcitation resulting in increasing in the arterial blood pressure (BP). The C1 neurons are a specific population of catecholaminergic neurons located in the RVLM region and they control BP under homeostatic imbalance. Thus, here we hypothesized that the ablation of C1 neurons mitigate the high blood pressure induced by high-salt intake. To test this hypothesis, we injected anti-DβH-SAP saporin at the RVLM and monitored the BP in unanesthetized animals exposed to high salt intake of 2% NaCl solution for 7 days. The injection of anti-DβH-SAP into the RVLM depleted 80% of tyrosine hydroxylase-positive neurons (TH+ neurons) in the C1, 38% in the A5, and no significant reduction in the A1 region, when compared to control group (saline as vehicle). High salt intake elicited a significant increase in BP in the control group, while in the anti-DβH-SAP group the depletion of TH+ neurons prevents the salt-induced hypertension. Moreover, the low frequency component of systolic BP and pulse interval were increased by high-salt intake in control animals but not in anti-DβH-SAP group, which indirectly suggests that the increase in the BP is mediated by increase in sympathetic activity. In conclusion, our data show that hypertension induced by high-salt intake is dependent on C1 neurons.},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Wong2020,
title = {Comparison of nonparametric and parametric methods for time-frequency heart rate variability analysis in a rodent model of cardiovascular disease},
author = {Emily M. Wong and Fern Tablin and Edward S. Schelegle},
url = {https://doi.org/10.1371/journal.pone.0242147},
year = {2020},
date = {2020-11-09},
journal = {PLoS ONE },
volume = {15},
number = {11},
pages = {e0242147},
abstract = {The aim of time-varying heart rate variability spectral analysis is to detect and quantify changes in the heart rate variability spectrum components during nonstationary events. Of the methods available, the nonparametric short-time Fourier Transform and parametric time-varying autoregressive modeling are the most commonly employed. The current study (1) compares short-time Fourier Transform and autoregressive modeling methods influence on heart rate variability spectral characteristics over time and during an experimental ozone exposure in mature adult spontaneously hypertensive rats, (2) evaluates the agreement between short-time Fourier Transform and autoregressive modeling method results, and (3) describes the advantages and disadvantages of each method. Although similar trends were detected during ozone exposure, statistical comparisons identified significant differences between short-time Fourier Transform and autoregressive modeling analysis results. Significant differences were observed between methods for LF power (p ≤ 0.014); HF power (p ≤ 0.011); total power (p ≤ 0.027); and normalized HF power (p = 0.05). Furthermore, inconsistencies between exposure-related observations accentuated the lack of agreement between short-time Fourier Transform and autoregressive modeling overall. Thus, the short-time Fourier Transform and autoregressive modeling methods for time-varying heart rate variability analysis could not be considered interchangeable for evaluations with or without interventions that are known to affect cardio-autonomic activity.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{He2020,
title = {The conductive function of biopolymer corrects myocardial scar conduction blockage and resynchronizes contraction to prevent heart failure},
author = {Sheng He and Jun Wu and Shu-Hong Li and Li Wang and Yu Sun and Jun Xie and Daniel Ramnath and Richard D. Weisel and Terrence M. Yau and Hsing-Wen Sung and Ren-Ke Li},
url = {https://doi.org/10.1016/j.biomaterials.2020.120285},
year = {2020},
date = {2020-08-03},
journal = {Biomaterials},
volume = {258},
abstract = {Myocardial fibrosis, resulting from ischemic injury, increases tissue resistivity in the infarct area, which impedes heart synchronous electrical propagation. The uneven conduction between myocardium and fibrotic tissue leads to dys-synchronous contraction, which progresses towards ventricular dysfunction. We synthesized a conductive poly-pyrrole-chitosan hydrogel (PPY–CHI), and investigated its capabilities in improving electrical propagation in fibrotic tissue, as well as resynchronizing cardiac contraction to preserve cardiac function . In an in vitro fibrotic scar model, conductivity increased in proportion to the amount of PPY-CHI hydrogel added. To elucidate the mechanism of interaction between myocardial ionic changes and electrical current, an equivalent circuit model was used, which showed that PPY-CHI resistance was 10 times lower, and latency time 5 times shorter, compared to controls. Using a rat myocardial infarction (MI) model, PPY-CHI was injected into fibrotic tissue 7 days post MI. There, PPY-CHI reduced tissue resistance by 30%, improved electrical conduction across the fibrotic scar by 33%, enhanced field potential amplitudes by 2 times, and resynchronized cardiac contraction. PPY-CHI hydrogel also preserved cardiac function at 3 months, and reduced susceptibility to arrhythmia by 30% post-MI. These data demonstrated that the conductive PPY-CHI hydrogel reduced fibrotic scar resistivity, and enhanced electrical conduction, to synchronize cardiac contraction.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Eftekhari2020,
title = {Long-term monitoring of intracranial pressure in freely-moving rats; impact of different physiological states},
author = {Sajedeh Eftekhari and Connar Stanley James Westgate and Katrine Printz Johansen and Signe Rath Bruun and Rigmor H. Jensen },
doi = {https://doi.org/10.1186/s12987-020-00199-z},
year = {2020},
date = {2020-06-09},
journal = {Fluids and Barriers of the CNS},
volume = {17},
number = {39},
abstract = {Background
Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. There is limited insight into the regulatory mechanisms of ICP under physiological conditions, and consequently also under pathological conditions. Thereby, to understand the mechanisms underlying ICP dynamics, precise, valid and long-term ICP recordings are of importance in the preclinical setting. Herein, we used a novel telemetric system for ICP recordings which allowed for long-term recordings in freely-moving rats. The aim was to investigate ICP dynamics under different physiological states and investigate how factors such as surgery/recovery, body position, light–dark, co-housing, weight and anesthesia may influence ICP and its waveforms.

Methods
A telemetric device was implanted epidurally in rats and signals were recorded continuously for up to 50 days (n = 14). Recording was divided into three experimental periods: a surgical recovery period (RP), a physiological period (PP) and an experimental period (EP). Histology was performed to study the morphology of implanted rats and non-implanted rats (n = 17).

Results
For the first time, we can demonstrate continuous ICP recordings in freely-moving and co-housed rats for up to 50 days with a high degree of stability. The mean ICP in the recording periods were; RP: 3.2 ± 0.6 mmHg, PP: 5.0 ± 0.6 mmHg and EP: 4.7 ± 0.6 mmHg. In the RP, the ICP was significantly lower compared to the PP (P = 0.0034). Significant light–dark difference in ICP with 21% increase in respiratory slow-wave amplitude was observed in the co-housed animals but not in single-housed animals. The ICP signal was raised during the dark period relative to the light (Δ0.3 ± 0.07 mmHg, P = 0.0043). Administration of anesthesia gave a short-term increase in ICP followed by a significant decrease in ICP. No signs of tissue damage or inflammation were found in the implanted brains.

Conclusions
ICP dynamics were influenced by several factors such as, use of anesthesia, light–dark difference and housing conditions. Our study demonstrates the importance of performing ICP physiological measurements in freely-moving animals. This has significant implications for moving the preclinical research field forward in order to properly study ICP physiology during disease development and to explore drug targets for alleviating increased ICP.},
keywords = {Intracranial Pressure, Rat, TRM54P25},
pubstate = {published},
tppubtype = {article}
}

@article{Maqoud2020,
title = {The hydroxypropyl-β-cyclodextrin-minoxidil inclusion complex improves the cardiovascular and proliferative adverse effects of minoxidil in male rats: Implications in the treatment of alopecia},
author = {Fatima Maqoud and Nicola Zizzo and Antonietta Mele and Nunzio Denora and Giuseppe Passantino and Rosa Scala and Annalisa Cutrignelli and Antonella Tinelli and Valentino Laquintana and Flavia la Forgia and Sergio Fontana and Massimo Franco and Angela Assunta Lopedota and Domenico Tricarico},
url = {https://doi.org/10.1002/prp2.585},
year = {2020},
date = {2020-05-07},
journal = {Pharmacol Res Perspect},
volume = {8},
number = {3},
pages = {e00585},
abstract = {The efficacy of minoxidil (MXD) ethanolic solutions (1%‐5% w/v) in the treatment of androgenetic alopecia is limited by adverse reactions. The toxicological effects of repeated topical applications of escalating dose (0.035%‐3.5% w/v) and of single and twice daily doses (3.5% w/v) of a novel hydroxypropyl‐β‐cyclodextrin MXD GEL formulation (MXD/HP‐β‐CD) and a MXD solution were investigated in male rats. The cardiovascular effects were evaluated by telemetric monitoring of ECG and arterial pressure in free‐moving rats. Ultrasonographic evaluation of cardiac morphology and function, and histopathological and biochemical analysis of the tissues, were performed. A pharmacovigilance investigation was undertaken using the EudraVigilance database for the evaluation of the potential cancer‐related effects of topical MXD. Following the application of repeated escalating doses of MXD solution, cardiac hypertrophy, hypotension, enhanced serum natriuretic peptides and K+‐ion levels, serum liver biomarkers, and histological lesions including renal cancer were observed. In addition, the administration of a twice daily dose of MXD solution, at SF rat vs human = 311, caused reductions in the systolic, diastolic, and mean blood pressure of the rats (−30.76 ± 3%, −28.84 ± 4%, and −30.66 ± 5%, respectively, vs the baseline; t test P < .05). These effects were not reversible following washout of the MXD solution. Retrospective investigation showed 32 cases of cancer associated with the use of topical MXD in humans. The rats treated with MXD HP‐β‐CD were less severely affected. MXD causes proliferative adverse effects. The MXD HP‐β‐CD inclusion complex reduces these adverse effects.},
keywords = {Blood Pressure, ECG, Rat, TRM54PB},
pubstate = {published},
tppubtype = {article}
}

@article{Wasserman2020,
title = {An Exploratory Report on Electrographic Changes in the Cerebral Cortex Following Mild Traumatic Brain Injury with Hyperthermia in the Rat},
author = {Joseph Wasserman and Laura Stone McGuire and Thomas Sick and Helen M. Bramlett and W. Dalton Dietrich},
url = {https://doi.org/10.1089/ther.2020.0002},
year = {2020},
date = {2020-05-05},
journal = {Therapeutic Hypothermia and Temperature Management},
abstract = {Traumatic brain injury (TBI) has the potential to perturb perception by disrupting electrical propagation within and between the thalamus and cerebral cortex. Moderate and severe TBI may result in posttraumatic epilepsy, a condition characterized by convulsive tonic-clonic seizures. Spike/wave discharges (SWDs) of generalized nonconvulsive seizures, also called absence seizures, may also occur as a consequence of brain trauma. As mild hyperthermia has been reported to exacerbate histopathological and behavioral outcomes, we used an unbiased algorithm to detect periodic increases in power across different frequency bands following single or double closed head injury (CHI) under normothermia and hyperthermia conditions. We demonstrated that mild TBI did not significantly alter the occurrence of events containing increases in power between the delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), and beta1 (12–20 Hz) frequency bands in the Sprague Dawley rat 12 weeks after injury. However, when hyperthermia (39°C) was induced before and after CHI, electrographic events containing a similar waveform and harmonic frequency to SWDs were observed in a subset of animals. Further experiments utilizing chronic recordings will need to be performed to determine if these trends lead to absence seizures.},
keywords = {EEG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Wasserman2020b,
title = {An Exploratory Report on Electrographic Changes in the Cerebral Cortex Following Mild Traumatic Brain Injury With Hyperthermia in the Rat},
author = {Joseph Wasserman and Laura Stone McGuire and Thomas Sick and Helen M. Bramlett and W. Dalton Dietrich},
url = {https://doi.org/10.1089/ther.2020.0002},
year = {2020},
date = {2020-05-05},
journal = {Therapeutic Hypothermia and Temperature Management},
volume = {Ahead of Print},
abstract = {Traumatic brain injury (TBI) has the potential to perturb perception by disrupting electrical propagation within and between the thalamus and cerebral cortex. Moderate and severe TBI may result in posttraumatic epilepsy, a condition characterized by convulsive tonic-clonic seizures. Spike/wave discharges (SWDs) of generalized nonconvulsive seizures, also called absence seizures, may also occur as a consequence of brain trauma. As mild hyperthermia has been reported to exacerbate histopathological and behavioral outcomes, we used an unbiased algorithm to detect periodic increases in power across different frequency bands following single or double closed head injury (CHI) under normothermia and hyperthermia conditions. We demonstrated that mild TBI did not significantly alter the occurrence of events containing increases in power between the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta1 (12-20 Hz) frequency bands in the Sprague Dawley rat 12 weeks after injury. However, when hyperthermia (39°C) was induced before and after CHI, electrographic events containing a similar waveform and harmonic frequency to SWDs were observed in a subset of animals. Further experiments utilizing chronic recordings will need to be performed to determine if these trends lead to absence seizures.},
keywords = {EEG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Huang2020,
title = {Glycemic control with insulin attenuates sepsis-associated encephalopathy by inhibiting glial activation via the suppression of the nuclear factor kappa B and mitogen-activated protein kinase signaling pathways in septic rats},
author = {Chun-Ta Huang and June-Horng Lue and Tong-Hong Cheng and Yi-Ju Tsai},
url = {https://doi.org/10.1016/j.brainres.2020.146822},
year = {2020},
date = {2020-04-06},
journal = {Brain Research},
volume = {1738},
pages = {146822},
abstract = {Sepsis-associated encephalopathy (SAE) is frequently encountered in critically ill patients. Hyperglycemia is a
common phenomenon among patients with sepsis, and glycemic control improves patient outcomes. Therefore,
here, we aimed to explore whether glycemic control using insulin inhibits the pro-inflammatory cytokine response
and glial activation in the cerebrum and is concomitantly associated with the relief of SAE. Using cecal
ligation and puncture (CLP), sepsis was induced in male Sprague-Dawley rats. The CLP rats were administered
intravenous glucose or subjected to subcutaneous insulin implant within the first hour after CLP. The survival
rate, blood glucose (BG) values, and behavioral expression were assessed daily for 5 days after CLP. At day 5
after CLP, electroencephalography (EEG) recordings and blood–brain barrier (BBB) permeability testing were
performed. Immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assays were used to
evaluate glial activation and the pro-inflammatory cytokine response qualitatively and quantitatively, respectively.
The glucose-treated CLP rats (BG > 390 mg/dL) exhibited a decline in survival rate; insensitivity to
mechanical and thermal stimuli; slowed EEG activity; and an increase in BBB permeability, pro-inflammatory
cytokine (TNF-α, IL-1β, and IL-6) levels, and glial activation (astrocytes and microglia) in the cerebral tissues
compared with CLP rats (BG ~ 270 mg/dL). Double-immunofluorescence showed that activated astrocytes and
microglia co-expressed phosphorylated nuclear factor kappa B and mitogen-activated protein kinases, respectively.
Furthermore, glycemic control using insulin therapy maintained the BG at 120–160 mg/dL and inhibited
the production of pro-inflammatory cytokines and glial activation in the cerebrum of septic rats. In addition, the
survival rate, sensory threshold, EEG activity, and BBB permeability recovered to near-normal levels in septic
rats after insulin therapy. Taken together, the results of this study elucidated the pathophysiological alterations
in brains subjected to sepsis, especially regarding glycemic control. These findings improve our understanding of
SAE and support the importance of glycemic control in sepsis.},
keywords = {EEG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Jefferys2020,
title = {Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval},
author = {John G. R. Jefferys and Alexander Ashby‐Lumsden and Thelma A. Lovick},
url = {https://doi.org/10.1111/epi.16479},
year = {2020},
date = {2020-03-22},
journal = {Epilepsia},
volume = {61},
pages = {798-809},
abstract = {Objective
To determine electrical changes in the heart in a chronic, nonstatus model of epilepsy.

Methods
Electrocorticography (ECoG) and electrocardiography (ECG) of nine animals (five made epileptic by intrahippocampal injection of tetanus neurotoxin (TeNT) and four controls), are monitored continuously by radiotelemetry for up to 7 weeks.

Results
Epileptic animals develop a median of 168 seizures, with postictal tachycardias reaching a mean of 487 beats/min and lasting a mean of 661 seconds. Ictal changes in heart rate include tachycardia and in the case of convulsive seizures, bradyarrhythmias resembling Mobitz type 1 second‐degree atrioventricular block; notably the P‐R interval increased before block. Postictally, the amplitude of T wave increases. Interictally, QT dependence on RR is modest and conventional QT corrections prove ineffective. Interictal QT intervals, measured at a heart rate of 400 bpm, increased from 65 to 75 ms, an increase dependent on seizure incidence over the preceding 10‐14 days.

Significance
Repeated seizures induce a sustained tachycardia and increase in QT interval of the ECG and evoke arrhythmias including periods of atrioventricular block during Racine type 4 and 5 seizures. These changes in cardiac function may predispose to development in fatal arrhythmias and sudden death in humans with epilepsy.},
keywords = {ECG, EEG, Rat, TR50BB},
pubstate = {published},
tppubtype = {article}
}

@article{Thakkar2020,
title = {Therapeutic Relevance of Elevated Blood Pressure After Ischemic Stroke in the Hypertensive Rats},
author = {Pratik C Thakkar and Ailsa L McGregor and P Alan Barber and Julian F R Paton and Carolyn J Barrett and Fiona D McBryde},
url = {https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.119.14219},
year = {2020},
date = {2020-03-07},
journal = {Hypertension},
volume = {75},
number = {3},
pages = {740-747},
abstract = {Over 80% of patients exhibit an acute increase in blood pressure (BP) following stroke. Current clinical guidelines make no distinction in BP management between patients with or without prior hypertension. Spontaneously hypertensive (SH) rats were preinstrumented with telemeters to record BP, intracranial pressure, and brain tissue oxygen in the predicted ischemic penumbra for 3 days before and 10 days after transient middle cerebral artery occlusion (n=8 per group) or sham (n=5). Before stroke, BP was either left untreated or chronically treated to a normotensive level (enalapril 10 mg/kg per day). Poststroke elevations in BP were either left uncontrolled, controlled (to the prestroke baseline level), or overcontrolled (to a normotensive level) via subcutaneous infusion of labetalol. Baseline values of intracranial pressure and brain tissue oxygen were similar between all groups, whereas BP was lower in treated SH rats (144±3 versus 115±5 mm Hg; P<0.001). Following middle cerebral artery occlusion, a similar rise in BP was observed in untreated (+16±2 mm Hg; P=0.005) and treated SH rats (+13±5 mm Hg; P=0.021). Intervening to prevent BP from increasing after stroke did not worsen outcome. However, reducing BP below prestroke baseline levels was associated with higher intracranial pressure (days 1-3; P<0.001), reduced cerebral perfusion pressure (days 2-4; P<0.001), higher mortality, slower functional recovery and larger infarct volumes. Although treating to maintain BP at the prestroke baseline level was not detrimental, our results suggest that when setting BP targets after stroke, consideration must be given to the potential negative impact of inadvertent excessive BP lowering in subjects with undiagnosed or poorly controlled hypertension.},
keywords = {Blood Pressure, Intracranial Pressure, Oxygen, Rat, TR57Y, TRM54PP2509},
pubstate = {published},
tppubtype = {article}
}

@article{Sachdeva2020,
title = {Acute Cardiovascular Responses to Vagus Nerve Stimulation Following Experimental Spinal Cord Injury},
author = {Rahul Sachdeva and Andrei V. Krassioukov and Jesse E. Bucksot and Seth A Hays},
doi = {http://doi.org/10.1089/neu.2019.6828},
year = {2020},
date = {2020-01-23},
journal = {Journal of Neurotrauma},
abstract = {Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to enhance plasticity and improve recovery in a range of neurological disorders. A recent study highlights the therapeutic promise of VNS in promoting motor recovery after spinal cord injury (SCI). Here we investigate the safety of acute VNS in a rat model of chronic SCI. We measured the cardiovascular response to various VNS paradigms following chronic high-thoracic SCI that is known to deleteriously impact cardiovascular control. Dose-response experiments with continuous VNS revealed an SCI-dependent increase in sensitivity for heart rate (HR) and blood pressure (BP) compared to controls. A clinically-relevant intermittent VNS resulted in transient reduction in HR in rats with SCI, however BP remained unaltered. In all experiments, the effect lasted only while the VNS stimulus train was present, as HR and BP restored to baseline values as soon as VNS ended. No prolonged episodes of persisting hypotension were seen in either group. Furthermore, VNS did not trigger autonomic dysreflexia or exacerbate the severity of autonomic dysreflexia when induced during or after stimulation sessions. Overall, these findings provide initial evidence that intermittent VNS at parameters used for targeted plasticity therapy (30 Hz, 0.8mA) appears safe and supports further investigation of this potential therapy for use following SCI.},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Eftekhari2019,
title = {Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension},
author = {Sajedeh Eftekhari and Connar Stanley James Westgate and Maria Schmidt Uldall and Rigmor Hoejland Jensen},
url = {https://link.springer.com/article/10.1186/s12987-019-0155-4},
year = {2019},
date = {2019-11-26},
journal = {Fluids and Barriers of the CNS},
abstract = {Background

Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. One of these challenging disorders is idiopathic intracranial hypertension (IIH), characterized by raised ICP of unknown cause with significant morbidity and limited therapeutic options. In this review, special focus is put on the preclinical research performed in order to understand the pathophysiology behind ICP regulation and IIH. This includes cerebrospinal fluid dynamics, molecular mechanisms underlying disturbances in brain fluids leading to elevated ICP, role of obesity in IIH, development of an IIH model and ICP measurements in rodents. The review also discusses existing and new drug targets for IIH that have been evaluated in vivo.

Conclusions

ICP monitoring in rodents is challenging and different methods have been applied. Some of these methods are invasive, depend on use of anesthesia and only allow short-term monitoring. Long-term ICP recordings are needed to study IIH but existing methods are hampered by several limitations. As obesity is one of the most common risk factors for IIH, a rodent obese model has been developed that mimics some key aspects of IIH. The most commonly used drugs for IIH have been evaluated in vivo for their efficacy at lowering ICP in the existing animal models. These studies suggest these drugs, including acetazolamide, might have limited or no reducing effect on ICP. Two drug targets that can impact ICP in healthy rodents are topiramate and a glucagon-like peptide-1 receptor (GLP-1R) agonist. However, it remains to evaluate their effect in an IIH model with more precise and valid ICP monitoring system. Therefore, continued evaluation in the preclinical research with refined tools is of great importance to further understand the pathophysiology behind disorders with raised ICP and to explore new drug targets.},
keywords = {Intracranial Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Duran2019,
title = {Heart rate variability in the tegu lizard, Salvator merianae, its neuroanatomical basis and role in the assessment of recovery from experimental manipulation},
author = {Livia M. Duran and Edwin W. Taylor and Pollyana V.W. Sanches and André L.Cruz and Driele Tavares and Marina R. Sartori and Augusto S. Abe and Cleo A.C. Leite},
doi = {https://doi.org/10.1016/j.cbpa.2019.110607},
year = {2019},
date = {2019-10-29},
journal = {Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology},
volume = {240},
abstract = {Using long-term, remote recordings of heart rate (fH) on fully recovered, undisturbed lizards, we identified several components of heart rate variability (HRV) associated with respiratory sinus arrhythmia (RSA): 1.) A peak in the spectral representation of HRV at the frequency range of ventilation. 2.) These cardiorespiratory interactions were shown to be dependent on the parasympathetic arm of the autonomic nervous system. 3.) Vagal preganglionic neurons are located in discrete groups located in the dorsal motor nucleus of the vagus and also, in a ventro-lateral group, homologous to the nucleus ambiguus of mammals. 4.) Myelinated nerve fibers in the cardiac vagus enabling rapid communication between the central nervous system and the heart. Furthermore, the study of the progressive recovery of fH in tegu following anesthesia and instrumentation revealed that ‘resting’ levels of mean fH and reestablishment of HRV occurred over different time courses. Accordingly, we suggest that, when an experiment is designed to study a physiological variable reliant on autonomic modulation at its normal, resting level, then postsurgical reestablishment of HRV should be considered as the index of full recovery, rather than mean fH.},
keywords = {ECG, Other species, TR50BB},
pubstate = {published},
tppubtype = {article}
}

@article{McBryde2019,
title = {Hypertensive Response to Ischemic Stroke in the Normotensive Wistar Rat: Mechanisms and Therapeutic Relevance},
author = {Pratik Thakkar and Ailsa McGregor and Paul Alan Barber and Julian F.R. Paton and Carolyn Barrett and Fiona McBryde},
url = {https://doi.org/10.1161/STROKEAHA.119.026459},
year = {2019},
date = {2019-08-06},
journal = {Stroke},
volume = {119.026459},
abstract = {Background and Purpose—
Over 80% of ischemic stroke patients show an abrupt increase in arterial blood pressure in the hours and days following ischemic stroke. Whether this poststroke hypertension is beneficial or harmful remains controversial and the underlying physiological basis is unclear.

Methods—
To investigate the dynamic cardiovascular response to stroke, adult Wistar rats (n=5–8 per group, 393±34 g) were instrumented with telemeters to blood pressure, intracranial pressure, renal sympathetic nerve activity, and brain tissue oxygen in the predicted penumbra (Po2). After 2 weeks of recovery, cardiovascular signals were recorded for a 3-day baseline period, then ischemic stroke was induced via transient middle cerebral artery occlusion, or sham surgery. Cardiovascular signals were then recorded for a further 10 days, and the functional sensorimotor recovery assessed using the cylinder and sticky dot tests.
Results—
Baseline values of all variables were similar between groups. Compared to sham, in the 2 days following stroke middle cerebral artery occlusion produced an immediate, transient rise above baseline in mean blood pressure (21±3 versus 2±4 mm Hg; P<0.001), renal sympathetic nerve activity (54±11% versus 7±4%; P=0.006), and cerebral perfusion pressure (12±5 versus 1±4; P≤0.001). Intracranial pressure increased more slowly, peaking 3 days after middle cerebral artery occlusion (14±6 versus −1±1 mm Hg; P<0.001). Treating with the antihypertensive agent nifedipine after stroke (1.5–0.75 mg/kg per hour SC) ameliorated poststroke hypertension (12±3 mm Hg on day 1; P=0.041), abolished the intracranial pressure increase (3±1; P<0.001) and reduced cerebral perfusion pressure (10±3 mm Hg; P=0.017). Preventing poststroke hypertension affected neither the recovery of sensorimotor function nor infarct size. Conclusions—
These findings suggest that poststroke hypertension is immediate, temporally matched to an increase in sympathetic outflow, and elevates cerebral perfusion pressure for several days after stroke, which may enhance cerebral perfusion. Preventing poststroke hypertension does not appear to worsen prognosis after stroke in young, normotensive, and otherwise healthy rats.},
keywords = {Blood Pressure, Intracranial Pressure, Oxygen, Rat, Sympathetic Nerve Activity, TR57Y, TRM54PP, TRM56SP},
pubstate = {published},
tppubtype = {article}
}

@article{Kim2019b,
title = {All-in-One, Wireless, Stretchable Hybrid Electronics for Smart, Connected, and Ambulatory Physiological Monitoring},
author = {Yun-Soung Kim and Musa Mahmood and Yongkuk Lee and Nam Kyun Kim and Shinjae Kwon and Robert Herbert and Donghyun Kim and Hee Cheol Cho and Woon-Hong Yeo},
url = {https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.201900939},
doi = {10.1002/advs.201900939},
year = {2019},
date = {2019-07-30},
journal = {Advanced Science},
volume = {1900939},
abstract = {Commercially available health monitors rely on rigid electronic housing coupled with aggressive adhesives and conductive gels, causing discomfort and inducing skin damage. Also, research-level skin-wearable devices, while excelling in some aspects, fall short as concept-only presentations due to the fundamental challenges of active wireless communication and integration as a single device platform. Here, an all-in-one, wireless, stretchable hybrid electronics with key capabilities for real-time physiological monitoring, automatic detection of signal abnormality via deep-learning, and a long-range wireless connectivity (up to 15 m) is introduced. The strategic integration of thin-film electronic layers with hyperelastic elastomers allows the overall device to adhere and deform naturally with the human body while maintaining the functionalities of the on-board electronics. The stretchable electrodes with optimized structures for intimate skin contact are capable of generating clinical-grade electrocardiograms and accurate analysis of heart and respiratory rates while the motion sensor assesses physical activities. Implementation of convolutional neural networks for real-time physiological classifications demonstrates the feasibility of multifaceted analysis with a high clinical relevance. Finally, in vivo demonstrations with animals and human subjects in various scenarios reveal the versatility of the device as both a health monitor and a viable research tool.},
keywords = {ECG, Rat, TR50BB},
pubstate = {published},
tppubtype = {article}
}

@article{Wang2019,
title = {TLR4 participates in sympathetic hyperactivity Post-MI in the PVN by regulating NF-κB pathway and ROS production.},
author = {Yu Wang and Hesheng Hu and Jie Yin and Yugen Shi and Jiayu Tan and Lu Zheng and Cailing Wang and Xiaolu Li and Mei Xue and Ju Liu and Ye Wang and Yan Li and Xinran Li and Fuhong Liu and Qiang Liu and SuhuaYan},
url = {https://doi.org/10.1016/j.redox.2019.101186},
year = {2019},
date = {2019-06-24},
journal = {Redox Biology},
volume = {24},
number = {101186},
abstract = {Sympathetic nerve hyperactivity is a primary reason for fatal ventricular arrhythmias (VAs) following myocardial infarction (MI). Pro-inflammatory cytokines produced in the paraventricular nucleus (PVN) post-MI are associated with sympathetic overexcitation; however, the precise mechanism needs further investigation. Our aim was to explore the mechanism of toll-like receptor 4 (TLR4) and its downstream molecular pathway in mediating sympathetic activity post-MI within the PVN. A rat MI model was developed via left anterior descending coronary artery ligation. TLR4 was primarily localized in microglia and increased markedly within the PVN at 3 days in MI rats. Sympathoexcitation also increased, as indicated by high levels of renal sympathetic nerve activity (RSNA) and norepinephrine (NE) concentration. TLR4 knockdown via shRNA microinjection to the PVN resulted in decreased activation of Fos protein (+) neurons in the PVN and peripheral sympathetic nerve activity. TLR4 knockdown also exhibited a lower arrhythmia score following programmed electrical stimulation than those treated with MI surgery only, indicating that the knockdown of TLR4 decreased the incidence of malignant ventricular arrhythmias following MI. LPS-induced inflammatory response was analyzed to explore the underlying mechanism of TLR4 in sympathetic hyperactivity. High levels of NF-κB protein, the pro-inflammatory cytokines IL-1β and TNF-α, and ROS production were observed in the LPS group. PVN-targeted injection of the NF-κB inhibitor PDTC attenuated NF-κB expression and sympathetic activity. Taken together, the results suggested that knockdown of microglial TLR4 within the PVN decreased sympathetic hyperactivity and subsequent VAs post-MI. The downstream NF-κB pathway and ROS production participated in the process. Interventions targeting TLR4 signaling in the PVN may be a novel approach to ameliorate the incidence of VAs post-MI.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Adamovich2019,
title = {Oxygen and Carbon Dioxide Rhythms Are Circadian Clock Controlled and Differentially Directed by Behavioral Signals},
author = {Y Adamovich and B Ladeuix and J Sobel and G Manella and A Neufeld-Cohen and MH Assadi and M Golik and Y Kuperman and A Tarasiuk and MP Koeners and G Asher G},
doi = {10.1016/j.cmet.2019.01.007},
year = {2019},
date = {2019-05-07},
journal = {Cell Metab},
volume = {29},
number = {5},
pages = {1092-1103},
abstract = {Daily rhythms in animal physiology are driven by endogenous circadian clocks in part through rest-activity and feeding-fasting cycles. Here, we examined principles that govern daily respiration. We monitored oxygen consumption and carbon dioxide release, as well as tissue oxygenation in freely moving animals to specifically dissect the role of circadian clocks and feeding time on daily respiration. We found that daily rhythms in oxygen and carbon dioxide are clock controlled and that time-restricted feeding restores their rhythmicity in clock-deficient mice. Remarkably, day-time feeding dissociated oxygen rhythms from carbon dioxide oscillations, whereby oxygen followed activity, and carbon dioxide was shifted and aligned with food intake. In addition, changes in carbon dioxide levels altered clock gene expression and phase shifted the clock. Collectively, our findings indicate that oxygen and carbon dioxide rhythms are clock controlled and feeding regulated and support a potential role for carbon dioxide in phase resetting peripheral clocks upon feeding.},
keywords = {Oxygen, Rat, TR57Y},
pubstate = {published},
tppubtype = {article}
}

@article{Kim2019,
title = {A rat model of complete atrioventricular block recapitulates clinical indices of bradycardia and provides a platform to test disease-modifying therapies},
author = {Nam Kyun Kim and David Wolfson and Natasha Fernandez and Minji Shin and Hee Cheol Cho},
url = {https://doi.org/10.1038/s41598-019-43300-9},
year = {2019},
date = {2019-05-06},
journal = {Scientific Reports},
volume = {9},
pages = {6930},
abstract = {Complete atrioventricular block (CAVB) is a life-threatening arrhythmia. A small animal model of chronic CAVB that properly reflects clinical indices of bradycardia would accelerate the understanding of disease progression and pathophysiology, and the development of therapeutic strategies. We sought to develop a surgical model of CAVB in adult rats, which could recapitulate structural remodeling and arrhythmogenicity expected in chronic CAVB. Upon right thoracotomy, we delivered electrosurgical energy subepicardially via a thin needle into the atrioventricular node (AVN) region of adult rats to create complete AV block. The chronic CAVB animals developed dilated and hypertrophied ventricles with preserved systolic functions due to compensatory hemodynamic remodeling. Ventricular tachyarrhythmias, which are difficult to induce in the healthy rodent heart, could be induced upon programmed electrical stimulation in chronic CAVB rats and worsened when combined with β-adrenergic stimulation. Focal somatic gene transfer of TBX18 to the left ventricular apex in the CAVB rats resulted in ectopic ventricular beats within days, achieving a de novo ventricular rate faster than the slow atrioventricular (AV) junctional escape rhythm observed in control CAVB animals. The model offers new opportunities to test therapeutic approaches to treat chronic and severe CAVB which have previously only been testable in large animal models.},
keywords = {ECG, Rat, TR50BB},
pubstate = {published},
tppubtype = {article}
}

@article{Zhou2019,
title = {Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats.},
author = {Jing-Jing Zhou and Hui-Jie Ma and Jianying Shao and Yan Wei and Xiangjian Zhang and Yi Zhang and De-Pei Li},
url = {https://www.ahajournals.org/doi/full/10.1161/JAHA.118.011434},
year = {2019},
date = {2019-04-29},
journal = {Journal of the American Heart Association},
volume = {8:e011434},
abstract = {Background-—Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 (OXR1) is upregulated in the paraventricular nucleus (PVN) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats (OZRs). We hypothesized that silencing OXR1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZRs.

Methods and Results-—An adeno-associated virus (AAV) vector containing a short hairpin RNA (shRNA) targeting rat OXR1 was designed to silence OXR1 expression in the PVN. The AAV-OXR1-shRNA or scrambled shRNA was injected into the PVN in OZRs. The arterial blood pressure in free-moving OZRs was continuously monitored by using a telemetry approach. The firing activity of spinally projecting PVN neurons in rat brain slices was recorded 3 to 4 weeks after injection of viral vectors. The free-moving OZRs treated with AAV-OXR1-shRNA had markedly lower OXR1 expression and lower mean arterial blood pressure, heart rate, and ratio of low- to highfrequency components of heart rate variability compared with OZRs treated with scrambled shRNA. Furthermore, AAV-OXR1-shRNA treatment markedly reduced renal sympathetic nerve activity and attenuated sympathoexcitatory response induced by microinjection of orexin A into the PVN. In addition, treatment with AAV-OXR1-shRNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZRs and attenuated the excitatory effect of orexin A on the firing activity of these neurons.

Conclusions-—These data suggest that chronic downregulation of OXR1 expression in the PVN reduces sympathetic vasomotor tone in obesity-related hypertension},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Ondicova2019,
title = {Ivabradine reduces baseline and stress-induced increase of heart rate and blood pressure and modulates neuroendocrine stress response in rats depending on stressor intensity},
author = {Katarina Ondicova and Noemi Hegedusova and Miroslav Tibensky and Boris Mravec},
url = {https://doi.org/10.4149/gpb_2018046},
year = {2019},
date = {2019-03-01},
journal = {Gen Physiol Biophys},
volume = {38},
number = {2},
pages = {165-173},
abstract = {Ivabradine, a selective inhibitor of the sinoatrial pacemaker, is used in clinical practice to reduce heart rate. However, its potential effect on the neuroendocrine stress response has not been investigated. Therefore, we determined the effect of administering ivabradine to rats on cardiovascular parameters and plasma levels of epinephrine, norepinephrine, and corticosterone. Ivabradine was administered intraperitoneally 30 min before exposing animals to either handling, restraint, or immobilization stress. Heart rate and blood pressure were monitored telemetrically. Blood samples were collected before, during, and after stressor exposure to determine the extent of the neuroendocrine stress response as reflected by plasma epinephrine, norepinephrine, and corticosterone levels. In animals pretreated with ivabradine, significantly lower values of heart rate and blood pressure were found during both the baseline period and during exposure to stressors, as well as during the rest period following stressor exposure. Ivabradine also significantly reduced handling-induced epinephrine and norepinephrine release into the bloodstream. However, ivabradine significantly potentiated restraint- and immobilization-induced increases of plasma epinephrine levels, whereas stress-induced changes in plasma norepinephrine and corticosterone levels were ambiguous. Our data shows that ivabradine significantly reduces blood pressure in rats during both baseline and stressful conditions, and also affects the neuroendocrine stress response. These findings show that viscerosensory signaling from the cardiovascular system may significantly modulate the neuroendocrine stress response.},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{White2019,
title = {Correction of medication nonadherence results in better seizure outcomes than dose escalation in a novel preclinical epilepsy model of adherence.},
author = {A. Cameron Hill and Kyle E. Thomson and Thomas G. Newell and H. Steve White},
doi = {10.1111/epi.14655},
year = {2019},
date = {2019-01-22},
journal = {Epilepsia},
volume = {60},
number = {3},
pages = {475-484},
abstract = {OBJECTIVE:
Medication nonadherence directly contributes to poor seizure control. A lack of emphasis on correcting poor adherence and failures in patient adherence can result in unwarranted alterations to a patient's drug regimen. We have modeled nonadherent patients in an animal model of epilepsy to study how alterations to pharmacotherapy, made without consideration of a patient's adherence, result in changes to seizure control.

METHODS:
Newly diagnosed rats with epilepsy were treated with carbamazepine (CBZ) during a 4-week baseline period to establish their baseline seizure rate in the presence of 50% adherence. Next, animals were randomized to one of three treatment interventions and monitored for 6 weeks. Groups included: (1) no change in therapy-rats continued the 50% adherent paradigm; (2) dose escalation-the dose of CBZ was doubled, and the 50% adherent paradigm continued; and (3) nonadherence corrected-rats continued the initial dose of CBZ, but the adherence rate was adjusted to 100% (ie, fully adherent).

RESULTS:
The rats in the no change in therapy arm displayed a 61% increase in seizure burden over the 6-week intervention phase. Similarly, rats in the dose escalation arm had a 66% worsening of their daily seizure burden. In contrast, rats in the nonadherence corrected arm displayed a 33% reduction in their daily seizure burden; a significant improvement when compared to the normalized seizure burden scores of rats in the other two treatment arms (P < 0.01). SIGNIFICANCE:
We found that failure to correct medication nonadherence resulted in an increase in daily seizure burden in rats, even following dose escalation. In the presence of nonadherence, dose escalation worsened seizure control. In contrast, correcting nonadherence alone resulted in improved seizure control. These findings suggest that improving adherence should be prioritized over dose escalation in the clinical management of uncontrolled epilepsy.},
keywords = {EEG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Kamada2018,
title = {Diabetes mellitus attenuates the pressure response against hypotensive stress by impairing the sympathetic regulation of the baroreflex afferent arc. },
author = {Kazuhiro Kamada and Keita Saku and Takeshi Tohyama and Toru Kawada and Hiroshi Mannoji and Kiyokazu Abe and Takuya Nishikawa and Genya Sunagawa and Takuya Kishi and Kenji Sunagawa and Hiroyuki Tsutsui},
url = {https://doi.org/10.1152/ajpheart.00515.2018},
year = {2018},
date = {2018-12-17},
journal = {Am J Physiol Heart Circ Physiol},
volume = {316},
number = {1},
pages = {H35-H44},
abstract = {Patients with diabetes mellitus (DM) often show arterial pressure (AP) lability associated with cardiovascular autonomic neuropathy. Because the arterial baroreflex tightly regulates AP via sympathetic nerve activity (SNA), we investigated the systematic baroreflex function, considering the control theory in DM by open-loop analysis. We used Zucker diabetic fatty (ZDF) rats as a type 2 DM model. Under general anesthesia, we isolated the carotid sinuses from the systemic circulation, changed intracarotid sinus pressure (CSP), and recorded SNA and AP responses. We compared CSP-AP (total loop), CSP-SNA (afferent arc), and SNA-AP (efferent arc) relationships between ZDF lean (n = 8) and ZDF fatty rats (n = 6). Although the total loop gain of baroreflex (ΔAP/ΔCSP) at the operating point did not differ between the two groups, the average gain in the lower CSP range was markedly reduced in ZDF fatty rats (0.03 ± 0.01 vs. 0.87 ± 0.10 mmHg/mmHg, P < 0.001). The afferent arc showed the same trend as the total loop, with a response threshold of 139.8 ± 1.0 mmHg in ZDF fatty rats. There were no significant differences in the gain of efferent arc between the two groups. Simulation experiments indicated a markedly higher AP fall and lower total loop gain of baroreflex in ZDF fatty rats than in ZDF lean rats against hypotensive stress because the efferent arc intersected with the afferent arc in the SNA unresponsive range. Thus, we concluded that impaired baroreflex sympathetic regulation in the lower AP range attenuates the pressure response against hypotensive stress and may partially contribute to AP lability in DM.},
keywords = {Blood Pressure, Rat, TRM54PB},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c0dbbd8e4b02d5e2ecc83b9,
title = {Angiotensin II-induced hypertension in rats is only transiently accompanied by lower renal oxygenation},
author = {Tonja W Emans and Daniela Patinha and Jaap A Joles and Maarten P Koeners and Ben J Janssen and Paul C T Krediet},
doi = {10.1038/s41598-018-34211-2},
isbn = {2045-2322},
year = {2018},
date = {2018-11-01},
journal = {Scientific Reports},
volume = {8},
number = {1},
pages = {16342},
abstract = {Activation of the renin-angiotensin system may initiate chronic kidney disease. We hypothesised that renal hypoxia is a consequence of hemodynamic changes induced by angiotensin II and occurs prior to development of severe renal damage. Male Sprague-Dawley rats were infused continuously with angiotensin II (350 ng/kg/min) for 8 days. Mean arterial pressure (n = 5), cortical (n = 6) and medullary (n = 7) oxygenation (pO2) were continuously recorded by telemetry and renal tissue injury was scored. Angiotensin II increased arterial pressure gradually to 150 ± 18 mmHg. This was associated with transient reduction of oxygen levels in renal cortex (by 18 ± 2%) and medulla (by 17 ± 6%) at 10 ± 2 and 6 ± 1 hours, respectively after starting infusion. Thereafter oxygen levels normalised to pre-infusion levels and were maintained during the remainder of the infusion period. In rats receiving angiotensin II, adding losartan to drinking water (300 mg/L) only induced transient increase in renal oxygenation, despite normalisation of arterial pressure. In rats, renal hypoxia is only a transient phenomenon during initiation of angiotensin II-induced hypertension.},
keywords = {Blood Pressure, Oxygen, Rat, TR57Y, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74c030e4b00e57e1f36632,
title = {Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury},
author = {C P C Ow and J P Ngo and M M Ullah and G Barsha and R C Meex and M J Watt and L M Hilliard and M P Koeners and R G Evans},
doi = {10.1152/ajprenal.00249.2018},
isbn = {1522-1466},
year = {2018},
date = {2018-11-01},
journal = {American journal of physiology.Renal physiology},
volume = {315},
number = {5},
pages = {F1369},
abstract = {Tissue hypoxia has been proposed as an important event in renal ischemia-reperfusion injury (IRI), particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats. We hypothesized that the kidney is hypoxic 24 h and 5 days after an hour of bilateral renal ischemia, driven by a disturbed balance between renal oxygen delivery (Do2) and oxygen consumption (Vo2). Renal Do2 was not significantly reduced in the subacute phase of IRI. In contrast, renal Vo2 was 55% less 24 h after reperfusion and 49% less 5 days after reperfusion than after sham ischemia. Inner medullary tissue Po2, measured by radiotelemetry, was 25 +/- 12% (mean +/- SE) greater 24 h after ischemia than after sham ischemia. By 5 days after reperfusion, tissue Po2 was similar to that in rats subjected to sham ischemia. Tissue Po2 measured by Clark electrode was consistently greater 24 h, but not 5 days, after ischemia than after sham ischemia. Cellular hypoxia, assessed by pimonidazole adduct immunohistochemistry, was largely absent at both time points, and tissue levels of hypoxia-inducible factors were downregulated following renal ischemia. Thus, in this model of severe IRI, tissue hypoxia does not appear to be an obligatory event during the subacute phase, likely because of the markedly reduced oxygen consumption.},
keywords = {Oxygen, Rat, TR57Y},
pubstate = {published},
tppubtype = {article}
}

@article{Wang2018,
title = {Microglial Mincle receptor in the PVN contributes to sympathetic hyperactivity in acute myocardial infarction rat.},
author = {Yu Wang and Jie Yin and Cailing Wang and Hesheng Hu and Xiaolu Li and Mei Xue and Ju Liu and Wenjuan Cheng and Ye Wang and Yan Li and Yugen Shi and Jiayu Tan and Xinran Li and Fuhong Liu and Qiang Liu and Suhua Yan},
url = {https://doi.org/10.1111/jcmm.13890},
year = {2018},
date = {2018-10-24},
journal = {J Cell Mol Med},
volume = {23},
number = {1},
pages = {112-125},
abstract = {Malignant ventricular arrhythmias (VAs) following myocardial infarction (MI) is a lethal complication resulting from sympathetic nerve hyperactivity. Numerous evidence have shown that inflammation within the paraventricular nucleus (PVN) participates in sympathetic hyperactivity. Our aim was to explore the role of Macrophage‐inducible C‐type lectin (Mincle) within the PVN in augmenting sympathetic activity following MI,and whether NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome/IL‐1β axis is involved in this activity. MI was induced by coronary artery ligation. Mincle expression localized in microglia within the PVN was markedly increased at 24 hours post‐MI together with sympathetic hyperactivity, as indicated by measurement of the renal sympathetic nerve activity (RSNA) and norepinephrine (NE) concentration. Mincle‐specific siRNA was administrated locally to the PVN, which consequently decreased microglial activation and sympathetic nerve activity. The MI rats exhibited a higher arrhythmia score after programmed electric stimulation than that treated with Mincle siRNA, suggesting that the inhibition of Mincle attenuated foetal ventricular arrhythmias post‐MI. The underlying mechanism of Mincle in sympathetic hyperactivity was investigated in lipopolysaccharide (LPS)‐primed naïve rats. Recombinant Sin3A‐associated protein 130kD (rSAP130), an endogenous ligand for Mincle, induced high levels of NLRP3 and mature IL‐1β protein. PVN‐targeted injection of NLRP3 siRNA or IL‐1β antagonist gevokizumab attenuated sympathetic hyperactivity. Together, the data indicated that the knockdown of Mincle in microglia within the PVN prevents VAs by attenuating sympathetic hyperactivity and ventricular susceptibility, in part by inhibiting its downstream NLRP3/IL‐1β axis following MI. Therapeutic interventions targeting Mincle signalling pathway could constitute a novel approach for preventing infarction injury.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74c07ce4b09477891613ac,
title = {Blockade of Rostral Ventrolateral Medulla Apelin Receptors Does Not Attenuate Arterial Pressure in SHR and L-NAME-Induced Hypertensive Rats},
author = {P R Griffiths and S J Lolait and L E Pearce and F D McBryde and J F R Paton and A M O'Carroll},
doi = {10.3389/fphys.2018.01488},
isbn = {1664-042X},
year = {2018},
date = {2018-10-01},
journal = {Frontiers in physiology},
volume = {9},
pages = {1488},
abstract = {Dysfunction of the apelinergic system, comprised of the neuropeptide apelin mediating its effects via the G protein-coupled apelin receptor (APJ), may underlie the onset of cardiovascular disease such as hypertension. Apelin expression is increased in the rostral ventrolateral medulla (RVLM) in spontaneously hypertensive rats (SHRs) compared to Wistar-Kyoto (WKY) normotensive rats, however, evidence that the apelinergic system chronically influences mean arterial blood pressure (MABP) under pathophysiological conditions remains to be established. In this study we investigated, in conscious unrestrained rats, whether APJ contributes to MABP and sympathetic vasomotor tone in the progression of two models of hypertension - SHR and L-NAME-treated rats - and whether APJ contributes to the development of hypertension in pre-hypertensive SHR. In SHR we showed that APJ gene (aplnr) expression was elevated in the RVLM, and there was a greater MABP increase following microinjection of [Pyr(1)]apelin-13 to the RVLM of SHR compared to WKY rats. Bilateral microinjection of a lentiviral APJ-specific-shRNA construct into the RVLM of WKY, SHR, and L-NAME-treated rats, chronically implanted with radiotelemeters to measure MABP, decreased aplnr expression in the RVLM and abolished acute [Pyr(1)]apelin-13-induced increases in MABP. However, chronic knockdown of aplnr in the RVLM did not affect MABP in either SHR or L-NAME-treated rats. Moreover, knockdown of aplnr in the RVLM of prehypertensive SHR did not protect against the development of hypertension. These results show that endogenous apelin, acting via APJ, is not involved in the genesis or maintenance of hypertension in either animal model used in this study.},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Hunter2018,
title = {Preserved Adrenal Function After Lumbar Spinal Cord Transection Augments Low Pressure Bladder Activity in the Rat},
author = {Diana V. Hunter and Seth D. Holland and Matt S. Ramer},
url = {https://www.frontiersin.org/articles/10.3389/fphys.2018.01239/full},
year = {2018},
date = {2018-09-03},
journal = {Front Physiol},
volume = {9},
pages = {1239},
abstract = {Spinal cord injury (SCI) disconnects supraspinal micturition centers from the lower urinary tract resulting in immediate and long-term changes in bladder structure and function. While cervical and high thoracic SCI have a greater range of systemic effects, clinical data suggest that those with lower (suprasacral) injuries develop poorer bladder outcomes. Here we assess the impact of SCI level on acute changes in bladder activity. We used two SCI models, T3 and L2 complete transections in male Wistar rats, and compared bladder pressure fluctuations to those of naïve and bladder-denervated animals. By 2 days after L2 transection, but not T3 transection or bladder denervation, small amplitude rhythmic contractions (1 mmHg, 0.06 Hz) were present at low intravesical pressures (<6 mmHg); these were still present 1 month following injury, and at 3 months, bladders from L2 SCI animals were significantly larger than those from T3 SCI or naïve animals. Low-pressure contractions were unaffected by blocking ganglionic signaling or bladder denervation at the time of measurements. L2 (and sham surgery) but not T3 transection preserves supraspinal adrenal control, and by ELISA we show lower plasma adrenal catecholamine concentration in the latter. When an adrenalectomy preceded the L2 transection, the aberrant low-pressure contractions more closely resembled those after T3 transection, indicating that the increased bladder activity after lumbar SCI is mediated by preserved adrenal function. Since ongoing low-pressure contractions may condition the detrusor and exacerbate detrusor-sphincter dyssynergia, moderating bladder catecholamine signaling may be a clinically viable intervention strategy.},
keywords = {Bladder Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{Rudiger2018,
title = {Heart rate elevations during early sepsis predict death in fluid-resuscitated rats with fecal peritonitis},
author = {Alain Rudiger and Victor Jeger and Mattia Arrigo and Christian A. Schaer and Florian F. Hildenbrand and Margarete Arras and Burkhardt Seifert and Mervyn Singer and Gabriele Schoedon and Donat R. Spahn and Dominique Bettex
},
url = {https://doi.org/10.1186/s40635-018-0190-5},
year = {2018},
date = {2018-08-20},
journal = {Intensive Care Medicine Experimental},
volume = {6},
number = {28},
abstract = {Background
In sepsis, early outcome prediction would allow investigation of both adaptive mechanisms underlying survival and maladaptive mechanisms resulting in death. The aim of this study was to test whether early changes in heart rate monitored by telemetry could predict outcome in a long-term rat model of fecal peritonitis.

Methods
Male Wistar rats (n = 24) were instrumented with a central venous line for administration of fluids, antibiotics and analgesics. A telemetry transmitter continuously collected electrocardiogram signals. Sepsis was induced by intraperitoneal injection of fecal slurry, and the animals were observed for 48 h. Additional animals underwent arterial cannulation at baseline (n = 9), 4 h (n = 16), or 24 h (n = 6) for physiology and laboratory measurements.

Results
48-h mortality was 33% (8/24), with all deaths occurring between 4 and 22 h. Septic animals were characterized by lethargy, fever, tachycardia, positive blood cultures, and elevated cytokine (IL-1, IL-6, TNF alpha) levels. An increase in heart rate ≥ 50 bpm during the first 4 h of sepsis predicted death with sensitivity and specificity of 88% (p = 0.001).

Conclusions
In this long-term rat sepsis model, prognostication could be made early by telemetry-monitored changes in heart rate. This model enables the study of underlying mechanisms and the assessment of any differential effects of novel therapies in predicted survivors or non-survivors.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c0dc3b5e4b0fec09b0a6cd9,
title = {Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats},
author = {T W Emans and B J Janssen and J A Joles and C T P Krediet},
doi = {10.1161/JAHA.118.009501},
isbn = {2047-9980},
year = {2018},
date = {2018-08-01},
journal = {Journal of the American Heart Association},
volume = {7},
number = {15},
pages = {e009501},
abstract = {Background Renal hypoxia, implicated as crucial factor in onset and progression of chronic kidney disease, may be attributed to reduced nitric oxide because nitric oxide dilates vasculature and inhibits mitochondrial oxygen consumption. We hypothesized that chronic nitric oxide synthase inhibition would induce renal hypoxia. Methods and Results Oxygen-sensitive electrodes, attached to telemeters, were implanted in either renal cortex (n=6) or medulla (n=7) in rats. After recovery and stabilization, baseline oxygenation ( pO 2) was recorded for 1 week. To inhibit nitric oxide synthase, N-omega-nitro-l-arginine (L-NNA; 40 mg/kg/day) was administered via drinking water for 2 weeks. A separate group (n=8), instrumented with blood pressure telemeters, followed the same protocol. L-NNA rapidly induced hypertension (165+/-6 versus 108+/-3 mm Hg; P<0.001) and proteinuria (79+/-12 versus 17+/-2 mg/day; P<0.001). Cortical pO 2, after initially dipping, returned to baseline and then increased. Medullary pO 2 decreased progressively (up to -19+/-6% versus baseline; P<0.05). After 14 days of L-NNA, amplitude of diurnal medullary pO 2 was decreased (3.7 [2.2-5.3] versus 7.9 [7.5-8.4]; P<0.01), whereas amplitudes of blood pressure and cortical pO 2 were unaltered. Terminal glomerular filtration rate (1374+/-74 versus 2098+/-122 muL/min), renal blood flow (5014+/-336 versus 9966+/-905 muL/min), and sodium reabsorption efficiency (13.0+/-0.8 versus 22.8+/-1.7 mumol/mumol) decreased (all P<0.001). Conclusions For the first time, we show temporal development of renal cortical and medullary oxygenation during chronic nitric oxide synthase inhibition in unrestrained conscious rats. Whereas cortical pO 2 shows transient changes, medullary pO 2 decreased progressively. Chronic L-NNA leads to decreased renal perfusion and sodium reabsorption efficiency, resulting in progressive medullary hypoxia, suggesting that juxtamedullary nephrons are potentially vulnerable to prolonged nitric oxide depletion.},
keywords = {Oxygen, Rat, TR57Y},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74bf3fe4b07cf352f5fc7d,
title = {Preservation of conductive propagation after surgical repair of cardiac defects with a bio-engineered conductive patch},
author = {S He and H Song and J Wu and S H Li and R D Weisel and H W Sung and J Li and R K Li},
url = {https://doi.org/10.1016/j.healun.2017.12.011},
isbn = {1557-3117},
year = {2018},
date = {2018-07-01},
journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation},
volume = {37},
number = {7},
pages = {912-924},
abstract = {BACKGROUND: Both stable and biodegradable biomaterials have been used to surgically repair congenital cardiac defects. However, neither type of biomaterial can conduct electrical activity. We evaluated the conductivity and efficacy of a newly synthesized conductive polypyrrole-chitosan (Ppy+Chi) gelfoam patch to support cardiomyocyte (CM) viability and function in vitro and to surgically repair a cardiac defect in vivo. METHODS: Ppy+Chi was incorporated into gelfoam (Gel) to form a 3-dimensional conductive patch. In vitro, patch characteristics were evaluated and biocompatibility and bioconductivity were investigated by culturing neonatal rat CMs on the patches. In vivo, a full-thickness right ventricular outflow tract defect was created in rats and the patches were implanted. Four weeks after patch repair, cardiac electrical activation and conduction velocity were evaluated using an optical mapping system. RESULTS: In vitro, the Ppy+Chi+Gel patch had a higher mean breaking stress than the Gel or Chi+Gel patches, and the highest conductivity. None of the patches altered cell growth. The Ca(2+) transient velocity of CMs cultured on the Ppy+Chi+Gel patch was 2.5-fold higher than that of CMs cultured on the Gel or Chi+Gel patches. In vivo, optical mapping at 4 weeks post-implantation demonstrated that Ppy+Chi+Gel patch-implanted hearts had faster conduction velocities, as measured on the epicardial surface. Continuous electrocardiographic telemetry did not reveal any pathologic arrhythmias after patch implantation. Ex-vivo patch conductivity testing also revealed that the Ppy+Chi+Gel patch was more conductive than the Gel and Chi+Gel patches. CONCLUSIONS: The Ppy+Chi+Gel patch was biocompatible, safe and conductive, making it an attractive candidate for a new biomaterial platform for cardiac surgical repair to preserve synchronous ventricular contraction.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74c01ee4b083cef79d1f25,
title = {Reduced Renal Mass, Salt-Sensitive Hypertension Is Resistant to Renal Denervation},
author = {I Tudorancea and T E Lohmeier and B T Alexander and D Pieptu and D N Serban and R Iliescu},
doi = {10.3389/fphys.2018.00455},
isbn = {1664-042X},
year = {2018},
date = {2018-04-01},
journal = {Frontiers in physiology},
volume = {9},
pages = {455},
abstract = {Aim: Activation of the sympathetic nervous system is common in resistant hypertension (RHT) and also in chronic kidney disease (CKD), a prevalent condition among resistant hypertensives. However, renal nerve ablation lowers blood pressure (BP) only in some patients with RHT. The influence of loss of nephrons per se on the antihypertensive response to renal denervation (RDNx) is unclear and was the focus of this study. Methods: Systemic hemodynamics and sympathetically mediated low frequency oscillations of systolic BP were determined continuously from telemetrically acquired BP recordings in rats before and after surgical excision of approximately 80% of renal mass and subsequent RDNx. Results: After reduction of renal mass, rats fed a high salt (HS) diet showed sustained increases in mean arterial pressure (108 +/- 3 mmHg to 128 +/- 2 mmHg) and suppression of estimated sympathetic activity ( approximately 15%), responses that did not occur with HS before renal ablation. After denervation of the remnant kidney, arterial pressure fell (to 104 +/- 4 mmHg), estimated sympathetic activity and heart rate (HR) increased concomitantly, but these changes gradually returned to pre-denervation levels over 2 weeks of follow up. Subsequently, sympathoinhibition with clonidine did not alter arterial pressure while significantly suppressing estimated sympathetic activity and HR. Conclusion: These results indicate that RDNx does not chronically lower arterial pressure in this model of salt-sensitive hypertension associated with substantial nephron loss, but without ischemia and increased sympathetic activity, thus providing further insight into conditions likely to impact the antihypertensive response to renal-specific sympathoinhibition in subjects with CKD.},
keywords = {Blood Pressure, Femoral, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74bfd7e4b08c84ab03efef,
title = {Improved cardiac outcomes with combined atenolol and diazepam intervention in seizure},
author = {M I Read and R N Millen and D M McCann and J C Harrison and D S Kerr and I A Sammut},
doi = {10.1111/epi.14039},
isbn = {1528-1167},
year = {2018},
date = {2018-04-01},
journal = {Epilepsia},
volume = {59},
number = {4},
pages = {854-865},
abstract = {OBJECTIVE: Altered autonomic activity has been implicated in the development of cardiac dysfunction during seizures. This study investigates whether intervening in seizure progression with diazepam will reduce seizure-induced cardiomyopathy. Second, this study examines the hypothesis that combining atenolol with diazepam, as an intervention after seizure onset, will combat cardiac injury during status epilepticus. METHODS: Male Sprague-Dawley rats were implanted with electroencephalographic/electrocardiographic electrodes to allow simultaneous recordings during seizures induced by intrahippocampal (2 nmol, 1 muL) kainic acid (KA). Subcutaneous saline, atenolol (5 mg.kg(-1) ), diazepam (5 mg.kg(-1) ), or atenolol and diazepam (n = 12/group) were administered at 60 minutes post-KA and daily for 7 days, at which point echocardiography, susceptibility to aconitine-induced arrhythmias, and histology were evaluated. RESULTS: Seizure activity was associated with immediately increased heart rate, QTc interval, and blood pressure (BP; 10%-30% across indices). Seven days postseizure, saline-treated animals were found to have reduced left ventricular function, increased fibrotic scarring, and an elevated risk of aconitine-induced arrhythmias. Diazepam treatment significantly reduced cumulative seizure behaviors by 79% compared to saline-treated animals but offered no cardiac protection. Diazepam significantly raised BP (35%) and increased the risk of bigeminal arrhythmias (36%) compared to saline-treated animals. Atenolol administration, either alone or with diazepam, reduced heart rate, QTc interval, and BP back to control levels. Atenolol also preserved cardiac morphology and reduced arrhythmia risk. SIGNIFICANCE: Attenuation of seizure with diazepam offered no cardiac protection; however, coadministration of atenolol with diazepam prevented the development of seizure-induced cardiac dysfunction. This study demonstrates that atenolol intervention should be strongly considered as an adjunct clinical treatment to reduce cardiomyopathy during seizures.},
keywords = {ECG, EEG, Rat, TR50BB},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c0dc3b5e4b0fec09b0a6cda,
title = {Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats},
author = {F D McBryde and B H Liu and E V Roloff and S Kasparov and J F R Paton},
doi = {10.1113/EP086744},
isbn = {1469-445X},
year = {2018},
date = {2018-03-01},
journal = {Experimental physiology},
volume = {103},
number = {3},
pages = {419-428},
abstract = {NEW FINDINGS: What is the central question of this study? Does chronic reduction of neuronally generated nitric oxide in the hypothalamic paraventricular nucleus affect the set-point regulation of blood pressure and sympathetic activity destined to the kidneys? What is the main finding and its importance? Within the hypothalamic paraventricular nucleus, nitric oxide generated by neuronal nitric oxide synthase plays a major constitutive role in suppressing long term the levels of both ongoing renal sympathetic activity and arterial pressure in conscious Wistar rats. This finding unequivocally demonstrates a mechanism by which the diencephalon exerts a tonic influence on sympathetic discharge to the kidney and may provide the basis for both blood volume and osmolality homeostasis. ABSTRACT: The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in cardiovascular and neuroendocrine regulation. Application of nitric oxide donors to the PVN stimulates GABAergic transmission, and may suppress sympathetic nerve activity (SNA) to lower arterial pressure. However, the role of endogenous nitric oxide within the PVN in regulating renal SNA chronically remains to be established in conscious animals. To address this, we used our previously established lentiviral vectors to knock down neuronal nitric oxide synthase (nNOS) selectively in the PVN of conscious Wistar rats. Blood pressure and renal SNA were monitored simultaneously and continuously for 21 days (n = 14) using radio-telemetry. Renal SNA was normalized to maximal evoked discharge and expressed as a percentage change from baseline. The PVN was microinjected bilaterally with a neurone-specific tetracycline-controllable lentiviral vector, expressing a short hairpin miRNA30 interference system targeting nNOS (n = 7) or expressing a mis-sense as control (n = 7). Recordings continued for a further 18 days. The vectors also expressed green fluorescent protein, and successful expression in the PVN and nNOS knockdown were confirmed histologically post hoc. Knockdown of nNOS expression in the PVN resulted in a sustained increase in blood pressure (from 95 +/- 2 to 104 +/- 3 mmHg, P 70%, P < 0.05). The study reveals a major role for nNOS-derived nitric oxide within the PVN in chronic set-point regulation of cardiovascular autonomic activity in the conscious, normotensive rat.},
keywords = {Blood Pressure, Rat, Sympathetic Nerve Activity, TRM56SP},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74c006e4b0947789161399,
title = {Alterations of Hippocampal Myelin Sheath and Axon Sprouting by Status Convulsion and Regulating Lingo-1 Expression with RNA Interference in Immature and Adult Rats},
author = {X J Song and W Han and R He and T Y Li and L L Xie and L Cheng and H S Chen and L Jiang},
doi = {10.1007/s11064-018-2474-2},
isbn = {1573-6903},
year = {2018},
date = {2018-03-01},
journal = {Neurochemical research},
volume = {43},
number = {3},
pages = {721-735},
abstract = {Seizure-induced brain damage is age-dependent, as evidenced by the different alterations of neural physiopathology in developing and mature brains. However, little is known about the age-dependent characteristics of myelinated fiber injury induced by seizures. Considering the critical functions of oligodendrocyte progenitor cells (OPCs) in myelination and Lingo-1 signaling in regulating OPCs' differentiation, the present study aimed to explore the effects of Lingo-1 on myelin and axon in immature and adult rats after status convulsion (SC) induced by lithium-pilocarpine, and the differences between immature and adult brains. Dynamic variations in electrophysiological activity and spontaneous recurrent seizures were recorded by electroencephalogram monitoring after SC. The impaired microstructures of myelin sheaths and decrease in myelin basic protein caused by SC were observed through transmission electron microscopy and western blot analysis respectively, which became more severe in adult rats, but improved gradually in immature rats. Aberrant axon sprouting occurred in adult rats, which was more prominent than in immature rats, as shown by a Timm stain. This damage was improved or negatively affected after down or upregulating Lingo-1 expression. These results demonstrated that in both immature and adult brains, Lingo-1 signaling plays important roles in seizure-induced damage to myelin sheaths and axon growth. The plasticity of the developing brain may provide a potential window of opportunity to prevent the brain from damage.},
keywords = {EEG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74bfece4b0b01390453d15,
title = {The impact of artifact correction methods of RR series on heart rate variability parameters},
author = {Rincon A I Soler and L E V Silva and R Fazan and L O Murta},
doi = {10.1152/japplphysiol.00927.2016},
isbn = {1522-1601},
year = {2018},
date = {2018-03-01},
journal = {Journal of applied physiology},
volume = {124},
number = {3},
pages = {646-652},
abstract = {Heart rate variability (HRV) analysis is widely used to investigate the autonomic regulation of the cardiovascular system. HRV is often analyzed using RR time series, which can be affected by different types of artifacts. Although there are several artifact correction methods, there is no study that compares their performances in actual experimental contexts. This work aimed to evaluate the impact of different artifact correction methods on several HRV parameters. Initially, 36 ECG recordings of control rats or rats with heart failure or hypertension were analyzed to characterize artifact occurrence rates and distributions, to be mimicked in simulations. After a rigorous analysis, only 16 recordings ( n = 16) with artifact-free segments of at least 10,000 beats were selected. RR interval losses were then simulated in the artifact-free (reference) time series according to real observations. Correction methods applied to simulated series were deletion, linear interpolation, cubic spline interpolation, modified moving average window, and nonlinear predictive interpolation. Linear (time- and frequency-domain) and nonlinear HRV parameters were calculated from corrupted-corrected time series, as well as for reference series to evaluate the accuracy of each correction method. Results show that NPI provides the overall best performance. However, several correction approaches, for example the simple deletion procedure, can provide good performance in some situations, depending on the HRV parameters under consideration. NEW & NOTEWORTHY This work analyzes the performance of some correction techniques commonly applied to the missing beats problem in RR time series. From artifact-free RR series, spurious values were inserted based on actual data of experimental settings. We intend our work to be a guide to show how artifacts should be corrected to preserve as much as possible the original heart rate variability properties.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Wong2018,
title = {Ultrafine Particulate Matter Combined With Ozone Exacerbates Lung Injury in Mature Adult Rats With Cardiovascular Disease. },
author = {Emily M Wong and William F Walby and Dennis W Wilson and Fern Tablin and Edward S Schelegle},
url = {https://academic.oup.com/toxsci/article/163/1/140/4831231},
year = {2018},
date = {2018-01-31},
journal = {Toxicol Sci},
volume = {163},
number = {1},
pages = {140-151},
abstract = {Particulate matter (PM) and ozone (O3) are dominant air pollutants that contribute to development and exacerbation of multiple cardiopulmonary diseases. Mature adults with cardiovascular disease (CVD) are particularly susceptible to air pollution-related cardiopulmonary morbidities and mortalities. The aim was to investigate the biologic potency of ultrafine particulate matter (UFPM) combined with O3 in the lungs of mature adult normotensive and spontaneously hypertensive (SH) Wistar-Kyoto rats. Conscious, mature adult male normal Wistar-Kyoto (NW) and SH rats were exposed to one of the following atmospheres: filtered air (FA); UFPM (∼ 250 μg/m3); O3 (1.0 ppm); or UFPM + O3 (∼ 250 μg/m3 + 1.0 ppm) combined for 6 h, followed by an 8 h FA recovery period. Lung sections were evaluated for lesions in the large airways, terminal bronchiolar/alveolar duct regions, alveolar parenchyma, and vasculature. NW and SH rats were similarly affected by the combined-pollutant exposure, displaying severe injury in both large and small airways. SH rats were particularly susceptible to O3 exposure, exhibiting increased injury scores in terminal bronchioles and epithelial degeneration in large airways. UFPM-exposure groups had minimal histologic changes. The chemical composition of UFPM was altered by the addition of O3, indicating that ozonolysis promoted compound degradation. O3 increased the biologic potency of UFPM, resulting in greater lung injury following exposure. Pathologic manifestations of CVD may confer susceptibility to air pollution by impairing normal lung defenses and responses to exposure.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{Zhang2018,
title = {Reduced N‐Type Ca 2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis},
author = {Dongze Zhang, Huiyin Tu, Liang Cao, Hong Zheng, Robert L. Muelleman, Michael C. Wadman, and Yu‐Long Li},
url = {https://www.ahajournals.org/doi/10.1161/JAHA.117.007457},
year = {2018},
date = {2018-01-15},
journal = {J Am Heart Assoc},
volume = {7},
number = {2},
pages = {e007457},
abstract = {BACKGROUND:
Attenuated cardiac vagal activity is associated with ventricular arrhythmogenesis and related mortality in patients with chronic heart failure. Our recent study has shown that expression of N-type Ca2+ channel α-subunits (Cav2.2-α) and N-type Ca2+ currents are reduced in intracardiac ganglion neurons from rats with chronic heart failure. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium receives projection of neuronal terminals only from the AVG. In this study we tested whether a decrease in N-type Ca2+ channels in AVG neurons contributes to ventricular arrhythmogenesis.

METHODS AND RESULTS:
Lentiviral Cav2.2-α shRNA (2 μL, 2×107 pfu/mL) or scrambled shRNA was in vivo transfected into rat AVG neurons. Nontransfected sham rats served as controls. Using real-time single-cell polymerase chain reaction and reverse-phase protein array, we found that in vivo transfection of Cav2.2-α shRNA decreased expression of Cav2.2-α mRNA and protein in rat AVG neurons. Whole-cell patch-clamp data showed that Cav2.2-α shRNA reduced N-type Ca2+ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Cav2.2-α shRNA transfection had premature ventricular contractions (P<0.05 versus 0% of nontransfected sham rats or scrambled shRNA-transfected rats). Additionally, an index of susceptibility to ventricular arrhythmias, inducibility of ventricular arrhythmias evoked by programmed electrical stimulation, was higher in rats with Cav2.2-α shRNA transfection compared with nontransfected sham rats and scrambled shRNA-transfected rats. CONCLUSIONS:
A decrease in N-type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.},
keywords = {ECG, Rat, TRM54PB},
pubstate = {published},
tppubtype = {article}
}

@article{Han2018,
title = {Left-Ventricular Energetics in Pulmonary Arterial Hypertension-Induced Right-Ventricular Hypertrophic Failure.},
author = {JC Han and SJ Guild and T Pham T and L Nisbet and K Tran and AJ Taberner and DS Loiselle},
url = {https://www.frontiersin.org/articles/10.3389/fphys.2017.01115/full},
year = {2018},
date = {2018-01-08},
journal = {Front Physiol},
volume = {8},
pages = {1115},
abstract = {Pulmonary arterial hypertension (PAH) alters the geometries of both ventricles of the heart. While the right ventricle (RV) hypertrophies, the left ventricle (LV) atrophies. Multiple lines of clinical and experimental evidence lead us to hypothesize that the impaired stroke volume and systolic pressure of the LV are a direct consequence of the effect of pressure overload in the RV, and that atrophy in the LV plays only a minor role. In this study, we tested this hypothesis by examining the mechanoenergetic response of the atrophied LV to RV hypertrophy in rats treated with monocrotaline. Experiments were performed across multiple-scales: the whole-heart in vivo and ex vivo, and its trabeculae in vitro. Under the in vivo state where the RV was pressure-overloaded, we measured reduced systemic blood pressure and LV ventricular pressure. In contrast, under both ex vivo and in vitro conditions, where the effect of RV pressure overload was circumvented, we found that LV was capable of developing normal systolic pressure and stress. Nevertheless, LV atrophy played a minor role in that LV stroke volume remained lower, thereby contributing to lower LV mechanical work output. Concomitantly lower oxygen consumption and change of enthalpy were observed, and hence LV energy efficiency was unchanged. Our internally consistent findings between working-heart and trabecula experiments explain the rapid improvement of LV systolic function observed in patients with chronic pulmonary hypertension following surgical relief of RV pressure overload.},
keywords = {Blood Pressure, Rat},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74bf73e4b083cef79d1f12,
title = {CaMKII Regulates Synaptic NMDA Receptor Activity of Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension},
author = {D P Li and J J Zhou and J Zhang and H L Pan},
doi = {10.1523/JNEUROSCI.2141-17.2017},
isbn = {1529-2401},
year = {2017},
date = {2017-11-01},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {37},
number = {44},
pages = {10690-10699},
abstract = {NMDAR activity in the hypothalamic paraventricular nucleus (PVN) is increased and critically involved in heightened sympathetic vasomotor tone in hypertension. Calcium/calmodulin-dependent protein kinase II (CaMKII) binds to and modulates NMDAR activity. In this study, we determined the role of CaMKII in regulating NMDAR activity of PVN presympathetic neurons in male spontaneously hypertensive rats (SHRs). NMDAR-mediated EPSCs and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in SHRs and male Wistar-Kyoto (WKY) rats. The basal amplitude of evoked NMDAR-EPSCs and puff NMDA currents in retrogradely labeled PVN neurons were significantly higher in SHRs than in WKY rats. The CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP) normalized the increased amplitude of NMDAR-EPSCs and puff NMDA currents in labeled PVN neurons in SHRs but had no effect in WKY rats. Treatment with AIP also normalized the higher frequency of NMDAR-mediated miniature EPSCs of PVN neurons in SHRs. CaMKII-mediated phosphorylation level of GluN2B serine 1303 (S1303) in the PVN, but not in the hippocampus and frontal cortex, was significantly higher in SHRs than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter the increased level of phosphorylated GluN2B S1303 in the PVN. In addition, microinjection of AIP into the PVN significantly reduced arterial blood pressure and lumbar sympathetic nerve discharges in SHRs. Our findings suggest that CaMKII activity is increased in the PVN and contributes to potentiated presynaptic and postsynaptic NMDAR activity to elevate sympathetic vasomotor tone in hypertension.SIGNIFICANCE STATEMENT Heightened sympathetic vasomotor tone is a major contributor to the development of hypertension. Although glutamate NMDA receptor (NMDAR)-mediated excitatory drive in the hypothalamus plays a critical role in increased sympathetic output in hypertension, the molecular mechanism involved in potentiated NMDAR activity of hypothalamic presympathetic neurons remains unclear. Here we show that the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) is increased and plays a key role in the potentiated presynaptic and postsynaptic NMDAR activity of hypothalamic presympathetic neurons in hypertension. Also, the inhibition of CaMKII in the hypothalamus reduces elevated blood pressure and sympathetic nerve discharges in hypertension. This new knowledge extends our understanding of the mechanism of synaptic plasticity in the hypothalamus and suggests new strategies to treat neurogenic hypertension.},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74bf1ce4b00e57e1f36619,
title = {beta1 -Adrenoceptor, but not beta2 -adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo},
author = {R F Cook and C T Bussey and K M Mellor and P A Cragg and R R Lamberts},
doi = {10.1113/EP086293},
isbn = {1469-445X},
year = {2017},
date = {2017-08-01},
journal = {Experimental physiology},
volume = {102},
number = {8},
pages = {911-923},
abstract = {NEW FINDINGS: What is the central question of the study? The sympathetic system regulates heart rate via beta-adrenoceptors; this is impaired during diabetes. However, the specific beta-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the beta1 -adrenoceptor subtype, and not the beta2 -adrenoceptor, regulated the lower resting heart rate and increased beta-adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence. beta-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of beta1 - and beta2 -adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (beta1 - and beta2 -adrenoceptor agonist, 0.1-300 mug kg(-1) ) in the presence of atenolol (beta1 -adrenoceptor antagonist, 2000 mug kg(-1) ) or nadolol (beta1 - and beta2 -adrenoceptor agonist, 4000 mug kg(-1) ) to determine the chronotropic contributions of the beta-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 +/- 62 versus 290 +/- 37 beats min(-1) non-diabetic versus diabetic, P < 0.05, mean +/- SD), which remained after atenolol or nadolol administration. Overall beta-adrenoceptor chronotropic responsiveness was increased in diabetic rats (change in heart rate at highest dose of isoprenaline: 135 +/- 66 versus 205 +/- 28 beats min(-1) , non-diabetic versus diabetic, P < 0.05), a difference that diminished after beta1 -adrenoceptor blockade with atenolol (change in heart rate at highest dose of isoprenaline: 205 +/- 37 versus 195 +/- 22 beats min(-1) , non-diabetic versus diabetic, P < 0.05). In conclusion, the beta1 -adrenoceptor is the main subtype to modulate chronotropic beta-adrenoceptor responses in healthy and diabetic rats. This study provides new insights into the pathological basis of dysregulation of heart rate in type 2 diabetes, which could be important for improving the current therapeutic strategies targeting diabetic chronotropic incompetence.},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74befde4b08c84ab03efda,
title = {Effect of type 2 diabetes, surgical incision, and volatile anesthesia on hemodynamics in the rat},
author = {C T Bussey and R R Lamberts},
url = {https://physoc.onlinelibrary.wiley.com/doi/full/10.14814/phy2.13352},
isbn = {2051-817X},
year = {2017},
date = {2017-07-01},
journal = {Physiological reports},
volume = {5},
number = {14},
pages = {10.14814/phy2.13352},
abstract = {Diabetic patients have increased cardiac complications during surgery, possibly due to impaired autonomic regulation. Anesthesia lowers blood pressure and heart rate (HR), whereas surgical intervention has opposing effects. The interaction of anesthesia and surgical intervention on hemodynamics in diabetes is unknown, despite being a potential perioperative risk factor. We aimed to determine the effect of diabetes on the integrative interaction between hemodynamics, anesthesia, and surgical incision. Zucker type 2 diabetic rats (DM) and their nondiabetic littermates (ND) were implanted with an intravenous port for drug delivery, and a radiotelemeter to measure mean arterial blood pressure (MAP) and derive HR (total n = 50). Hemodynamic pharmacological responses were assessed under conscious, isoflurane anesthesia (~2-2.5%), and anesthesia-surgical conditions; the latter performed as a laparotomy. MAP was not different between groups under conscious conditions (ND 120 +/- 6 vs. DM 131 +/- 4 mmHg, P > 0.05). Anesthesia reduced MAP, but not differently in DM (ND -30 +/- 6 vs. DM -38 +/- 4 DeltammHg, P > 0.05). Despite adequate anesthesia, surgical incision increased MAP, which tended to be less in DM (ND +21 +/- 4 vs. DM +13 +/- 2 DeltammHg},
keywords = {Blood Pressure, Rat, TRM54P},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c74bf57e4b063d617047e27,
title = {Protective Effect of N-Acetylcysteine Amide on Blast-Induced Increase in Intracranial Pressure in Rats},
author = {U Kawoos and R M McCarron and M Chavko},
doi = {10.3389/fneur.2017.00219},
isbn = {1664-2295},
year = {2017},
date = {2017-06-01},
journal = {Frontiers in neurology},
volume = {8},
pages = {219},
abstract = {Blast-induced traumatic brain injury is associated with acute and possibly chronic elevation of intracranial pressure (ICP). The outcome after TBI is dependent on the progression of complex processes which are mediated by oxidative stress. So far, no effective pharmacological protection against TBI exists. In this study, rats were exposed to a single or repetitive blast overpressure (BOP) at moderate intensities of 72 or 110 kPa in a compressed air-driven shock tube. The degree and duration of the increase in ICP were proportional to the intensity and frequency of the blast exposure(s). In most cases, a single dose of antioxidant N-acetylcysteine amide (NACA) (500 mg/kg) administered intravenously 2 h after exposure to BOP significantly attenuated blast-induced increase in ICP. A single dose of NACA was not effective in improving the outcome in the group of animals that were subjected to repetitive blast exposures at 110 kPa on the same day. In this group, two treatments with NACA at 2 and 4 h post-BOP exposure resulted in significant attenuation of elevated ICP. Treatment with NACA prior to BOP exposure completely prevented the elevation of ICP. The findings indicate that oxidative stress plays an important role in blast-induced elevated ICP as treatment with NACA-ameliorated ICP increase, which is frequently related to poor functional recovery after TBI.},
keywords = {Intracranial Pressure, Rat, TRM54P25},
pubstate = {published},
tppubtype = {article}
}

@article{Jeger2017,
title = {Improving animal welfare using continuous nalbuphine infusion in a long-term rat model of sepsis},
author = {Victor Jeger and Mattia Arrigo and Florian F. Hildenbrand and Daniel Müller and Paulin Jirkof and Till Hauffe,and Burkhardt Seifert and Margarete Arras and Donat R. Spahn and Dominique Bettex and Alain Rudiger},
url = {https://icm-experimental.springeropen.com/articles/10.1186/s40635-017-0137-2},
year = {2017},
date = {2017-04-20},
journal = {Intensive Care Med Exp},
volume = {5},
pages = {23},
abstract = {Background
Sepsis research relies on animal models to investigate the mechanisms of the dysregulated host response to infection. Animal welfare concerns request the use of potent analgesics for the Refinement of existing sepsis models, according to the 3Rs principle. Nevertheless, adequate analgesia is often missing, partly because the effects of analgesics in this particular condition are unknown. We evaluated the use of nalbuphine, an opioid with kappa agonistic and mu antagonistic effects, in rats with and without experimental sepsis.

Methods
Male Wistar rats were anesthetized with isoflurane and instrumented with a venous line for drug administration. Arterial cannulation allowed for blood pressure measurements and blood sampling in short-term experiments of non-septic animals. Nalbuphine (or placebo) was administered intravenously at a dose of 1 mg/kg/h. Long-term (48 h) experiments in awake septic animals included repetitive clinical scoring with the Rat Grimace Scale and continuous heart rate monitoring by telemetry. Sepsis was induced by intraperitoneal injection of faecal slurry. Nalbuphine plasma levels were measured by liquid chromatography—high resolution mass spectrometry.

Results
In anesthetized healthy animals, nalbuphine led to a significant reduction of respiratory rate, heart rate, and mean arterial pressure during short-term experiments. In awake septic animals, a continuous nalbuphine infusion did not affect heart rate but significantly improved the values of the Rat Grimace Scale. Nalbuphine plasma concentrations remained stable between 4 and 24 h of continuous infusion in septic rats.

Conclusions
In anaesthetised rats, nalbuphine depresses respiratory rate, heart rate, and blood pressure. In awake animals, nalbuphine analgesia improves animal welfare during sepsis.},
keywords = {ECG, Rat, TR50B},
pubstate = {published},
tppubtype = {article}
}

@article{RefWorks:doc:5c0dc3b5e4b0fec09b0a6cdb,
title = {Circadian Rhythm in Kidney Tissue Oxygenation in the Rat},
author = {T W Emans and B J Janssen and J A Joles and C T P Krediet},
doi = {10.3389/fphys.2017.00205},
isbn = {1664-042X},
year = {2017},
date = {2017-04-01},
journal = {Frontiers in physiology},
volume = {8},
pages = {205},
abstract = {Blood pressure, renal hemodynamics, electrolyte, and water excretion all display diurnal oscillation. Disturbance of these patterns is associated with hypertension and chronic kidney disease. Kidney oxygenation is dependent on oxygen delivery and consumption that in turn are determined by renal hemodynamics and metabolism. We hypothesized that kidney oxygenation also demonstrates 24-h periodicity. Telemetric oxygen-sensitive carbon paste electrodes were implanted in Sprague-Dawley rats (250-300 g), either in renal medulla (n = 9) or cortex (n = 7). Arterial pressure (MAP) and heart rate (HR) were monitored by telemetry in a separate group (n = 8). Data from 5 consecutive days were analyzed for rhythmicity by cosinor analysis. Diurnal electrolyte excretion was assessed by metabolic cages. During lights-off, oxygen levels increased to 105.3 +/- 2.1% in cortex and 105.2 +/- 3.8% in medulla. MAP was 97.3 +/- 1.5 mmHg and HR was 394.0 +/- 7.9 bpm during lights-off phase and 93.5 +/- 1.3 mmHg and 327.8 +/- 8.9 bpm during lights-on. During lights-on, oxygen levels decreased to 94.6 +/- 1.4% in cortex and 94.2 +/- 8.5% in medulla. There was significant 24-h periodicity in cortex and medulla oxygenation. Potassium excretion (1,737 +/- 779 vs. 895 +/- 132 mumol/12 h},
keywords = {Oxygen, Rat, TR57Y},
pubstate = {published},
tppubtype = {article}
}