Simvastatin Treatment Attenuates Increased Respiratory Variability and Apnea/Hypopnea Index in Rats With Chronic Heart Failure

Haack, Karla K.V.; Marcus, Noah J.; Rio, Rodrigo Del; Zucker, Irving H.; Schultz, Harold D.

doi:10.1161/hypertensionaha.113.02535

Cited by 46 publications

(49 citation statements)

References 58 publications

(71 reference statements)

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“…Blood pressure was measured in conscious, freely moving rats using radiotelemetry as previously described (Haack et al, 2014). In brief, animals were anesthetized with 2–4% isoflurane via inhalation.…”

Section: Methodsmentioning

confidence: 99%

Central TrkB blockade attenuates ICV angiotensin II-hypertension and sympathetic nerve activity in male Sprague-Dawley rats

Becker

Wang

Zucker

2017

Autonomic Neuroscience

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Increased sympathetic nerve activity and the activation of the central renin-angiotensin system are commonly associated with cardiovascular disease states such as hypertension and heart failure, yet the precise mechanisms contributing to the long-term maintenance of this sympatho-excitation are incompletely understood. Due to the established physiological role of neurotrophins contributing towards neuroplasticity and neuronal excitability along with recent evidence linking the renin-angiotensin system and brain-derived neurotrophic factor (BDNF) along with its receptor (TrkB), it is likely the two systems interact to promote sympatho-excitation during cardiovascular disease. However, this interaction has not yet been fully demonstrated, in vivo. Thus, we hypothesized that central angiotensin II (Ang II) treatment will evoke a sympatho-excitatory state mediated through the actions of BDNF/TrkB. We infused Ang II (20 ng/min) into the right lateral ventricle of male Sprague-Dawley rats for twelve days with or without the TrkB receptor antagonist, ANA-12 (50 ng/h). We found that ICV infusion of Ang II increased mean arterial pressure (+40.4 mmHg), increased renal sympathetic nerve activity (+19.4% max activity), and induced baroreflex dysfunction relative to vehicle. Co-infusion of ANA-12 attenuated the increase in blood pressure (−20.6 mmHg) and prevented the increase in renal sympathetic nerve activity (−22.2% max) and baroreflex dysfunction relative to Ang II alone. Ang II increased thirst and decreased food consumption, and Ang II + ANA-12 augmented the thirst response while attenuating the decrease in food consumption. We conclude that TrkB signaling is a mediator of the long-term blood pressure and sympathetic nerve activity responses to central Ang II activity. These findings demonstrate the involvement of neurotrophins such as BDNF in promoting Ang II-induced autonomic dysfunction and further implicate TrkB signaling in modulating presympathetic autonomic neurons during cardiovascular disease.

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Section: Methodsmentioning

confidence: 99%

Central TrkB blockade attenuates ICV angiotensin II-hypertension and sympathetic nerve activity in male Sprague-Dawley rats

Becker

Wang

Zucker

2017

Autonomic Neuroscience

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“…Furthermore, simvastatin has been shown to reduce the incidence of arrhythmias and oscillatory breathing and reduce CB chemoreflex sensitivity in CHF rats (Haack et al , 2014). These improvements corresponded with an increase in KLF2 and eNOS expression and a decrease in AT1R expression in the CB.…”

Section: Translational Impact Of Cb Hyperactivity In Chfmentioning

confidence: 99%

Mechanisms of carotid body chemoreflex dysfunction during heart failure

Schultz

Marcus

Rio

2015

Experimental Physiology

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Recent advances have drawn interest in the potential for carotid body (CB) ablation or desensitization as an effective strategy for clinical treatment and management of cardio-respiratory diseases including hypertension, heart failure, diabetes mellitus, metabolic syndrome, and renal failure. These disease states have in common sympathetic overactivity, which plays an important role in the development and progression of the disease and is often associated with breathing dysregulation, which in turn likely mediates or aggravates the autonomic imbalance. Evidence from both chronic heart failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic activity and the development of periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a tonic increase in afferent activity from CB glomus cells is likely to be a main driving force. This report will focus on our understanding of mechanisms that alter CB function in CHF and their potential translational impact on treatment of CHF.

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“…Indeed, therapeutic doses of statins decrease Rho kinase activity in patients with atherosclerosis in an LDL-independent manner 63 . Our lab has similarly found that statin treatment improves autonomic function in experimental and clinical heart failure independent of LDL-lowering effects 64–68 , and clinical studies in patients with hypertension and chronic kidney disease support the sympatholytic effect of statins in humans regardless of the presence of hyperlipidemia 69–72 . Given the strong associative 73–75 and experimental 76,77 data linking autonomic function and mortality in cardiovascular disease, the sympatholytic effects of statins through Rho kinase inhibition may be an important mechanism by which these drugs reduce cardiovascular risk.…”

Section: Discussionmentioning

confidence: 75%

Central Angiotensin-II Increases Blood Pressure and Sympathetic Outflow via Rho Kinase Activation in Conscious Rabbits

et al. 2016

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Elevated sympathetic tone and activation of the renin-angiotensin system are pathophysiologic hallmarks of hypertension, and the interactions between these systems are particularly deleterious. The importance of Rho kinase as a mediator of the effects of Angiotensin-II in the periphery is clear, but the role of Rho kinase in sympatho-excitation caused by central angiotensin-II is not well-established. We hypothesized that angiotensin-II mediates its effects in the brain by activation of the RhoA/Rho kinase pathway. Chronically instrumented, conscious rabbits received the following intracerebroventricular infusion treatments for two weeks via osmotic minipump: angiotensin-II, the Rho kinase inhibitor Fasudil, angiotensin-II plus Fasudil, or a vehicle control. Angiotensin-II increased mean arterial pressure over the course of the infusion, and this effect was prevented by co-administration of Fasudil. Angiotensin-II increased cardiac and vascular sympathetic outflow as quantified by the heart rate response to metoprolol and the depressor effect of hexamethonium; co-administration of Fasudil abolished both of these effects. Angiotensin-II increased baseline renal sympathetic nerve activity in conscious animals and impaired baroreflex control of sympathetic nerve activity; again Fasudil co-infusion prevented these effects. Each of these endpoints showed a statistically significant interaction between angiotensin-II and Fasudil. Quantitative immunofluorescence of brain slices confirmed that Rho kinase activity was increased by angiotensin-II and decreased by Fasudil. Taken together, these data indicate that the hypertension, elevated sympathetic outflow, and baroreflex dysfunction caused by central angiotensin-II are mediated by Rho kinase activation and suggest that Rho kinase inhibition may be an important therapeutic target in sympatho-excitatory cardiovascular diseases.

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Simvastatin Treatment Attenuates Increased Respiratory Variability and Apnea/Hypopnea Index in Rats With Chronic Heart Failure

Cited by 46 publications

References 58 publications

Central TrkB blockade attenuates ICV angiotensin II-hypertension and sympathetic nerve activity in male Sprague-Dawley rats

Central TrkB blockade attenuates ICV angiotensin II-hypertension and sympathetic nerve activity in male Sprague-Dawley rats

Mechanisms of carotid body chemoreflex dysfunction during heart failure

Central Angiotensin-II Increases Blood Pressure and Sympathetic Outflow via Rho Kinase Activation in Conscious Rabbits

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