Central angiotensin-II increases blood pressure and sympathetic outflow via Rho kinase activation in conscious rabbits

• Type of Material: Article
• Authors: Peter R. Pellegrino, University of Nebraska; Alicia M. Schiller, University of Nebraska; Karla Haack, Emory University; Irving H. Zucker, University of Nebraska
• Language: English
• Date: 2016-11-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07792
• Title of Journal or Parent Work: Hypertension
• ISSN: 0194-911X
• Volume: 68
• Issue: 5
• Start Page: 1271
• End Page: 1280
• Grant/Funding Information: K.K.V. Haack was partially supported by NIH NHLBI F32 HL116172.; A.M. Schiller was partially supported by AHA award 13PRE14700045.; P.R. Pellegrino was partially supported by NIH NHLBI grant F30 HL118974 and American Heart Association (AHA) award 13PRE16210015.; This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute (NIH NHLBI) grant P01 HL62222.
• Keywords: Analysis of Variance; Renin-Angiotensin System; Rho-associated kinases; Sympathetic Nervous System; angiotensin II; Consciousness; Male; Angiotensin II; cardiovascular diseases; rho-Associated Kinases; Rabbits; Baroreflex; Animals; intraventricular infusions; Hypertension; RhoA GTP-binding protein; hypertension; Disease Models, Animal; baroreflex; Random Allocation
• Research Categories: Biology, Cell; Biology, Physiology

Abstract

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 (AngII) in the periphery is clear, but the role of Rho kinase in sympathoexcitation caused by central AngII is not well established. We hypothesized that AngII mediates its effects in the brain by the activation of the RhoA/Rho kinase pathway. Chronically instrumented, conscious rabbits received the following intracerebroventricular infusion treatments for 2 weeks via osmotic minipump: AngII, Rho kinase inhibitor Fasudil, AngII plus Fasudil, or a vehicle control. AngII increased mean arterial pressure over the course of the infusion, and this effect was prevented by the coadministration of Fasudil. AngII increased cardiac and vascular sympathetic outflow as quantified by the heart rate response to metoprolol and the depressor effect of hexamethonium; coadministration of Fasudil abolished both of these effects. AngII increased baseline renal sympathetic nerve activity in conscious animals and impaired baroreflex control of sympathetic nerve activity; again Fasudil coinfusion prevented these effects. Each of these end points showed a statistically significant interaction between AngII and Fasudil. Quantitative immunofluorescence of brain slices confirmed that Rho kinase activity was increased by AngII and decreased by Fasudil. Taken together, these data indicate that hypertension, elevated sympathetic outflow, and baroreflex dysfunction caused by central AngII are mediated by Rho kinase activation and suggest that Rho kinase inhibition may be an important therapeutic target in sympathoexcitatory cardiovascular diseases.