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

Peter R. Pellegrino, Alicia M Schiller, Karla K V Haack, Irving H Zucker

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1271-1280
Number of pages10
JournalHypertension
Volume68
Issue number5
DOIs
StatePublished - Nov 1 2016

Fingerprint

rho-Associated Kinases
Angiotensin II
Rabbits
Blood Pressure
Baroreflex
Intraventricular Infusions
Hypertension
Hexamethonium
Metoprolol
Brain
Renin-Angiotensin System
fasudil
Fluorescent Antibody Technique
Blood Vessels
Arterial Pressure
Cardiovascular Diseases
Heart Rate

Keywords

  • Rho-associated kinases
  • RhoA GTP-binding protein
  • angiotensin II
  • baroreflex
  • cardiovascular diseases
  • hypertension
  • intraventricular infusions

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Central angiotensin-II increases blood pressure and sympathetic outflow via Rho kinase activation in conscious rabbits. / Pellegrino, Peter R.; Schiller, Alicia M; Haack, Karla K V; Zucker, Irving H.

In: Hypertension, Vol. 68, No. 5, 01.11.2016, p. 1271-1280.

Research output: Contribution to journalArticle

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