1. ¹Department of Internal Medicine, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
2. ²Department of Pharmacology, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
3. ³Department of Physiology, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

Correspondence: Dr FM Faraci, Department of Internal Medicine, E318-2-GH, University of Iowa, Carver College of Medicine, Iowa City, IA 52242-1081, USA. E-mail: frank-faraci@uiowa.edu

Received 12 May 2005; Revised 28 June 2005; Accepted 6 July 2005; Published online 10 August 2005.

Abstract

Very little is known regarding the mechanisms of action of angiotensin II (Ang II) or the consequences of Ang II-dependent hypertension in the cerebral circulation. We tested the hypothesis that Ang II produces constriction of cerebral arteries that is mediated by activation of AT_1A receptors and Rho-kinase. Basilar arteries (baseline diameter 130 m) from mice were isolated, cannulated and pressurized to measure the vessel diameter. Angiotensin II was a potent constrictor in arteries from male, but not female, mice. Vasoconstriction in response to Ang II was prevented by an inhibitor of Rho-kinase (Y-27632) in control mice, and was reduced by 85% in mice deficient in expression of AT_1A receptors. We also examined the chronic effects of Ang II using a model of Ang II-dependent hypertension, mice which overexpress human renin (R⁺) and angiotensinogen (A⁺). Responses to the endothelium-dependent agonist acetylcholine were markedly impaired in R⁺A⁺ mice (P<0.01) compared with controls, but were restored to normal by a superoxide scavenger (PEG-SOD). A-23187 (another endothelium-dependent agonist) produced vasodilation in control mice, but no response or vasoconstriction in R⁺A⁺ mice. In contrast, dilation of the basilar artery in response to a NO donor (NONOate) was similar in R⁺A⁺ mice and controls. Thus, Ang II produces potent constriction of cerebral arteries via activation of AT_1A receptors and Rho-kinase. There are marked gender differences in cerebral vascular responses to Ang II. Endothelial function is greatly impaired in a genetic model of Ang II-dependent hypertension via a mechanism that involves superoxide.