Cerebral vascular effects of angiotensin II: new insights from genetic models

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 similar to 130 mu 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 similar to 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.