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 AT1A receptors and Rho-kinase. Basilar arteries (baseline diameter approximately 130 microm) 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 approximately 85% in mice deficient in expression of AT1A 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 AT1A 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.
Faraci
Frank M
FM
Department of Internal Medicine, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1081, USA. frank-faraci@uiowa.edu
Lamping
Kathryn G
KG
Modrick
Mary L
ML
Ryan
Michael J
MJ
Sigmund
Curt D
CD
Didion
Sean P
SP
D000804:Angiotensin II / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012083:Renin / Q000235:genetics; D012737:Sex Factors; D013481:Superoxides; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D013481:Superoxides; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D012083:Renin