title: Impaired endothelial function in transgenic mice expressing both human renin and human angiotensinogen.
abstract: OBJECTIVE
  Chronic hypertension is a risk factor for carotid vascular disease and stroke. Mechanisms that account for alterations in carotid and cerebral vascular function during hypertension are poorly defined and based almost exclusively on studies in the spontaneously hypertensive rat, a model in which hypertension has an unknown etiology and in which the genetic background is dissimilar to the most commonly used normotensive control, the Wistar-Kyoto rat.
  
  
  METHODS
  In this study we examined vascular function in a defined model of hypertension, double transgenic mice that overexpress both human renin (R+) and human angiotensinogen (A+). We studied vessels in vitro from R+/A+ mice as well as nontransgenic (R-/A-) and single transgenic (R-/A+ or R+/A-) littermate controls.
  
  
  RESULTS
  After submaximal precontraction with U46619 or prostaglandin F(2alpha), acetylcholine, which produces relaxation mediated by endothelial nitric oxide synthase, produced marked relaxation of carotid arteries in control mice but was impaired in R+/A+ mice. For example, 1 micromol/L acetylcholine relaxed the carotid artery by 79+/-4% versus 44+/-7% (P<0.01) in control and R+/A+ mice, respectively. Impaired responses to acetylcholine in R+/A+ mice could be restored toward normal with indomethacin (10 micromol/L). In contrast, relaxation of the carotid artery in response to nitroprusside and papaverine was similar in R+/A+ mice and control mice.
  
  
  CONCLUSIONS
  These findings indicate that acetylcholine-induced relaxation of carotid artery is impaired selectively in mice made hypertensive by expression of human renin and human angiotensinogen. The mechanism of this impairment may involve production of a cyclooxygenase-derived contracting factor.
authors.affiliation: Departments of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine, Iowa City 52242-1081, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Didion
authors.forename: C D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: F M
authors.initials: FM
authors.lastname: Faraci
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002317:Cardiovascular Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000808:Angiotensinogen; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D012083:Renin; D000109:Acetylcholine; D007213:Indomethacin