(Stroke. 2000;31:760.)
© 2000 American Heart Association, Inc.
Original Contributions |
Impaired Endothelial Function in Transgenic Mice Expressing Both Human Renin and Human Angiotensinogen
From the Departments of Internal Medicine (S.P.D., C.D.S., F.M.F.), Pharmacology (F.M.F.), and Physiology (C.D.S.), Cardiovascular Center, University of Iowa College of Medicine, Iowa City.
Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, E315-GH, University of Iowa College of Medicine, Iowa City, IA 52242-1081.
Background and Purpose—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 F2
, 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
µmol/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
µmol/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.
Editorial Comment
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota
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