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(Hypertension. 2004;43:1074.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Angiotensin II–Induced Vascular Dysfunction Is Mediated by the AT_1A Receptor in Mice

Michael J. Ryan; Sean P. Didion; Satya Mathur; Frank M. Faraci; Curt D. Sigmund

From the Departments of Internal Medicine (M.J.R., S.P.D., S.M. F.M.F., C.D.S.), Pharmacology (F.M.F.), and Physiology and Biophysics (C.D.S.), Cardiovascular Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.

Correspondence to Michael J. Ryan, PhD, Department of Internal Medicine, University of Iowa, 3181 MEBRF, Iowa City, IA 52242. E-mail ryanm{at}physiology.uiowa.edu

Many of the actions of angiotensin II (Ang II) are mediated by angiotensin type 1 receptors (AT₁), of which there are 2 pharmacologically indistinguishable subtypes (AT_1A and AT_1B). The purpose of this study was to evaluate the effect of an AT_1A homozygous deletion (AT_1A^–/–) on vascular reactivity. AT_1A^–/– mice and control littermates (AT_1A^+/+) were infused with vehicle (saline) or Ang II (1000 ng · kg^–1 · min^–1) for 7 days by osmotic pumps. Systolic pressure was increased in AT_1A^+/+ mice (45±8 mm Hg, P<0.0001) but unchanged in AT_1A^–/– mice (5±3 mm Hg, P>0.13) on day 7. The carotid artery response to the vasodilators acetylcholine (ACh), nitroprusside, and papaverine and to the vasoconstrictors phenylephrine, U46619, 5-hydroxytryptamine (5-HT), and KCl were not different between vehicle-infused AT_1A^+/+ and AT_1A^–/– animals. Carotid relaxation to ACh was impaired and contraction to 5-HT was increased in Ang II–infused AT_1A^+/+ mice. Ang II did not affect carotid responses in AT_1A^–/– mice. Superoxide, measured by lucigenin (5 µmol/L), and hydroethidine staining were not different between AT_1A^+/+ and AT_1A^–/– mice after vehicle or Ang II infusion, suggesting that it was not contributing to the altered ACh and 5-HT responses. The Rho-kinase inhibitor Y-27632 (1 µmol/L) attenuated the 5-HT response in both vehicle- and Ang II–infused AT_1A^+/+ mice. Moreover, concentration-dependent relaxation to Y-27632 and RhoA protein expression were not different in vehicle- or Ang II–infused AT_1A^+/+. These data demonstrate that the AT_1A receptor is required for Ang II–induced changes in carotid artery function.

Key Words: endothelium • receptors, angiotensin II • carotid arteries • acetylcholine

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