Angiotensin II–Induced Vascular Dysfunction Is Mediated by the AT 1A Receptor in Mice

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Abstract
Many of the actions of angiotensin II (Ang II) are mediated by angiotensin type 1 receptors (AT 1 ), 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 (Δ45±8 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.