Angiotensin II -: Induced vascular dysfunction is mediated by the AT1A receptor in mice

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 (Delta45 +/- 8 mm Hg, P < 0.0001) but unchanged in AT(1A)(-/-) mice (Delta5 +/- 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 mumol/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 mumol/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.