ANGIOTENSIN-II RESPONSES IN AT(1A) RECEPTOR-DEFICIENT MICE - A ROLE FOR AT(1B) RECEPTORS IN BLOOD-PRESSURE REGULATION

Most of the classic functions of the renin-angiotensin system are medi ated by type 1 (AT(1)) angiotensin receptors, of which two subtypes, A T(1A) and AT(1B), have been identified. However, distinct functions fo r these two AT(1) receptors have been difficult to separate. We examin ed the presser effects of angiotensin II in Agtr1A -/- mice, which lac k AT(1A) receptors. In enalapril-pretreated Agtr1A -/- mice, angiotens in II caused significant and dose-proportional increases in mean arter ial pressure. This presser response was not blocked by pretreatment wi th sympatholytic agents but was completely inhibited by the AT(1)-rece ptor antagonists, losartan and candesartan, suggesting that it is dire ctly mediated by AT(1B) receptors. Chronic treatment of Agtr1A -/- mic e with losartan reduced systolic blood pressure from 80 +/- 5 to 72 +/ - 4 mmHg (P < 0.04), suggesting a role for AT(1B) receptors in chronic blood pressure regulation. These studies provide the first demonstrat ion of in vivo pressor effects mediated by AT(1B) receptors and demons trate that, when AT(1A) receptors are absent, the AT(1B) receptor cont ributes to the regulation of resting blood pressure.