REGULATION OF BLOOD-PRESSURE BY THE TYPE 1A ANGIOTENSIN-II RECEPTOR GENE

The renin-angiotensin system plays a critical role in sodium and fluid homeostasis. Genetic or acquired alterations in the expression of com ponents of this system are strongly implicated in the pathogenesis of hypertension. To specifically examine the physiological and genetic fu nctions of the type 1A receptor for angiotensin II, we have disrupted the mouse gene encoding this receptor in embryonic stem cells by gene targeting. Agtr1A(-/-) mice were born in expected numbers, and the his tomorphology of their kidneys, heart, and vasculature was normal. AT(1 ) receptor-specific angiotensin II binding was not detected in the kid neys of homozygous Agtr1A(-/-) mutant animals, and Agtr1A (+/-) hetero zygotes exhibited a reduction in renal AT(1) receptor-specific binding to approximate to 50% of wild-type [Agtr1A(+/+)] levels. Presser resp onses to infused angiotensin II were virtually absent in Agtr1A(-/-) m ice and were qualitatively altered in Agtr1A(+/-) heterozygotes. Compa red with wild type controls, systolic blood pressure measured by tail cuff sphygmo- manometer was reduced by 12 mmHg (1 mmHg = 133 Pa) in Ag tr1A(+/-) mice and by 24 mmHg in Agtr1A(-/-) mice. Similar differences in blood pressure between the groups were seen when intraarterial pre ssures were measured by carotid cannulation. These studies demonstrate that type 1A angiotensin II receptor function is required for vascula r and hemodynamic responses to angiotensin II and that altered express ion of the Agtr1A gene has marked effects on blood pressures.