Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors

Angiotensin II activates two distinct receptors, the angiotensin II receptors type 1 (AT(1)) and type 2 (AT(2)). In rodents, two AT(1) subtypes were identified (AT(1a) and AT(1b)). To determine receptor-specific functions and possible angiotensin II effects independent of its three known receptors we generated mice deficient in either one of the angiotensin II receptors, in two, or in all three (triple knockouts). Triple knockouts were vital and fertile, but survival was impaired. Hypotension and renal histological abnormalities in triple knockouts were comparable to those in mice lacking both AT(1) subtypes. All combinations lacking AT(1a) were distinguished by reduced heart rate. AT(1a) deletion impaired the in vivo pressor response to angiotensin II bolus injection, whereas deficiency for AT(1b) and/or AT(2) had no effect. However, the additional lack of AT(1b) in AT(1a)-deficient mice further impaired the vasoconstrictive capacity of angiotensin II. Although general vasoconstrictor properties were not changed, angiotensin II failed to alter blood pressure in triple knockouts, indicating that there are no other receptors involved in direct angiotensin II pressor effects. Our data identify mice deficient in all three angiotensin II receptors as an ideal tool to better understand the structure and function of the renin-angiotensin system and to search for angiotensin II effects independent of AT(1) and AT(2).