Divergent functions of angiotensin II receptor isoforms in the brain

The renin-angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. The major biologically active peptide of the RAS is angiotensin II, which acts through G protein-coupled receptors of two pharm acological classes, AT(1) and AT(2). AT(1) receptors, expressed in brain an d peripheral tissues, mediate most classically recognized actions of the RA S, including blood pressure homeostasis and regulation of drinking and wate r balance. In rodents, two highly homologous AT(1) receptor isoforms, terme d AT(1A) and AT(1B) receptors, are expressed at different levels in major f orebrain cardiovascular and fluid regulatory centers, with AT(1A) expressio n generally exceeding AT(1B) expression, but the relative contributions of these receptor subtypes to central angiotensin II responses are not known. We used gene targeting in combination with a unique system for maintaining catheters in the cerebral ventricles of conscious mice to test whether ther e are differential roles for AT(1A) and AT(1B) receptors in responses elici ted by angiotensin II in the brain. Here we show that the blood pressure in crease elicited by centrally administered angiotensin II can be selectively ascribed to the AT(1A) receptor. However, the drinking response requires t he presence of AT(1B) receptors. To our knowledge, this is the first demons tration of a primary and nonredundant physiological function for AT(1B) rec eptors.