Divergent functions of angiotensin II receptor isoforms in the brain

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Abstract
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 pharmacological classes, AT1 and AT2. AT1 receptors, expressed in brain and peripheral tissues, mediate most classically recognized actions of the RAS, including blood pressure homeostasis and regulation of drinking and water balance. In rodents, two highly homologous AT1 receptor isoforms, termed AT1A and AT1B receptors, are expressed at different levels in major forebrain cardiovascular and fluid regulatory centers, with AT1A expression generally exceeding AT1B 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 there are differential roles for AT1A and AT1B receptors in responses elicited by angiotensin II in the brain. Here we show that the blood pressure increase elicited by centrally administered angiotensin II can be selectively ascribed to the AT1A receptor. However, the drinking response requires the presence of AT1B receptors. To our knowledge, this is the first demonstration of a primary and nonredundant physiological function for AT1B receptors.