Divergent functions of angiotensin II receptor isoforms in the brain

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, AT(1) and AT(2). AT(1) 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 AT(1) receptor isoforms, termed AT(1A) and AT(1B) receptors, are expressed at different levels in major forebrain cardiovascular and fluid regulatory centers, with AT(1A) expression 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 there are differential roles for AT(1A) and AT(1B) 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 AT(1A) receptor. However, the drinking response requires the presence of AT(1B) receptors. To our knowledge, this is the first demonstration of a primary and nonredundant physiological function for AT(1B) receptors.

Figure 1

Blood pressure responses to centrally administered angiotensin II. A summary of the change in MAP (mmHg) elicited by three different doses of angiotensin II (50, 100, and 200 ng) administered intracerebroventricularly (ICV) in wild-type mice (+/+) and in mice with gene-targeted deletions of AT_1A (AT-1A^–/–) or AT_1B (AT-1B^–/–) receptors. ^AP < 0.001 versus wild-type.

Figure 2

Effects of centrally administered angiotensin II on water drinking. A summary of the number of drinking episodes elicited by ICV angiotensin II (50, 100, and 200 ng) in wild-type mice (+/+) and in mice with gene-targeted deletions of AT_1A (AT-1A^–/–) or AT_1B (AT-1B^–/–) receptors. AP < 0.05 versus wild-type; ^BP < 0.001 versus wild-type and P < 0.01 versus AT-1B^–/–.

Figure 3

Effect of the specific AT1 receptor antagonist losartan on central angiotensin-II–induced drinking. A summary of the water drinking effects elicited by ICV angiotensin II (200 ng) before and after ICV administration of losartan (10 μg) in wild-type mice (+/+) and in mice with gene-targeted deletions of AT_1A (AT-1A^–/–) or AT_1B (AT-1B^–/–) receptors. ^AP < 0.001 versus before losartan.