Divergent functions of angiotensin II receptor isoforms in the brain (original) (raw)
Six days after cannulation of the lateral brain ventricles and the carotid artery in mice with a gene targeted deletion of the AT1A (_Agtr1a_–/–) or the AT1B (_Agtr1b_–/–) receptor or in wild-type littermates, we measured intra-arterial pressures in conscious freely moving mice. MAPs were similar in wild-type (114 ± mmHg) and _Agtr1b_–/– mice (111 ± mmHg; P > 0.05). However, basal blood pressure in the _Agtr1a_–/– mice (99 ± mmHg) was significantly lower than that of wild-type controls (P < 0.01), confirming a role for the AT1A receptor in normal maintenance of blood pressure (10).
The vasopressor effect of central angiotensin II has been suggested to be a critical component in both chronic blood pressure regulation and the pathogenesis of hypertension (2). As shown in Figure 1, ICV injection of angiotensin II caused an acute, dose-dependent increase in blood pressure in wild-type mice. This response is identical to that seen in other species (2). The vascular effects of ICV injection of angiotensin II in _Agtr1b_–/– mice was virtually identical to those seen in controls (Figure 1), suggesting that the AT1B receptor does not have an essential contribution to this response. By contrast, ICV injection of angiotensin II induced only a very minor increase in blood pressure in _Agtr1a_–/– mice (Figure 1). Thus, the CNS actions of angiotensin II to increase blood pressure are primarily mediated by AT1A receptors.
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 AT1A (AT-1A–/–) or AT1B (AT-1B–/–) receptors. A_P_ < 0.001 versus wild-type.
Along with its effects to raise blood pressure, angiotensin II that is generated in the CNS has potent dipsogenic actions. These effects are believed to stimulate drinking behavior during states of volume depletion (2). As shown in Figure 2, ICV administration of angiotensin II to wild-type mice elicited a robust drinking response that is similar to that reported in many other species (2). We next examined the effects of AT1 receptor gene mutations on the dipsogenic effects of angiotensin II. Compared to wild-type mice, there was a small but statistically significant (P < 0.05) reduction in the drinking response to the highest doses of angiotensin II in the AT1A receptor-deficient mice. By contrast, in the AT1B-deficient mice, drinking evoked by central angiotensin II was markedly diminished compared with either wild-type (P < 0.001) or Agtr1a–/– animals (P < 0.01). These data indicate that AT1B receptors are the primary mediators of the central dipsogenic actions of angiotensin II, whereas AT1A receptors make only a modest contribution to this response. This is the first demonstration of a primary and nonredundant physiological function of AT1B receptors.
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 AT1A (AT-1A–/–) or AT1B (AT-1B–/–) receptors. A_P_ < 0.05 versus wild-type; B_P_ < 0.001 versus wild-type and P < 0.01 versus AT-1B–/–.
Most previous studies have suggested that AT1 receptors are responsible for the entire dipsogenic action of angiotensin II. However, a few studies have suggested roles for AT2 and other non-AT1 receptors in these responses (e.g., ref. 18). To test for a contribution of non-AT1 receptors to this response in wild-type mice, and to evaluate whether these responses might be more pronounced in AT1-mutant animals, we examined the effects of losartan, a specific AT1 receptor antagonist with equivalent potency for AT1A and AT1B receptors. As shown in Figure 3, the AT1 receptor antagonist completely blocked angiotensin II–induced drinking in wild-type and AT1A receptor–deficient mice. Likewise, the small residual response in the _Agtr1b_–/– mice was also abrogated by losartan. These data indicate that in mice, non-AT1 receptors play no significant role in the stimulation of drinking by angiotensin II.
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 AT1A (AT-1A–/–) or AT1B (AT-1B–/–) receptors. A_P_ < 0.001 versus before losartan.