ANG II, the main circulating effector hormone of the renin-angiotensin system, is produced by enzymatic cleavage of angiotensinogen. The present study aimed to examine whether targeted deletion of the angiotensinogen gene ( Agt) altered brain ANG II receptor density or responsiveness to ANG II. In vitro autoradiography was used to examine the distribution and density of angiotensin type 1 (AT1) and type 2 receptors. In most brain regions, the distribution and density of angiotensin receptors were similar in brains of Agt knockout mice ( Agt −/− ) and wild-type mice. In Agt −/− mice, a small increase in AT1 receptor binding was observed in the rostral ventrolateral medulla (RVLM), a region that plays a critical role in blood pressure regulation. To examine whether Agt −/− mice showed altered responses to ANG II, blood pressure responses to intravenous injection (0.01–0.1 μg/kg) or RVLM microinjection (50 pmol in 50 nl) of ANG II were recorded in anesthetized Agt −/− and wild-type mice. Intravenous injections of phenylephrine (4 μg/kg and 2 μg/kg) were also made in both groups. The magnitude of the pressor response to intravenous injections of ANG II or phenylephrine was not different between Agt −/− and wild-type mice. Microinjection of ANG II into the RVLM induced a pressor response, which was significantly smaller in Agt −/− compared with wild-type mice (+10 ± 1 vs. +23 ± 4 mmHg, respectively, P = 0.004). Microinjection of glutamate into the RVLM (100 pmol in 10 nl) produced a robust pressor response, which was not different between Agt −/− and wild-type mice. A diminished response to ANG II microinjection in the RVLM of Agt −/− mice, despite an increased density of AT1 receptors suggests that signal transduction pathways may be altered in RVLM neurons of Agt −/− mice, resulting in attenuated cellular excitation.
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