Changes in angiotensin type 1 receptor binding and angiotensin-induced pressor responses in the rostral ventrolateral medulla of angiotensinogen knockout mice

1 Department of Physiology, University of Melbourne, Victoria, Australia; 2 Howard Florey Institute, Florey Neurosciences Institutes, University of Melbourne, Victoria, Australia; and 3 Department of Physiology, Monash University, Victoria, Australia Submitted August 11, 2009 ; accepted in final form November 23, 2009 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 (AT 1 ) 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 AT 1 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 AT 1 receptors suggests that signal transduction pathways may be altered in RVLM neurons of Agt –/– mice, resulting in attenuated cellular excitation. blood pressure; brain microinjection; angiotensin II; brain renin-angiotensin system Address for reprint requests and other correspondence: A. M. Allen, Dept. of Physiology, Univ. of Melbourne, Victoria 3010, Australia (e-mail: a.allen{at}unimelb.edu.au ).