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

Angiotensin II (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 was 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 which 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 microg/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 (4mug/kg and 2mug/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 to 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. Key words: blood pressure, brain microinjection, angiotensin II, brain renin angiotensin system.