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Hypertension contributes to multiple forms of cardiovascular disease and thus morbidity and mortality. The mechanisms inducing hypertension remain unclear although the involvement of homeostatic systems, such as the renin-angiotensin and sympathetic nervous systems, is established. A pivotal role of the angiotensin type 1 receptor in the proximal tubule of the kidney for the development of experimental hypertension is established. Yet, other systems are involved. This study tests whether the expression of angiotensin type 1A receptors in catecholaminergic cells contributes to hypertension development. Using a Cre-lox approach, we deleted the angiotensin type 1A receptor from all catecholaminergic cells. This deletion did not alter basal metabolism or blood pressure but delayed the onset of angiotensin-dependent hypertension and reduced the maximal response. Cardiac hypertrophy was also reduced. The knockout mice showed attenuated activation of the sympathetic nervous system during angiotensin II infusion as measured by spectral analysis of the blood pressure. Increased reactive oxygen species production was observed in forebrain regions, including the subfornical organ, of the knockout mouse but was markedly reduced in the rostral ventrolateral medulla. These studies demonstrate that stimulation of the angiotensin type 1A receptor on catecholaminergic cells is required for the full development of angiotensin-dependent hypertension and support an important role for the sympathetic nervous system in this model.

In adult mice we determined whether expression of angiotensin II (Ang II) type 1A receptors (AT(1A)Rs) in C1 neurons mediates the excitation of the rostral ventrolateral medulla (RVLM) by Ang II. Blood pressure, heart rate, and sympathetic nerve activity were measured in anesthetized, artificially ventilated wild-type (n=15) and AT(1A)R knockout (AT(1A)(-/-); n=9) mice. Microinjection of Ang II (50 nL of 0.1 to 1.0 mmol/L) into the RVLM induced a dose-related, sympathetically mediated pressor response (maximum of 17+/-2 mm Hg) in wild-type mice. These microinjections had no effect in AT(1A)(-/-) mice. Endogenous AT(1)Rs occur on catecholaminergic C1 neurons in the RVLM. We induced AT(1A)R or green fluorescent protein expression in C1 neurons of AT(1A)(-/-) mice through bilateral microinjection of replication-deficient lentiviruses, with transgene expression under the control of a phox2 transcription factor binding promoter (PRSx8) (Lv-PRSx8-AT(1A), n=10, and Lv-PRSx8-GFP, n=5). Transgene expression was observed in a significant proportion of RVLM C1 neurons. In anesthetized Lv-PRSx8-AT(1A) injected mice, unilateral RVLM microinjection of Ang II (50 nL of 1 mmol/L) increased blood pressure (17+/-4 mm Hg) and sympathetic nerve activity (155+/-32%). No response to Ang II occurred in Lv-PRSx8-GFP microinjected mice. These results show that Ang II-mediated excitation of RVLM neurons in adult mice depends on the AT(1A)R with little or no effect of type 1B or 2 receptors. Expression of the AT(1A)R predominantly in C1 catecholamine neurons restores the response to Ang II in the AT(1A)(-/-) mouse and demonstrates that these neurons are sympathoexcitatory in the mouse.