Angiotensin type 1A receptors transfected into the A1 neurons inhibit baroreflex gain and the cardiovascular response to stress in AT_1A^−/− mice

Brain angiotensin (AngII) is an important neuromodulator of cardiovascular responses induced by stress in several brain regions. The catecholaminergic A1 neurones of the caudal ventrolateral medulla (CVLM), which is important for autonomic regulation, is rich in AT_1A receptors. We therefore examined whether the expression of AT_1A receptors in the A1 cells of AT_1A^−/− mice alters baroreflex sensitivity and cardiovascular responses to stress. Bilateral microinjections of lentivirus with the catecholamine-selective PRSx8 promoter driving expression of either green fluorescent protein (GFPv) or AT_1A receptors (AT1v mice) were made into the CVLM of AT_1A^−/− mice. Telemetry devices were used to record mean arterial pressure (MAP), heart rate (HR) and locomotor activity. No differences in MAP or HR were recorded 5 weeks following lentivirus microinjection. However, baroreflex sensitivity was reduced by 25% in AT1v mice (P<0.003). Cage-switch stress for one hour induced greater activation of forebrain and hypothalamic neurons but 35% smaller MAP responses in AT1v mice compared with GFPv mice (P<0.001). Reduced MAP mid frequency power reflected attenuated sympathetic activation (P_{group x stress}=0.04). The reduction in cardiac baroreflex sensitivity during the one-hour aversive stimulus was similar in both groups. These results suggest that AT_1A receptors in noradrenergic A1 neurons of the CVLM do not contribute to basal BP or HR but they normally inhibit cardiac vagal baroreflex activity. However, during an activated state AT_1A receptors in the CVLM amplify forebrain regions involved in emotional and autonomic processing during stress resulting in increased locomotor activity. This is accompanied by lesser increase in blood pressure due to sympatho-inhibitory influences possibly directed to muscle dilatation to promote flight. Thus AT_1A receptors on A1 neurons appear to provide a major advantage in adaptation to aversive situations.