Sympathoexcitation by central ANG II: Roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM

Abstract

Chronic heart failure is often associated with sympathoexcitation and blunted arterial baroreflex function. These phenomena have been causally linked to elevated central ANG II mechanisms. Recent studies have shown that NAD(P)H oxidase-derived reactive oxygen species (ROS) are important mediators of ANG II signaling and therefore might play an essential role in these interactions. The aims of this study were to determine whether central subchronic infusion of ANG II in normal animals has effects on O₂⁻ production and expression of NAD(P)H oxidase subunits as well as ANG II type 1 (AT₁) receptors in the rostral ventrolateral medulla (RVLM). Twenty-four male New Zealand White rabbits were divided into four groups and separately received a subchronic intracerebroventricular infusion of saline alone, ANG II alone, ANG II with losartan, and losartan alone for 1 wk. On day 7 of intracerebroventricular infusion, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) values were recorded, and arterial baroreflex sensitivity was evaluated while animals were in the conscious state. We found that ANG II significantly increased baseline RSNA (161.9%; P < 0.05), mRNA and protein expression of AT₁ receptors (mRNA, 66.7%; P < 0.05; protein, 85.1%; P < 0.05), NAD(P)H oxidase subunits (mRNA, 120.0–200.0%; P < 0.05; protein, 90.9–197.0%; P < 0.05), and O₂⁻ production (83.2%; P < 0.05) in the RVLM. In addition, impaired baroreflex control of HR (Gain_max reduced by 48.2%; P < 0.05) and RSNA (Gain_max reduced by 53.6%; P < 0.05) by ANG II was completely abolished by losartan. Losartan significantly decreased baseline RSNA (−49.5%; P < 0.05) and increased baroreflex control of HR (Gain_max increased by 64.8%; P < 0.05) and RSNA (Gain_max increased by 67.9%; P < 0.05), but had no significant effects on mRNA and protein expression of AT₁ receptor and NAD(P)H oxidase subunits and O₂⁻ production in the RVLM. These data suggest that in normal rabbits, NAD(P)H oxidase-derived ROS play an important role in the modulation of sympathetic activity and arterial baroreflex function by subchronic central treatment of exogenous ANG II via AT₁ receptors.