Central Angiotensin-(1–7) Improves Vagal Function Independent of Blood Pressure in Hypertensive (mRen2)27 Rats

Abstract

Hypertensive transgenic (mRen2)27 rats with overexpression of the mRen2 gene have impaired baroreflex sensitivity for heart rate control and high nicotinamide adenine dinucleotide phosphate oxidase and kinase-to-phosphatase signaling activity in medullary tissue compared with normotensive Hannover Sprague-Dawley control rats. They also exhibit insulin resistance at a young age. To determine whether blocking angiotensin II actions, supplementing angiotensin-(1-7), or scavenging reactive oxygen species in brain differentially alters mean arterial pressure, baroreflex sensitivity, or metabolic function, while altering medullary signaling pathways in these animals, we compared intracerebroventricular infusions of the angiotensin II type 1 receptor antagonist candesartan (4 μg/5 μL/h), angiotensin-(1-7) (0.1 μg/5 μL/h), a reactive oxygen species scavenger tempol (25 μg/5 μL/h), or artificial cerebrospinal fluid (5 μL/h) for 2 weeks. Mean arterial pressure was reduced in candesartan-treated rats without significantly improving the vagal components of baroreflex function or heart rate variability. In contrast, angiotensin-(1-7) treatment significantly improved the vagal components of baroreflex function and heart rate variability at a dose that did not significantly lower mean arterial pressure. Tempol significantly reduced nicotinamide adenine dinucleotide phosphate oxidase activity in brain dorsal medullary tissue but had no effect on mean arterial pressure or autonomic function. Candesartan tended to reduce fat mass, but none of the treatments significantly altered indices of metabolic function or mitogen-activated protein kinase signaling pathways in dorsal medulla. Although additional dose response studies are necessary to determine the potential maximal effectiveness of each treatment, the current findings demonstrate that blood pressure and baroreflex function can be essentially normalized independently of medullary nicotinamide adenine dinucleotide phosphate oxidase or mitogen-activated protein kinase in hypertensive (mRen2)27 rats.