title: 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.
authors.affiliation: Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1032, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Nautiyal
authors.forename: Hossam A
authors.initials: HA
authors.lastname: Shaltout
authors.forename: Daniel C
authors.initials: DC
authors.lastname: de Lima
authors.forename: Kenia
authors.initials: K
authors.lastname: do Nascimento
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.forename: Debra I
authors.initials: DI
authors.lastname: Diz
mesh_terms: D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002555:Cerebrospinal Fluid / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D057967:Infusions, Intraventricular; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012083:Renin / Q000235:genetics; D013113:Spin Labels; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003497:Cyclic N-Oxides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C473112:Ren2 protein, mouse; D013113:Spin Labels; D013777:Tetrazoles; D000803:Angiotensin I; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; D012083:Renin; C118790:angiotensin I (1-7); C081643:candesartan; C001803:tempol