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(Hypertension. 2008;51:1326.)
© 2008 American Heart Association, Inc.

Original Articles

Modulation of Reflex Function by Endogenous Angiotensins in Older Transgenic Rats With Low Glial Angiotensinogen

Amy C. Arnold; Atsushi Sakima; Detlev Ganten; Carlos M. Ferrario; Debra I. Diz

From the Hypertension and Vascular Research Center and Physiology and Pharmacology Department (A.C.A., C.M.F., D.I.D.), Wake Forest University School of Medicine, Winston-Salem, NC; and the Cardiovascular Medicine (A.S.), Nephrology and Neurology, University of the Ryukyus School of Medicine, Okinawa, Japan; Charite—Universitatsmedizin (D.G.), Berlin, Germany.

Correspondence to Debra I. Diz, Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1032. E-mail ddiz{at}wfubmc.edu

Age-related impairments in baroreflex sensitivity in Sprague-Dawley rats are associated with low solitary tract nucleus content of angiotensin-(1-7). However, transgenic rats with low-brain angiotensinogen resulting from glial overexpression of an antisense oligonucleotide to angiotensinogen (ASrAOGEN) are spared age-related declines in cardiovascular function characteristic of Sprague-Dawley rats. We examine whether cardiovascular and reflex actions of angiotensin-(1-7) persist in the solitary tract nucleus of older (16 to 22 months) ASrAOGEN rats. Baroreflex sensitivity for control of heart rate and chemosensitive vagal afferent activation in response to phenylbiguanide were measured before and after bilateral microinjection of the angiotensin II type 1 receptor antagonist candesartan and angiotensin-(1-7) receptor antagonist (D-Ala⁷)-angiotensin-(1-7) in urethane/chloralose-anesthetized rats. In older anesthetized ASrAOGEN rats, candesartan had no effect, whereas (D-Ala⁷)-angiotensin-(1-7) significantly reduced baroreflex sensitivity (1.80±0.43 versus 0.50±0.17 ms/mm Hg). Phenylbiguanide responses were attenuated by injection of candesartan (–79±6 versus –55±12 mm Hg and –277±12 versus –156±27 bpm; P<0.05). In addition, resting blood pressure was reduced by injection of candesartan or (D-Ala⁷)-angiotensin-(1-7). Within the solitary tract nucleus of older ASrAOGEN rats, it appears that glial angiotensinogen is the main source of angiotensin II attenuation of baroreflex sensitivity; endogenous angiotensin-(1-7) from nonglial sources enhances baroreflex sensitivity; nonglial sources of angiotensin II contribute to chemosensitive vagal afferent activation; and receptors for both peptides modulate resting arterial pressure under anesthesia. These results suggest a novel mechanism for the preservation of baroreflex sensitivity during aging.

Key Words: transgenic rats • brain renin-angiotensin system • solitary tract nucleus • aging