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In Vivo Expression of Angiotensin-(1-7) Lowers Blood Pressure and Improves Baroreflex Function in Transgenic (mRen2)27 Rats

Garcia-Espinosa, Maria A. PhD*; Shaltout, Hossam A. PhD; Gallagher, Patricia E. PhD; Chappell, Mark C. PhD; Diz, Debra I. PhD

Journal of Cardiovascular Pharmacology: August 2012 - Volume 60 - Issue 2 - p 150–157
doi: 10.1097/FJC.0b013e3182588b32
Original Article

Abstract: Transgenic (mRen2)27 rats are hypertensive with impaired baroreflex sensitivity for control of heart rate compared with Hannover Sprague–Dawley rats. We assessed blood pressure and baroreflex function in male hemizygous (mRen2)27 rats (30–40 weeks of age) instrumented for arterial pressure recordings and receiving into the cisterna magna either an Ang-(1-7) fusion protein or a control fusion protein (CTL-FP). The maximum reduction in mean arterial pressure achieved was −38 ± 7 mm Hg on day 3, accompanied by a 55% enhancement in baroreflex sensitivity in Ang-(1-7) fusion protein-treated rats. Both the high-frequency alpha index (HF-α) and heart rate variability increased, suggesting increased parasympathetic tone for cardiac control. The mRNA levels of several components of the renin–angiotensin system in the dorsal medulla were markedly reduced including renin (−80%), neprilysin (−40%), and the AT1a receptor (−40%). However, there was a 2-fold to 3-fold increase in the mRNA levels of the phosphatases PTP-1b and dual-specificity phosphatase 1 in the medulla of Ang-(1-7) fusion protein-treated rats. Our finding that replacement of Ang-(1-7) in the brain of (mRen2)27 rats reverses in part the hypertension and baroreflex impairment is consistent with a functional deficit of Ang-(1-7) in this hypertensive strain. We conclude that the increased mRNA expression of phosphatases known to counteract the phosphoinositol 3 kinase and mitogen-activated protein kinases, and the reduction of renin and AT1a receptor mRNA levels may contribute to the reduction in arterial pressure and improvement in baroreflex sensitivity in response to Ang-(1-7).

*Radiation Oncology Department

Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC.

Reprints: Debra I. Diz, PhD, The Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1032 (e-mail: ddiz@wfubmc.edu).

Conflict of Interest: No relationships to disclose.

Received February 27, 2012

Accepted April 2, 2012

© 2012 Lippincott Williams & Wilkins, Inc.