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(Hypertension. 1999;33:360-365.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Angiotensin II Type 1 Receptor Antisense Gene Therapy Prevents Altered Renal Vascular Calcium Homeostasis in Hypertension

Craig H. Gelband; Phyllis Y. Reaves; Jenafer Evans; Hongwei Wang; Michael J. Katovich; Mohan K. Raizada

From the Department of Physiology, College of Medicine, and the Department of Pharmacodynamics, College of Pharmacy (M.J.K.), University of Florida, Gainesville, Fla.

Correspondence to Craig H. Gelband, PhD, Department of Physiology, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610. E-mail Gelband{at}phys.med.ufl.edu

Abstract—Intracellular Ca²⁺ ([Ca²⁺]_i) homeostasis regulates vascular smooth muscle tone, and alteration in [Ca²⁺]_i handling is associated with the development and establishment of hypertension. We have previously established in the spontaneously hypertensive rat (SHR) that virally mediated delivery of angiotensin II type 1 receptor antisense (AT₁R-AS) prevents the development of high blood pressure and some pathophysiology associated with hypertension for 120 days. In light of this, our objectives in this study were to determine whether AT₁R-AS gene therapy (1) could have a longer duration in the prevention of hypertension and (2) would attenuate the alterations in renal vascular Ca²⁺ homeostasis and therefore vasoconstriction, characteristics of hypertension. Intracardiac delivery of AT₁R-AS in neonates prevented the development of hypertension in SHR for at least 210 days. At this time, untreated SHR renal resistance arterioles showed a significantly enhanced contractile response to KCl and angiotensin II (Ang II) when compared with normotensive Wistar-Kyoto rats. In addition, L-type Ca²⁺ current density and Ang II–dependent increases in [Ca²⁺]_i were significantly increased in cells dissociated from renal resistance arterioles of the untreated SHR. AT₁R-AS treatment prevented all of the above vascular alterations associated with the hypertensive state in SHR. Finally, Western blot analysis of L-type Ca²⁺ channel (_1C) protein levels in renal resistance arterioles of untreated SHR showed no significant difference when compared with control. These results are novel and demonstrate that viral-mediated delivery of AT₁R-AS not only attenuates the development of hypertension on a long-term basis but prevents changes in renal vascular Ca²⁺ homeostasis associated with the disease.

Key Words: angiotensin II • arterioles • calcium, intracellular • Ca²⁺ current • excitation-contraction coupling • gene therapy

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