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(Hypertension. 2000;35:209.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin I–Converting Enzyme Antisense Prevents Altered Renal Vascular Reactivity, but Not High Blood Pressure, in Spontaneously Hypertensive Rats
From the Department of Physiology, University of Florida College of Medicine (C.H.G., H.W., M.L.G., K.K., D.S.G., P.Y.R., M.K.R.); the Department of Pharmacodynamics, University of Florida College of Pharmacy (M.J.K.); and the University of Florida Brain Institute (M.K.R.), Gainesville, Fla.
Correspondence to Craig H. Gelband, PhD, Department of Physiology, University of Florida College of Medicine, PO Box 100274, Gainesville, FL 32610. E-mail Gelband{at}phys.med.ufl.edu
Abstract—The renin-angiotensin system plays a critical role in the control of blood pressure, and its hyperactivity is associated with the development of human primary hypertension. Because low-dose angiotensin I–converting enzyme (ACE) inhibitors cause small reductions in blood pressure that are associated with the complete reversal of altered vascular pathophysiology, our objective in this study was to determine whether ACE antisense (ACE-AS) gene delivery prevents alterations in renal vascular physiology in the parents and F1 offspring of AS-treated spontaneously hypertensive rats (SHR). A single bolus intracardiac injection of ACE-AS (2x108 colony-forming units) in SHR neonates caused a modest (18±3 mm Hg, n=7 to 9) lowering of blood pressure, which was maintained in the F1 generation offspring (n=7 to 9). Alterations in renal vascular reactivity, electrophysiology, and [Ca2+]i homeostasis are underlying mechanisms associated with the development and establishment of hypertension. Renal resistance arterioles from truncated ACE sense–treated SHR showed a significantly enhanced contractile response to KCl and phenylephrine (n=24 rings from 6 animals, P<0.01) and significantly attenuated acetylcholine-induced relaxations (n=24 rings from 6 animals, P<0.01) compared with arterioles from ACE-AS–treated SHR. In addition, compared with cells dissociated from arterioles of ACE-AS–treated SHR, cells from truncated ACE sense–treated animal vessels had a resting membrane potential that was 22±4 mV more depolarized (n=38, P<0.01), an enhanced L-type Ca2+ current density (2.2±0.3 versus 1.2±0.2 pA/pF, n=23, P<0.01), a decreased Kv current density (16.2±1.3 versus 5.4±2.2 pA/pF, n=34, P<0.01), and increased Ang II–dependent changes in [Ca2+]i (n=142, P<0.01). Similar effects of ACE-AS treatment were observed in the F1 offspring. These results demonstrate that ACE-AS permanently prevents alterations in renal vascular pathophysiology in spite of the modest effect that ACE-AS had on high blood pressure in SHR.
Key Words: hypertension, renal • calcium channels • potassium channels • arterioles • gene therapy
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