Circulation, Vol 89, 2212-2218, Copyright © 1994 by American Heart Association
MR Tschudi, L Criscione, D Novosel, K Pfeiffer and TF Luscher
BACKGROUND: Coronary artery disease is an important complication of
hypertension. Therefore, the effects of antihypertensive therapy on the
endothelial nitric oxide (NO)/L-arginine pathway and vascular smooth muscle
were studied in left anterior descending coronary arteries of Wistar-Kyoto
(WKY) rats and spontaneously hypertensive rats (SHR). Angiotensin II (AT1)
receptor antagonists CGP 48369 and valsartan, angiotensin-converting enzyme
inhibitor benazepril HCl, and calcium antagonist nifedipine were used as
antihypertensive agents. METHODS AND RESULTS: Rings were examined in
myograph systems for isometric tension recording. In untreated WKY and SHR
rings, acetylcholine (10(-9) to 10(- 5) mol/L) but not bradykinin,
substance P (both 10(-6) mol/L), or thrombin (1 U/mL) induced comparable
endothelium-dependent relaxations. These relaxations were markedly
decreased by NG-monomethyl-L-arginine (10(-4) mol/L) and fully prevented by
N omega-nitro-L-arginine methyl ester (10(-4) mol/L) or methylene blue
(10(-5) mol/L). In vitro treatment of WKY and SHR rings with benazeprilat,
CGP 48369, or valsartan (3 x 10(-7) mol/L) did not affect responses to
acetylcholine. In SHR, chronic therapy for 8 weeks with benazepril HCl, CGP
48369, valsartan, or nifedipine (each 10 mg.kg-1.d-1 PO) similarly reduced
blood pressure and increased endothelium-dependent relaxations to
acetylcholine (log shift at IC50, ie, half-maximal inhibition of a
preceding contraction, 10-, 8-, 13-, and 13-fold, P < .05 versus
control), whereas relaxations to the NO donor 3-morpholino sydnonimine
(SIN-1, 10(-9) to 10(-5) mol/L) remained unaffected. In WKY, chronic
therapy with nifedipine (10 mg.kg-1.d-1 PO) affected neither blood pressure
nor relaxations to acetylcholine or SIN-1. CONCLUSIONS: In rat coronary
arteries, NO is synthesized via the endothelial L-arginine pathway and
released after stimulation with acetylcholine. In SHR, chronic
antihypertensive therapy with either angiotensin receptor antagonists, an
angiotensin-converting enzyme inhibitor, or a calcium antagonist
specifically increased the normal endothelium-dependent relaxations to
acetylcholine, probably because of their blood pressure- lowering effects,
whereas the responsiveness of vascular smooth muscle to NO remained
unaffected.
ARTICLES
Antihypertensive therapy augments endothelium-dependent relaxations in coronary arteries of spontaneously hypertensive rats
Department of Research, University Hospitals Basel, Switzerland.
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