(Circulation. 1997;96:1250-1256.)
© 1997 American Heart Association, Inc.
Articles |
Additional Hypotensive Effect of Endothelin-1 Receptor Antagonism in Hypertensive Dogs Under Angiotensin-Converting Enzyme Inhibition
From the Divisions of Endocrinology and Internal Medicine (J.E.D.), University Hospital UCL of Mont-Godinne, Yvoir, Belgium; the Departments of Physiology and Cardiology (P.-E.M., D.H., H.V.M., G.H., A.A.C.) and the Unit of Diabetology and Nutrition (O.L., J.-M.K.), University of Louvain, Brussels, Belgium; the Cardiovascular Center (G.P.H.), Aalst, Belgium; and the Pharma Division (J.-P.C.), Preclinical Research, F. Hoffman-La Roche Ltd, Basel, Switzerland.
Correspondence to Julian Donckier, MD, PhD, Endocrinology and Internal Medicine, University Hospital of Mont-Godinne, B-5530 Yvoir, Belgium.
Background Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI).
Methods and Results Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+0.23 mg/kg per hour to 3 mg/kg+7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (P=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173±26 to 130±25 mm Hg; P<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98±21 mm Hg (P<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (P<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (P<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan.
Conclusions Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.
Key Words: angiotensin • hypertension • enzymes • endothelin • vasodilation
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