Additional hypotensive effect of endothelin-1 receptor antagonism in hypertensive dogs under angiotensin-converting enzyme inhibition

被引:25
作者
Donckier, JE
Massart, PE
Hodeige, D
VanMechelen, H
Clozel, JP
Laloux, O
Ketelslegers, JM
Charlier, AA
Heyndrickx, GR
机构
[1] UNIV HOSP MT GODINNE, DIV INTERNAL MED, UCL, B-5530 YVOIR, BELGIUM
[2] UNIV LOUVAIN, DEPT PHYSIOL, BRUSSELS, BELGIUM
[3] UNIV LOUVAIN, DEPT CARDIOL, BRUSSELS, BELGIUM
[4] UNIV LOUVAIN, UNIT DIABETOL & NUTR, BRUSSELS, BELGIUM
[5] CTR CARDIOVASC, ALAST, BELGIUM
[6] F HOFFMANN LA ROCHE & CO LTD, DIV PHARMA, CH-4002 BASEL, SWITZERLAND
关键词
angiotensin; hypertension; enzymes; endothelin; vasodilation;
D O I
10.1161/01.CIR.96.4.1250
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 clogs 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 I 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.
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页码:1250 / 1256
页数:7
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