ADDITIONAL HYPOTENSIVE EFFECT OF ENDOTHELIN-1 RECEPTOR ANTAGONISM IN HYPERTENSIVE DOGS UNDER ANGIOTENSIN-CONVERTING ENZYME-INHIBITION

Background Endothelin-1 (ET-1) may play a role in hypertension. ET-1 r eceptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under AC E inhibitors (ACEI). Methods and Results Thirty anesthetized and 18 co nscious hypertensive clogs were studied randomly. Anesthetized dogs we re divided into 4 groups: group 1 received cumulative doses of bosenta n (bolus+30-minute infusion: 0.1 mg/kg+0.23 mg/kg per hour to 3 mg/kg7 mg/kg per hour); group 2, tile same dose-responses after 1 mg/kg ena laprilat; group 3, the vehicle after enalaprilat, and group 4, the dos e responses to bosentan followed by enalaprilat. The conscious dogs we re divided into 3 groups: group 5 received 2 cumulative doses of bosen tan group 6, the vehicle; and group 7, enalaprilat alone. In groups I and 2, bosentan produced dose-related decreases (P=.0001) in left vent ricular 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 addition al 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 2 2% decrease in mean AOP (P<.005). The additive effect of the bosentan- ACEI association was also observed in group 4. In group 5, bosentan re duced 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 bo sentan. Conclusions Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.