RESUMO
OBJECTIVE: To evaluate whether the cumulative hypotensive effect of the endothelin-1 receptor antagonist bosentan, previously demonstrated in the presence of an angiotensin converting enzyme inhibitor, persists under angiotensin II receptor blockade with losartan. DESIGN: The model of hypertension was canine renovascular hypertension (Page hypertension). METHODS: Ten conscious dogs, studied on two occasions, were administered losartan (a 0.1 mg/kg bolus plus 90 min infusion at 0.1 mg/kg per min) and then bosentan vehicle (experiment I) or losartan and then two cumulative doses of bosentan (a 0.3 mg/kg bolus plus 30 min infusion at 0.7 mg/kg per min; and a 3 mg/kg bolus plus 30 min infusion at 7 mg/kg per min; experiment II). RESULTS: At the end of the study, mean aortic pressure in dogs had decreased by 14% in experiment I (from 139 +/- 4.7 to 119 +/- 4.7 mmHg, P<0.05), whereas a 28% reduction occurred in experiment II (from 145 +/- 8.9 to 104 +/- 5.0 mmHg, P<0.005), corresponding to an additional 14% decrease after administration of bosentan (P<0.005 between groups). This cumulative effect of bosentan was related to a decrease in systemic vascular resistance (from 1220 +/- 119 to 847 +/- 189 mmHg/ml per min per kg x 10(3), P<0.05). Plasma angiotensin II level increased similarly in both experiments (in experiment I from 133 +/- 43 to 622 +/- 145 pg/ml, P=0.01; in experiment II from 198 +/- 63 to 771 +/- 134 pg/ml, P<0.005) whereas plasma endothelin-1 level increased only in experiment II (from 3.8 +/- 0.4 to 32.7 +/- 3.2 pg/ml, P<0.001). CONCLUSION: The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.
