ANGIOTENSIN-II AND ENDOTHELIN-1 RECEPTOR ANTAGONISTS HAVE CUMULATIVE HYPOTENSIVE EFFECTS IN CANINE PAGE HYPERTENSION

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 hypertensi on). Methods Ten conscious dogs, studied on two occasions, were admini stered losartan (a 0.1 mg/kg bolus plus 90 min infusion at 0.1 mg/kg p er 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 infusi on 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 occurr ed in experiment II (from 145 +/- 8.9 to 104 +/- 5.0 mmHg, P< 0.005), corresponding to an additional 14% decrease after administration of bo sentan (P< 0.005 between groups). This cumulative effect of bosentan w as related to a decrease in systemic vascular resistance (from 1220 +/ - 119 to 847 +/- 189 mmHg/ml per min per kg . 10(3), P< 0.05), Plasma angiotensin II level increased similarly in both experiments (in exper iment 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 end othelin-1 level increased only in experiment II (from 3.8 +/- 0.4 to 3 2.7 +/- 3.2 pg/ml, P< 0.001). Conclusion The cumulative hypotensive ef fect of bosentan suggests that, besides angiotensin II, endothelin-1 i s independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives. (C) 1998 Lippincott-Raven Publ ishers.