NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS .8. ATTENUATION OF ACUTE HYPOXIA-INDUCED PULMONARY-HYPERTENSION IN THE DOG

It has been proposed that endothelin-1 (ET-1), a potent endogenous vas oactive peptide, may play an important role in the regulation of pulmo nary blood flow. The purpose of the present study was to characterize the effects of ET-1 and a nonpeptide mixed ET(A) and ET(B) receptor an tagonist, SE 209670, in isolated segments of the canine pulmonary arte ry and to examine the effects of SE 209670 in a canine model of acute hypoxia-induced pulmonary hypertension. In isolated segments of the pu lmonary artery, SE 209670 (3-300 nM) produced a concentration-dependen t antagonism of contraction elicited by ET-1 (pA(2) = 8.9; slope = 0.9 ) and had no effect on phenylephrine responses. In addition, SB 209670 antagonized the small, endothelium-dependent relaxation induced by sa rafotoxin 6c in phenylephrine (10 mu M)-precontracted vessels (pK(B) = 8.6). In anesthetized dogs, the driving pressure across the pulmonary circulation increased approximately 100% during the hypoxic period (a rea under the curve [AUC] = 267.1 +/- 25.3 mm Hg . min). SB 209670 tre atment (3 and 30 mu g/kg/min i.v.) reduced pulmonary vascular resistan ce and produced a profound dose-related inhibition of hypoxia-induced pulmonary hypertension (AUC = 158.3 +/- 22.7 mm Hg min and 50.1 +/- 4. 9 mm Hg . min, respectively). None of the other hemodynamic or arteria l blood gas parameters differed significantly in the vehicle and treat ment groups. In addition, SE 209670 produced a significant reversal of hypoxia-induced pulmonary hypertension (AUC = 267.1 +/- 25.3 mm Hg . min vs. 167.8 +/- 23.4 mm Hg . min) when administered at the plateau o f the hypoxic response. It was found that SB 209670 administration sig nificantly elevated plasma levels of ET-1-LI (greater than or equal to 25-fold). These results suggest that ET-1 is an important mediator of hypoxia-induced pulmonary hypertension in the dog and that SB 209670, a potent and selective mixed ET(A) and ET(B) receptor antagonist in t he pulmonary circulation, may represent an important therapeutic appro ach to the treatment of pulmonary hypertension.