Nonpeptide endothelin receptor antagonists. VIII: attentuation of acute hypoxia-induced pulmonary hypertension in the dog

• Published in: The Journal of pharmacology and experimental therapeutics 1997-02, Vol.280 (2), p.695-701
• Main Authors: Willette, R N, Ohlstein, E H, Mitchell, M P, Sauermelch, C F, Beck, G R, Luttmann, M A, Hay, D W
• Format: Article
• Language: English
• Subjects: Animals; Blood Pressure; Dogs; Endothelin Receptor Antagonists; Endothelin-1 - pharmacology; Endothelin-1 - physiology; Heart Rate; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - physiopathology; Hypoxia; In Vitro Techniques; Indans - pharmacology; Male; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Muscle, Smooth, Vascular - physiopathology; Phenylephrine - pharmacology; Pulmonary Artery - drug effects; Pulmonary Artery - physiology; Pulmonary Artery - physiopathology; Vasoconstrictor Agents - pharmacology; Viper Venoms - pharmacology
• ISSN: 0022-3565

It has been proposed that endothelin-1 (ET-1), a potent endogenous vasoactive peptide, may play an important role in the regulation of pulmonary 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 antagonist, SB 209670, in isolated segments of the canine pulmonary artery and to examine the effects of SB 209670 in a canine model of acute hypoxia-induced pulmonary hypertension. In isolated segments of the pulmonary artery, SB 209670 (3-300 nM) produced a concentration-dependent antagonism of contraction elicited by ET-1 (pA2 = 8.9; slope = 0.9) and had no effect on phenylephrine responses. In addition, SB 209670 antagonized the small, endothelium-dependent relaxation induced by sarafotoxin 6c in phenylephrine (10 microM)-precontracted vessels (pKB = 8.6). In anesthetized dogs, the driving pressure across the pulmonary circulation increased approximately 100% during the hypoxic period (area under the curve [AUC] = 267.1 +/- 25.3 mm Hg x min). SB 209670 treatment (3 and 30 microg/kg/min i.v.) reduced pulmonary vascular resistance and produced a profound dose-related inhibition of hypoxia-induced pulmonary hypertension (AUC = 158.3 +/- 22.7 mm Hg x min and 50.1 +/- 4.9 mm Hg x min, respectively). None of the other hemodynamic or arterial blood gas parameters differed significantly in the vehicle and treatment groups. In addition, SB 209670 produced a significant reversal of hypoxia-induced pulmonary hypertension (AUC = 267.1 +/- 25.3 mm Hg x min vs. 167.8 +/- 23.4 mm Hg x min) when administered at the plateau of the hypoxic response. It was found that SB 209670 administration significantly elevated plasma levels of ET-1-LI (> or = 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 the pulmonary circulation, may represent an important therapeutic approach to the treatment of pulmonary hypertension.