Vol. 283, Issue 3, 1130-1137, 1997

Nonpeptide Endothelin Receptor Antagonists. X. Inhibition of Endothelin-1- and Hypoxia-Induced Pulmonary Pressor Responses in the Guinea Pig by the Endothelin Receptor Antagonist, SB 217242

David C. Underwood, Steve Bochnowicz, Ruth R. Osborn, Mark A. Luttmann and Douglas W. P. Hay

Department of Pulmonary Pharmacology, UW2532, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania

This study investigated the effects of the nonpeptide endothelin (ET) receptor antagonist, SB 217242, against ET-1-induced pulmonary pressor responses and in a model of hypoxia-induced pulmonary hypertension in the guinea pig. In guinea pig isolated pulmonary artery rings, SB 217242 (3-300 nM) produced a concentration-dependent inhibition of ET-1-induced contractions, with a pA₂ of 8.1. SB 217242 (1 or 3 mg/kg i.v.) elicited a dose-related inhibition of ET-1-induced increases in pulmonary artery and airway insufflation pressure responses in anesthetized guinea pigs. Chronic exposure to hypoxia (9% O₂ for 0-14 days) produced a time-dependent increase in mean pulmonary artery pressure. After a 10-day exposure to hypoxia there was about a 100% elevation in pulmonary artery pressure, and right ventricular mass and plasma irET levels increased 3-fold compared with normoxic animals. SB 217242, administered by continuous intraperitoneal infusion via mini osmotic pump (0.36, 3.6 or 10.8 mg/day), significantly reduced (by about 50%) hypoxia-induced pulmonary artery pressure increases at all three doses used. The hypoxia-induced right ventricular hypertrophy was significantly attenuated by the 3.6 and 10.8 mg/day doses. Based on hematocrit, hemoglobin and red blood cell counts, SB 217242 did not affect the normal physiological erythropoietic response to hypoxia. There were no appreciable differences in the maximum contractile effects of ET-1 or the potency of SB 217242 (pK_B values, 8.3 and 8.0, respectively) versus ET-1-induced responses in isolated pulmonary arteries from hypoxic versus normoxic guinea pigs. However, there was a marked reduction in endothelium-dependent relaxation of precontracted pulmonary artery isolated from hypoxic compared with normoxic animals. The results of the present study provide further preclinical evidence for a pathophysiological role of ET-1 and the potential therapeutic utility of ET receptor antagonists, such as SB 217242, in pulmonary hypertension.