Effect of SB 217242 on Hypoxia-Induced Cardiopulmonary Changes in the High Altitude-Sensitive Rat

Abstract

The effects of SB 217242, a non-peptide endothelin (ET) receptor antagonist, were investigated against hypoxia-induced cardiopulmonary changes in high altitude-sensitive rats. In isolated pulmonary artery rings, SB 217242 (30 nm) antagonized ET-1-induced contractions with apKBof 8.0. There was no difference in the sensitivity to ET-1 or the potency of SB 217242 in pulmonary artery from normoxic rats vs. rats exposed to hypoxia (9% O2) for 14 days. However, there was a marked reduction in the maximum response to ET-1, but not to KCl or phenylephrine, in pulmonary artery from hypoxic rats; this phenomenon was inhibited by treatment of animals with SB 217242 (10.8 mg/day, ip by osmotic pump) for the 14-day hypoxic period. Furthermore, there was a significant reduction in carbachol-induced, endothelium-dependent relaxation of precontracted pulmonary artery from hypoxic animals; SB 217242 treatment during the hypoxic period did not influence this difference. Vehicle-treated rats exposed to 14-day hypoxia had 173% higher pulmonary artery pressures and 75% higher right/left+septum ventricular mass ratios compared to normoxic animals. SB 217242 (3.6 or 10.8 mg/day, ip) markedly reduced (80 and 95%, respectively) hypoxia-induced increases in pulmonary artery pressure. Right ventricular hypertrophy was inhibited by 40% at the 10.8 mg/day dose. Marked medial thickening and luminal stenosis of small and medium-sized pulmonary arteries was observed in hypoxic rats. The SB 217242-treated, hypoxia-exposed rats had comparable small and medium-sized arteries to normoxic rats. Rats treated with SB 217242 (10.8 mg/day) for the last 14 days of a 28-day hypoxic exposure had significantly lower pulmonary artery pressures than those of vehicle-treated rats. In addition, the effects of the selective ETAreceptor antagonist, SB 247083, and the selective ETBreceptor antagonist, A-192621 (3.6 or 10.8 mg/day, ip), were compared against hypoxia-induced increases in pulmonary artery pressure and plasma ET concentrations. SB 247083, but not A-192621, inhibited hypoxia-induced pulmonary hypertension, whereas A-192621, but not SB 247083, significantly exacerbated hypoxia-induced increases in ET concentrations, suggesting that hypoxia-induced pulmonary pressor responses are mediated via ETAreceptor activation, while ETBreceptor blockade may alter clearance of hypoxia-induced elevated plasma ET. The inhibitory effects of SB 217242 on the functional and remodeling changes induced by hypoxia provide further evidence that ET may play a central role in pulmonary hypertension and that ET receptor antagonists may have a utility in the treatment of this disease.