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 n m) antagonized ET-1-induced contractions with a p KB of 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 ETA receptor antagonist,
SB 247083, and the selective ETB receptor 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 ETA receptor activation, while ETB receptor 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.