Effect of SB 217242 on hypoxia-induced cardiopulmonary changes in the high altitude-sensitive rat.
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.
Underwood
D C
DC
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA. David_C_Underwood@sbphrd.com
Bochnowicz
S
S
Osborn
R R
RR
Luttmann
M A
MA
Louden
C S
CS
Hart
T K
TK
Elliott
J D
JD
Hay
D W
DW
D000531:Altitude; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism*; D007189:Indans / Q000494:pharmacology*; D008297:Male; D011422:Propionates / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017466:Receptors, Endothelin / Q000187:drug effects
C120508:A 192621; D001572:Benzofurans; D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; D011422:Propionates; D011759:Pyrrolidines; D017466:Receptors, Endothelin; C113045:SB 247083; C098288:enrasentan