The ETAAntagonist CI-1020 Inhibits Hypoxic Pulmonary Vasoconstriction in Small Isolated Rat Pulmonary Arteries

Abstract

Hypoxic pulmonary vasoconstriction (HPV) of rat pulmonary arteries in vitro occurs in four phases. Initial vasodilation (phase 1), is followed by transient contraction (phase 2), further vasodilation (phase 3) and finally a second sustained contraction (phase 4). We have investigated the role of ET-1 in HPV using the ETAreceptor antagonist CI-1020. Small rat pulmonary arteries (SPA, n=32, diameter=454±22 μM) were mounted in a wire myograph. Two contractions to 80 μMKCl ensured response reproducibility and relaxation to 10 μM acetyl choline following constriction with 100 μMprostaglandin F2α(PGF2α) to indicate endothelial integrity. A control hypoxic response was produced following priming with 5 μMPGF2α. Vessels (n=8) were then exposed to either vehicle or CI-1020 (1, 10 or 100 μM) for 30 min in the dark before re-exposure to PGF2αand hypoxia. Responses were standardized as a percentage of contraction to 80 mM KCl. Vehicle caused an increase in phase 2 of HPV of +2.51±4.20% (expressed as difference between pre- and post-drug values). CI-1020 (1, 10 and 100 μM) caused a significant reduction in phase 2 of HPV of −9.76±1.40%, −9.23±2.30% and −7.96±1.70%, respectively (P<0.05). These results suggest that phase 2 of HPV in rat SPA is attributed, in part, to the action of ET-1 at the ETAreceptor.