PHARMACOLOGICAL EVIDENCE FOR THE ROLE OF MEDIATORS IN HYPOXIA-INDUCED VASOCONSTRICTION IN SHEEP ISOLATED INTRAPULMONARY ARTERY RINGS

The aim of this study was to determine the likely mediator(s) involved in the hypoxic-induced contraction in sheep pulmonary artery rings in vitro by studying the effects of selective receptor antagonists and enzyme inhibitors. Hypoxia caused a contraction in arteries under resting force and when precontracted with 5-hydroxytryptamine (5-HT). Flurbiprofen, a cyclooxygenase inhibitor, reduced the hypoxic contraction in 5-HT-precontracted rings but augmented the first part of the hypoxic contraction under baseline force. Inhibition of nitric oxide by haemolysate increased the hypoxic contraction under resting force. Superoxide dismutase and N-t-butyl-alpha-phenylnitrone (PBN), free radical scavenging agents, and trypsin, a proteolytic enzyme, did not produce any significant effect on hypoxia-induced constriction. Propranolol plus phentolamine, beta- and alpha-adrenoceptor antagonists respectively, did not produce any effect on hypoxic contraction under resting force, whereas these antagonists augmented hypoxic contraction in the presence of 5-HT. This combination of antagonists also caused a reduction of 5-HT contraction which was the result of alpha-2-adrenoceptor blockade. Verapamil, a calcium channel blocking drug, significantly reduced the 5-HT contraction, but did not reduce that caused by hypoxia either under resting force or in precontracted rings. These results suggest that hypoxic constriction in sheep isolated intrapulmonary artery is in part caused by reduced release of vasodilator prostanoids. This contraction does not involve voltage-operated calcium channels and is limited by release of endothelium-derived nitric oxide.