IN-VITRO HYPOXIA ATTENUATES VASORELAXATION BY POTASSIUM CHANNEL OPENING DRUGS AND NITROPRUSSIDE IN ISOLATED PULMONARY-ARTERIES FROM RATS

The effects of in vitro hypoxia on relaxant responses to various vasod ilator drugs were examined on norepinephrine-contracted ring preparati ons of rat pulmonary artery. The physiological salt solution that bath ed the tissues was equilibrated with gas mixtures that contained 95%, 12%, 6%, 4% or 0% oxygen (oxygen tension of solution, > 650, 94, 44, 3 5 or less than or equal to 11 mm Hg, respectively). Severe in vitro hy poxia (oxygen tension, 4 mm Hg) attenuated responses to pinacidil (neg ative log EC,, values: control, 5.61; hypoxia, 4.92). This effect of h ypoxia was not prevented by endothelium removal or by indomethacin. Le ss severe hypoxia (oxygen tension less than or equal to 35 mm Hg) atte nuated responses to nitroprusside (negative log EC,,: control, 8.34; h ypoxia, 7.76). This effect of hypoxia was prevented by endothelium rem oval but not by indomethacin, N-G-nitro-L-arginine methyl ester or the endothelin antagonist, cyclo(D-Trp-D-Asp-Pro-D-Val-Leu), and was not mimicked by endothelin. These effects of in vitro hypoxia were rapidly reversible and were distinct from the previously reported effects of chronic in vivo hypoxia on responses of pulmonary arteries to these dr ugs. It was also found that severe in vitro hypoxia abolished response s to acetylcholine and cromakalim and potentiated responses to sodium nitrite (negative log EC(50): control, 3.79; hypoxia, 4.97) but had no effect on responses to colforsin (also known as forskolin). It was sp eculated that 1) the hypoxia-induced attenuation of responses to the p otassium channel opening drugs, pinacidil and cromakalim, may be the r esult of the hypoxia depleting intracellular ATP and hyperpolarizing t he smooth muscle cell membrane, thereby precluding drug-induced hyperp olarization, and 2) the attenuation of responses to nitroprusside by h ypoxia may be due to impairment of nitric oxide formation from nitropr usside.