Effects of hypoxia on endothelium-dependent relaxation of rat pulmonary artery

Abstract

We have previously reported that the isolated rat branch pulmonary artery (PA) contracts when made hypoxic and that the contraction is dependent in large part on the presence of a functioning endothelium. This study tested if the hypoxic contraction was caused by reduced endothelium-derived relaxing factor (EDRF) activity. To do so we tested if chemical inhibitors of EDRF mimicked the effect of hypoxia, if PA guanosine 3',5'-cyclic monophosphate (cGMP) fell during hypoxic contraction, and if stimulation of smooth muscle cGMP attenuated hypoxic contraction. We found that the EDRF inhibitors hemoglobin and methylene blue caused a concentration-dependent increase in PA force that equaled that produced by hypoxia. PA cGMP decreased in endothelium-intact rings from 105 +/- 14 pM/g (wet wt) during normoxia to 41 +/- 9 pM/g during hypoxia. In endothelium-denuded rings normoxic cGMP was reduced to 32 +/- 10 pM/g with no further decrease during hypoxia. The endothelium-independent stimulators of cGMP, nitric oxide, and 8-bromo-cGMP, reduced maximum hypoxic contraction by 80 +/- 11 and 93 +/- 3%, respectively, whereas the endothelium-dependent stimulator acetylcholine did not. PA adenosine 3',5'-cyclic monophosphate (cAMP) fell only slightly during hypoxia and cAMP inhibitors failed to mimic the hypoxic contraction. We conclude that the hypoxic contraction of isolated rat PA is caused largely by decreased EDRF activity.