INFLUENCE OF OXYGEN ON ENDOTHELIUM-DERIVED RELAXING FACTOR NITRIC-OXIDE AND K+-DEPENDENT REGULATION OF VASCULAR TONE

We investigated the effect of hypoxia on acetylcholine (ACh) stimulated, endothelium-derived relaxing factor/nitric oxide (EDRF/NO)-dependent relaxation, and on basal tension in rat aortic rings. ACh (10(-9)-10(-6)M)-mediated relaxation at high [95%, E(max) - 76.2 +/- 4.5% of phenylephrine (PE)-induced constriction] and normal (20%, E(max) -81.2 +/- 3.6%) O-2 levels was inhibited by hypoxia (5%, E(max) -36.2 +/- 7.2%); residual hypoxic relaxation was blocked by the K+ channel antagonist glibenclamide. To address whether O-2 influenced EDRF/NO and K+ channel contributions to basal tone, the effect of stepwise reduction of available O-2 (95, 20, 5, and 0%) was studied in intact and endothelial cell (EC)-denuded rings. The effects in these rings were compared with results of the same progressive reduction in O-2 in the presence of the NO-synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) (10(-4)M) or glibenclamide (10(-4)M). EC-intact and EC-denuded rings constricted to 0.80 +/- 0.10 and 1.41 +/- 0.15 g, respectively. Reducing O-2 to 20% had no significant effect on vascular tension, but 5% caused constriction (p < 0.05) in EC-intact rings (0.90 +/- 0.15 g). This hypoxic vasoconstriction was blocked by L-NAME, but not by glibenclamide, suggesting that hypoxic vasoconstriction was mediated by withdrawal of EDRF/NO. In contrast, EC-denuded rings showed a significant relaxant response at 5% O-2. When O-2 was then reduced further (95% N-2/5% CO2), both EC-intact and EC-denuded rings relaxed, and this relaxation reached baseline tension (0.10 +/- 0.1 g). Relaxation was not blocked by L-NAME, but was partially prevented by glibenclamide (final tension 0.8 +/- 0.2 g). Thus, EDRF/NO-dependent effects appeared significant at or above normoxia. Under hypoxic conditions, however, relaxation was mediated by other mechanisms, including ATP-dependent K+-channel activity.