Endothelium-dependent and -independent responses to severe hypoxia in rat pulmonary artery

The changes in pulmonary artery (PA) tone that develop during hypoxia are complex and appear to involve multiple vasoregulatory pathways. This study was designed to identify the phases of the response to severe hypoxia in isolated segments of rat PA and to evaluate the mechanisms involved. Exposure of preconstricted PA segments to severe hypoxia (i.e., PO2 < 3 Torr) resulted in transient relaxation followed by vigorous hypoxic vasoconstriction (HVC), which averaged 0.26 +/- 0.02 g (or 43.9 +/- 3.7% of the maximal force developed in response to phenylephrine). HVC was followed by sustained and nearly complete inhibition of existing tone. The first two phases of the response were endothelium dependent and could be blocked by nonspecific inhibitors of endothelium-derived relaxing factor (EDRF) activity and by 500 microM N omega-nitro-L-arginine, a specific inhibitor of nitric oxide (NO) formation. The transient early relaxation could also be inhibited by superoxide dismutase (50 U/ml). In contrast, the late relaxation phase was neither endothelium dependent nor could it be blocked by inhibitors of EDRF/NO activity. Rat PA segments were relaxed by pinacidil and lemakalim, both of which activate ATP-sensitive potassium channels. Preincubation with glibenclamide, a selective inhibitor of these channels, blocked this response and also reduced late hypoxic vasodilation by nearly 40% (P < 0.001). These findings demonstrate that the response of rat PA to hypoxia involves both endothelium-dependent and endothelium-independent components. The initial relaxation results from enhanced EDRF/NO activity, which is likely due to diminished breakdown by superoxide radicals.(ABSTRACT TRUNCATED AT 250 WORDS)