Mechanism of hypoxic pulmonary vasoconstriction involves ETA receptor-mediated inhibition of K-ATP channel

There is controversy on the role of endothelin (ET)-1 in the mechanism of h ypoxic pulmonary vasoconstriction (HPV). Although HPV is inhibited by ET-1 subtype A (ETA)-receptor antagonists in animals, it has been reported that ETA-receptor blockade does not; affect HPV in isolated lungs. Thus we reass essed the role of ET-1 in HPV in both rats and isolated blood- and physiolo gical salt solution (PSS)-perfused rat lungs. In rats, the ETA-receptor ant agonist BQ-123 and the nonselective ETA- and ETB-receptor antagonist PD-145 065, but not the ETB-receptor antagonist BQ-788, inhibited HPV. Similarly, BQ-123, but not BQ-788, attenuated HPV in blood-perfused lungs. In PSS-perf used lungs, either BQ-123, BQ-788, or the combination of both attenuated HP V equally. Inhibition of HPV by combined BQ-123 and BQ-788 in PSS-perfused lungs was prevented by costimulation with angiotensin II. The ATP-sensitive K+ (K-ATP)-channel blocker glibenclamide also prevented inhibition of HPV by BQ-123 in both lungs and rats. These results suggest that ET-1 contribut es to HPV in both isolated lungs and intact animals through ETA receptor-me diated suppression of K-ATP-channel activity.