VASORELAXATION BY PINACIDIL IN ISOLATED-PERFUSED LUNGS IS ENHANCED INRATS WITH HYPOXIC PULMONARY-HYPERTENSION BUT IS DEPENDENT ON THE CONSTRICTOR

The potassium channel opening drug, pinacidil, has been examined in is olated perfused lungs taken from rats with hypoxic pulmonary hypertens ion (housed in 10% oxygen for 7 days) and control rats. Inhibition by pinacidil (1 to 30 mu M) of noradrenaline (NA)-induced vasoconstrictio n (NA infusions; beta-adrenoceptors blocked) and of hypoxic pulmonary vasoconstriction (HPV; ventilation of 3.5-4.5 min with 0-1% oxygen) we re compared. The vasoconstrictor responses in preparations from contro l and hypoxic rats, respectively, were (mm Hg) NA 6.6+/-0.68 (6); 8.2/-1.45 (9); HPV 7.8+/-1.03 (12); 8.8+/-0.93 (13). These responses were reversibly inhibited by pinacidil. In lungs from control rats pinacid il was 10-fold less potent against NA than against HPV, but in lungs f rom hypoxic rats it was equipotent against NA and HPV. When tested aga inst NA, but not HPV, pinacidil was significantly more potent in lungs from hypoxic rats than control rats. It is postulated that NA-induced vasoconstriction in lungs from hypoxic rats, and HPV in both groups o f rats, involve calcium influx through voltage-operated calcium channe ls. Consequently, these responses are readily inhibited by drugs such as pinacidil which open potassium channels and hyperpolarise the cell membrane. In contrast in lungs from control rats, NA-induced constrict ion may involve mainly intracellular calcium release and thus be less readily inhibited by the hyperpolarising effect of pinacidil.