Functional effects of 4-aminopyridine (4-AP) on pulmonary and systemic vessels from normoxic control and hypoxic pulmonary hypertensive rats

The effects of the outward rectifying potassium channel blocker, 4-aminopyridine, on contractile tone and on contractile responses to the spasmogens, 5-hydroxy-tryptamine and endothelin-l, were examined in pulmonary arteries (main and intralobar) and systemic vessels (aorta and mesenteric artery) from rats with and without hypoxic pulmonary hypertension. Hypoxic pulmonary hypertension was induced by exposure of rats to 10% oxygen for 1 week. The development of pulmonary hypertension was associated with (i) depolarization of the cell membrane in intralobar pulmonary artery, but not aorta, and (ii) an increase in sensitivity to 5-hydroxytryptamine in pulmonary, but not systemic, vessels; sensitivity to endothelin-l was unchanged. 4-Aminopyridine contracted all of the vessels studied. In pulmonary hypertension the sensitivity to 4-aminopyridine was increased ten-fold in pulmonary vessels but was unchanged in systemic vessels. Threshold concentrations of 4-aminopyridine (less than or equal to 3 x 10(-3) M) augmented contractions to 5-hydroxytryptamine in main pulmonary artery and aorta from control rats but failed to augment contractions to 5-hydroxytryptamine in main pulmonary artery from pulmonary hypertensive rats. Responses to endothelin-l were not augmented by 4-aminopyridine. The membrane depolarization and the increases in sensitivity to 4-aminopyridine and 5-hydroxytryptamine seen in pulmonary hypertension are compatible with the concept that potassium channel function is altered in pulmonary, but not systemic, vessels from pulmonary hypertensive rats. Our data suggest that in main pulmonary artery a common mechanism is responsible for (i) the augmentation of 5-hydroxytryptamine responses by 4-aminopyridine in control rats, and (ii) the sensitization to 5-hydroxytryptamine seen in pulmonary hypertensive, compared with control, rats in the absence of 4-aminopyridine. Hence, we conclude that the sensitization to 5-hydroxytryptamine may be due to downregulation of 4-aminopyridine-sensitive potassium channels.