PULMONARY VASODILATION TO ENDOTHELIN ISOPEPTIDES INVIVO IS MEDIATED BY POTASSIUM CHANNEL ACTIVATION

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of ET-1 (1-mu-g), ET-2 (1-mu-g), and ET-3 (3-mu-g) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg iv), indomethacin (2.5 mg/kg iv), and ICI 118551 (1 mg/kg iv) but was significantly diminished by glybenclamide (5 mg/kg ia). This dose of glybenclamide significantly diminished the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100-mu-g) and cromakalim (10 and 30-mu-g), whereas pulmonary vasodilator responses to acetylcholine (0.03 and 0.1-mu-g), prostagladin I2 (0.1 and 0.3-mu-g), and isoproterenol (0.03 and 0.1-mu-g) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data comprise the first publication demonstrating that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data further suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides does depend on the preexisting level of pulmonary vasomotor tone. The present data suggest that in the lung ET-1, ET-2, and ET-3 may serve as endogenous agonists for potassium channels, a newly described vasodilator mechanism in the pulmonary vascular bed of intact adult animals. Moreover, ET-1 may act as an endothelium-derived hyperpolarizing factor.