ENDOTHELIN-3 IS A POTENT PULMONARY VASODILATOR IN THE RAT

The properties of endothelin-3 (ET-3) were investigated in isolated pulmonary artery rings and isolated blood-perfused lungs of the rat. ET-3 elicited a concentration-dependent relaxation of pulmonary artery rings, an effect inhibited by the nitric oxide synthesis inhibitor L-N(G)-monomethyl-L-arginine. At 0.1-mu-M, the response to ET-3 was biphasic, resulting in a sustained contraction. In the isolated lung, ET-3 caused a dose-dependent increase in pulmonary arterial pressure. In lungs ventilated with 3% oxygen, 10 nM ET-3 completely reversed the resultant hypoxic vasconstriction (HPV) by 100 +/- 8%, an effect unchanged by either indomethacin (1-mu-M) or glibenclamide (10-mu-M). L-N(G)-monomethyl-L-arginine attenuated both the ET-3 dilation in prostaglandin F2-alpha-constricted lungs and the dose-dependent vasodilation of HPV by acetylcholine. ET-3 (10 nM) slowed the response time to peak pulmonary arterial pressure generation by hypoxia, the size of the response being unchanged. These results demonstrate that ET-3 has both vasodilator and constrictor actions in the rat lung and that, like acetylcholine, the former is mediated in part via the release of nitric oxide. ET-3 also has the ability to modulate HPV.