Endothelin_breceptor agonists produce pulmonary vasodilation in intact newborn lambs with pulmonary hypertension

The hemodynamic effects of endothelin-1 (ET-1) are mediated by at least two distinct receptors: ET_aand ET_breceptors. Recently, ET_breceptor agonists (4 Ala ET-1 and IRL 1620) were developed. To investigate the role of ET_breceptor activation on the pulmonary and systemic circulations, we studied the hemodynamic effects of intrapulmonary arterial injections of these receptor agonists in 10 intact newborn lambs. At rest, 4 Ala ET-1 (290-1,725 ng/kg) changed no hemodynamic variables. IRL 1620 (180-1,095 ng/kg) decreased mean pulmonary arterial pressure (PAP, 16.8% ± 15.0 and 17.8% ± 8.5, p < 0.05) and left pulmonary artery blood flow (21.6% ± 22.1 and 33.4% ± 27.7, p < 0.05) at the two highest doses only. During U46619-induced pulmonary hypertension, both 4 Ala ET-1 (3.2% ± 8.0 to 15.9% ± 6.4, p < 0.05) and IRL 1620 (8.7% ± 6.3 to 21.9% ±4.1, p < 0.05) produced selective dose-dependent decreases in PAP. The decrease in mean PAP induced by 4 Ala ET-1 and IRL 1620 was attenuated by N^ω-nitro-L-arginine [an inhibitor of endothelium-derived nitric oxide (EDNO) synthesis] (16.6% ± 3.5 vs. 5.9% ± 2.3 and 16.2% ± 3.4 vs. 6.6% ± 2.8, p < 0.05) and by glybenclamide (a blocker of ATP-dependent potassium channels) (18.2% ± 7.9 vs. 7.5% ± 8.3 and 14.7% ± 3.6 vs. 6.3% ± 3.2, p < 0.05). ET_breceptor activation produces selective pulmonary vasodilation during pulmonary hypertension in intact newborn lambs. The vasodilating properties are mediated in part by release of EDNO and by potassium channel activation.