The inhaled ET_A receptor antagonist LU-135252 acts as a selective pulmonary vasodilator

To investigate the hypothesis that the inhaled ET_A receptor antagonist LU-135252 acts as selective pulmonary vasodilator, we compared inhaled LU-135252 and inhaled nitric oxide (iNO) in an experimental model of acute lung injury (ALI), in a prospective, randomized, controlled animal study. A total of 30 anaesthetized, tracheotomized and mechanically ventilated pigs underwent induction of ALI by repeated saline washout of surfactant. The animals were then randomly assigned to receive the nebulized ET_A receptor antagonist LU-135252 (0.3mg·kg^-1, inhaled over 20min; ET_A-A group; n = 10), inhaled NO (30p.p.m. continuously; iNO group; n = 10) or nebulized saline buffer (5ml inhaled over 20min; control group; n = 10). Measurements of pulmonary gas exchange and haemodynamics were performed hourly over a 4h period after induction of ALI. In the ET_A-A group, the arterial oxygen tension (Pao₂) increased from 58±3 to 377±39mmHg at 4h after intervention, while the intrapulmonary shunt (Q_S/Q_T) decreased from 53±4% to 18±2% (P<0.01 compared with controls). In the iNO group, PaO₂ increased from 62±4 to 224±48mmHg, and Q_S/Q_T decreased from 47±2% to 27±5%, at 4h after induction of ALI (P<0.05 compared with controls). In the ET_A-A and iNO groups, the increase in mean pulmonary artery pressure was significantly attenuated compared with controls (ETA-A group, 14±4%; iNO group, 6±4%; values at 4h; P<0.01compared with controls). In contrast, there were no significant differences in changes of mean arterial pressure and cardiac output between groups. Thus, in this experimental model of ALI, both inhaled LU-135252 and iNO significantly improved gas exchange and prevented an increase in mean pulmonary artery pressure, without significant systemic effects, when compared with controls. Our results indicate the occurrence of selective pulmonary vasodilation in both treatment groups.