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 (0.3 mg x kg(-1), inhaled over 20 min; ET(A)-A group; n=10), inhaled NO (30 p.p.m. continuously; iNO group; n=10) or nebulized saline buffer (5 ml inhaled over 20 min; control group; n=10). Measurements of pulmonary gas exchange and haemodynamics were performed hourly over a 4 h period after induction of ALI. In the ET(A)-A group, the arterial oxygen tension (Pa(2)) increased from 58+/-3 to 377+/-39 mmHg at 4 h 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, Pa(2) increased from 62+/-4 to 224+/-48 mmHg, and Q(S)/Q(T) decreased from 47+/-2% to 27+/-5%, at 4 h 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 4 h; P<0.01 compared 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.
Deja
Maria
M
Klinik für Anaesthesiologie und Operative Intensivmedizin Charité, Campus Virchow-Klinikum, Medizinische Fakultät der Humboldt-Universitaet, Augustenburger Platz 1, D-13353 Berlin, Germany.
Wolf
Steffen
S
Busch
Thilo
T
Petersen
Bodil
B
Jaghzies
Ursel
U
Boemke
Willehad
W
Kaisers
Udo
U
D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000187:drug effects; D023421:Models, Animal; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use; D010666:Phenylpropionates / Q000008:administration & dosage* / Q000627:therapeutic use; D011446:Prospective Studies; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011667:Pulmonary Veins; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D011897:Random Allocation; D044022:Receptor, Endothelin A; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D018709:Statistics, Nonparametric; D013552:Swine; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000627:therapeutic use
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D014665:Vasodilator Agents; D009569:Nitric Oxide; C107831:darusentan