Acute Cardiopulmonary Effects of a Dual–endothelin Receptor Antagonist on Oleic Acid–induced Pulmonary Arterial Hypertension in Dogs

The objective of this study was to evaluate the cardiopulmonary effects of a dual-endothelin (ET) receptor antagonist, Tezosentan, on oleic acid (OA)-induced acute lung injury with pulmonary arterial hypertension in dogs. Twelve pentobarbital-anesthetized dogs with intravenous OA-induced acute lung injury (ALI) were divided into 2 groups. The control group (n=6) received saline treatment, whereas the treatment group (n=6) received the ET receptor antagonist, Tezosentan (1 mg/kg intravenous [i.v.]+1 mg/kg/h i.v. infusion). Cardiopulmonary parameters were monitored continuously for 1 hour. OA administration resulted in a significant increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) and a decrease in mean systemic arterial pressure (MSAP), systemic vascular resistance (SVR), and cardiac output (CO) in all dogs. Tezosentan treatment markedly attenuated the pulmonary hypertension, with a 32% decrease in MPAP (from 23 +/- 2 mm Hg to 15 +/- 2 mm Hg; P<.01) and a 22% decrease in PVR (from 860 +/- 105 dyn.s.cm(-5) to 670 +/- 96 dyn.s.cm(-5); P<.01) at the end of study. MSAP and SVR were unchanged after Tezosentan treatment, and there was an increase in cardiac output and a decline in peak inspiratory pressure (PIP) in the Tezosentan group compared with the control group. These results indicate that the dual-ET receptor antagonist, Tezosentan, can attenuate the pulmonary hypertension induced by OA. Thus, dual-ET receptor antagonists such as Tezosentan may be useful in the management of acute pulmonary arterial hypertension, complicating the course of OA-induced lung injury.