ACUTE CARDIOPULMONARY EFFECTS OF A DUAL–ENDOTHELIN RECEPTOR ANTAGONIST ON OLEIC ACID–INDUCED PULMONARY ARTERIAL HYPERTENSION IN DOGS

Abstract

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 [IV] + 1 mg/kg/h IV 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−5to 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.