Myocardial depression in sepsis is frequently encountered clinically and contributes to morbidity and mortality. Increased plasma levels of endothelin-1 (ET-1) have been described in septic shock and previous reports have shown beneficial effects on cardiovascular performance and survival in septic models using ET receptor antagonists. The aim of the current study was to investigate specific cardiac effects of ET receptor antagonism in endotoxicosis. 16 domestic pigs were anesthetized and subjected to endotoxin for five hours. Eight of these pigs were given tezosentan (dual ET receptor antagonist) after three hours. Cardiac effects were evaluated using the left ventricular (LV) pressure-volume relationship. Endotoxin was not associated with any effects on parameters of LV contractile function (end-systolic elastance (Ees), preload recruitable stroke work (PRSW), powermax/end-diastolic volume (PWR_max/EDV) and dP/dT_max/ end-diastolic volume (dP/dT_max/EDV)) but with impairments in isovolumic relaxation (time constant for pressure decay, tau) and mechanical efficiency. Tezosentan administration decreased Ees, PWRmax/EDV and dPdTmax/EDV while improving tau and LV stiffness. Thus, dual ET receptor antagonism was associated with a decline in contractile function but, in contrast, improved diastolic function. Positive hemodynamic effects from ET receptor antagonism in acute endotoxemia may be due to changes in cardiac load and enhanced diastolic function rather than improved contractile function.