Differentiated and dose-related cardiovascular effects of a dual endothelin receptor antagonist in endotoxin shock

Objective. To evaluate the effects of endothelin receptor antagonism on cardiac performance in endotoxin shock. Design: Prospective, experimental study. Setting. A university-affiliated research institution. Subjects. Domestic anesthetized landrace pigs. Interventions. Thirty-seven pigs were anesthetized and subjected to echocardiography, coronary sinus catheterization, and monitoring of central and regional hemodynamics in order to assess cardiac performance. All animals received endotoxin for 5 hrs. Twenty pigs served as endotoxin controls. Tezosentan, a dual endothelin-A and -B receptor antagonist, was administered during established endotoxemic shock. Seven pigs received an infusion of tezosentan of I mg(.)kg(-1.)hr(-1) (tezo(1)), and an additional ten pigs received a higher dose of 10 mg(.)kg(-1.)hr(-1) (tezo(10)). Measurements and Main Results. Endotoxemia evoked a state of shock with pulmonary hypertension and metabolic acidosis. A decrease in stroke volume and coronary perfusion pressure as well as an increase in troponin I was also noted. Tezosentan administration resulted in a significant increase in cardiac index, stroke volume index, left ventricular stroke work index, and left ventricular end-diastolic area index. Decreases in systemic and pulmonary vascular resistance indexes were also evident after intervention. This was achieved without changes in heart rate or systemic arterial or pulmonary artery occlusion pressures in tezo(1) animals compared with controls. In addition, metabolic variables were improved by tezosentan. These effects were sustained only in the tezo(1) group. In the higher dosage, tezosentan resulted in a deterioration of cardiac performance and 50% mortality rate. The endotoxin-induced increase in troponin I was attenuated in the tezo(1) group compared with controls. Conclusions: In this porcine model of volume-resuscitated, endotoxemic shock, endothelin-receptor blockade with tezosentan improved cardiac performance. However, the effect was not sustained with higher doses of tezosentan, possibly due to reduced coronary perfusion pressure. These findings show differentiated, dose-dependent effects by dual endothelin receptor blockade on endotoxin-induced cardiovascular dysfunction.