Endothelin causes portal and pulmonary hypertension in porcine endotoxemic shock.

A porcine model of endotoxemic shock was used to test the hypothesis that endothelins (ET) mediate the sustained increases in portal and pulmonary vascular resistances. Anesthetized pigs (n = 18) were instrumented and pretreated with 1) saline as a control; 2) indomethacin (Idm), a cyclooxygenase (Cox) inhibitor; or 3) Idm + bosentan (Bos), a mixed ET-receptor antagonist, and then were treated with endotoxin to produce shock and followed for 240 min. Global and regional hemodynamic parameters and plasma levels of ET-1 and thromboxane B2 were measured. The results show that 1) ET is independently responsible for the sustained increase in pulmonary vascular resistance; 2) ET and Cox products combine to increase portal venous resistance; 3) ET independently reduces cardiac output and attenuates or negates global systemic arterial vasodilation (presumptively mediated by nitric oxide) and exhibits regional differences, having little if any influence on the gut arterial bed. When considered with our prior study of nitric oxide regulation of the same beds in endotoxemic shock (N. Brienza, T. Ayuse, J. P. Revelly, C. P. O'Donnell, and J. L. Robotham, J. Appl. Physiol. 78: 784-792, 1995), the similarities between the portal venous and pulmonary arterial beds suggest that these two beds reflect phenomena occurring in microvascular and/or venous beds in multiple organs. The overall results suggest that a dynamic balance exists between NO and ET regulating arterial and microvascular and/or venous vasomotor activity during the evolution of endotoxemic shock.