ENDOTHELIN CAUSES PORTAL AND PULMONARY-HYPERTENSION IN PORCINE ENDOTOXEMIC SHOCK

A porcine model of endotoxemic shock was used to test the hypothesis t hat endothelins (ET) mediate the sustained increases in portal and pul monary vascular resistances. Anesthetized pigs (n = 18) were instrumen ted and pretreated with I)saline as a control; 2)indomethacin (Idm), a cyclooxygenase (Cox) inhibitor; or 3) Idm + bosentan (Bos), a mixed E T-receptor antagonist, and then were treated with endotoxin to produce shock and followed for 240 min. Global and regional hemodynamic param eters and plasma levels of ET-1 and thromboxane Bz were measured. The results show that 1) ET is independently responsible for the sustained increase in pulmonary vascular resistance; 2) ET and Cox products com bine to increase portal venous resistance; 3)ET independently reduces cardiac output and attenuates or negates global systemic arterial vaso dilation (presumptively mediated by nitric oxide) and exhibits regiona l differences, having little if any influence on the gut arterial bed. When considered with our prior study of nitric oxide regulation of th e 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, 19 95), the similarities between the portal venous and pulmonary arterial beds suggest that these two beds reflect phenomena occurring in micro vascular and/or venous beds in multiple organs. The overall results su ggest that a dynamic balance exists between NO and ET regulating arter ial and microvascular and/or venous vasomotor activity during the evol ution of endotoxemic shock.