Role of endogenous endothelin in normal hemodynamic status of anesthetized dogs

Endothelin (ET) is a potent vasoconstrictor that may be involved in a number of cardiovascular disorders, although its role in normal hemodynamics remains unclear. Twenty-two anesthetized open-chest dogs were instrumented for measurement of systemic and pulmonary hemodynamics, cardiac output, coronary blood flow, and cardiac contractility. Big ET induced peripheral and coronary vasoconstriction, which occurred before significant elevations in plasma ET and which was nearly completely blocked by bosentan, a new nonpeptidic mixed (ETA and ETB) ET receptor antagonist. Bosentan also prevented the peripheral dilatation caused by the specific ETB receptor agonist, sarafotoxin S6c, but did not prevent the peripheral vasoconstriction induced by angiotensin II. Bosentan alone had no significant hemodynamic effect in the normal anesthetized dog, although it did induce a reactive increase in the plasma level of ET-1 and ET-3. This study demonstrates that, despite blocking both ETA and ETB receptors, bosentan alone had no hemodynamic effect, suggesting that ET does not play a major role in the normal hemodynamic status of anesthetized dogs.