Cardiopulmonary effects of endothelin-1 in the guinea pig: role of thromboxane A2.

The effects of endothelin-1 (ET-1) on the cardiovascular and bronchial systems were examined in a heart/lung preparation of guinea pig. The role of arachidonic acid metabolites through cyclo-oxygease (COX) and lipoxygenase (LOX) pathways was investigated. Bolus injection of ET-1 (25-400 ng) caused dose-related bronchoconstriction, pulmonary vascular hypertension, and cardiac output reduction. When indomethacin (30 microM) or the thromboxane receptor antagonist Bay u 3405 (1 microM) were added to the perfusing blood, the cardiopulmonary effects of ET-1 were almost completely abolished. Conversely, the presence of the LOX inhibitor Bay x 1005 (10 microM) did not affect the ET-1 produced actions. We concluded that ET-1 exerts both bronchial and pulmonary vascular effects through an indirect mechanism. COX products, most likely thromboxane A2 but not arachidonic acid metabolites via the LOX pathway, make the major contribution to the bronchoconstrictor and pulmonary vascular hypertensive effects of ET-1.