Blockade of thromboxane/endoperoxide receptor-mediated responses in the pulmonary vascular bed of the cat by sulotroban

Abstract

The effects of sulotroban (BM13.177; SK&F 95587), a thromboxane (TX) A 2/endoperoxide (PGH 2) receptor blocking agent on responses to the TXA 2/PGH 2 mimics, U46619 and U44069, were investigated in the pulmonary vascular bed of the intact-chest cat under constant flow conditions. Injections of U46619 and U44069 directly into the perfused lobar artery caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following administration of sulotroban in a dose of 5 mg/kg i.v., dose-response curves for U46619 and U44069 were shifted to the right in a parallel manner. The duration of the blocking effect of sulotroban was investigated, and responses to U46619 returned to approximately 50% of control in 120 min and were not significantly different from control 240 min after administration of the receptor antagonist. Sulotroban was without significant effect on responses to prostaglandin (PG) D 2 or F 2α or serotonin, histamine, norepinephrine, angiotensin II or BAY K8644, an agent which enhances calcium entry. Sulotroban was without effect on responses to endothelin (ET)-1, sarafotoxin (S) 6a or S6c and platelet-activating factor (PAF). Sulotroban did not alter baseline vascular pressures in the cat and responses to the PG and TXA 2/PGH 2 precursor, arachidonic acid, were reduced. The present data show that sulotroban selectively blocks TXA 2/PGH 2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed. These data suggest that responses to ET-1, S6a, S6c and PAF are not dependent on the activation of TXA 2/PGH 2 receptors and are consistent with the hypothesis that discrete TXA 2/PGH 2 receptors unrelated to receptors activated by PGF 2α or PGD 2 are present in the pulmonary vascular bed of the cat.