EVIDENCE FOR PARTIAL AGONIST PROPERTIES OF DALTROBAN (BM-13,505) AT TP RECEPTORS IN THE ANESTHETIZED OPEN-CHEST RAT

We sought to determine whether the intrinsic pulmonary hypertensive ac tivity of the purported thromboxane A(2)/prostanoid (TP) receptor anta gonist, daltroban, was mediated by TP receptors, using the high effica cy TP receptor agonist, U-46619, and the silent TP receptor antagonist , SQ 29,548. In pentobarbitone-anaesthetized, open chest rats (n = 4-1 0 per group), non-cumulative injections of U-46619, dose-dependently i ncreased mean pulmonary arterial pressure (MPAP) with an ED50 (geometr ic mean with 95% confidence limits in parentheses) of 1.4 (1.1-2.3) mu g/kg i.v.. Daltroban increased MPAP in a bell-shaped manner, with an apparent ED50 [29 (21-35)mu g/kg i.v.] being 21 fold less potent than that of U-46619. The maximal pulmonary hypertensive responses evoked b y daltroban represented about half those induced by U-46619 (25.4 +/- 1.0 vs. 12.7 +/- 2 mmHg: P < 0.05 between groups). The TP receptor ant agonist SQ 29,548 fully antagonized increases in MPAP evoked by equihy pertensive doses of U-46619 (1.25 mu g/kg) or daltroban (80 mu g/kg). Further experiments were carried out to determine whether daltroban an tagonized the pulmonary hypertensive responses evoked by the high effi cacy agonist, U-46619, or by itself as receptor theory would predict f or a partial agonist. Daltroban (10-2500 mu g/kg) antagonized, althoug h not fully, U-46619 (20 mu g/kg)-evoked pulmonary hypertensive respon ses, since prominent intrinsic pulmonary hypertensive effects of daltr oban were observed in the same range of doses. Furthermore, in contras t to U-46619 (1.25 mu g/kg), daltroban (80 mu g/kg) failed to evoke a second pulmonary hypertensive response following a previous injection, as would be expected for a partial agonist. Collectively, the results strongly suggest that daltroban behaves as a partial agonist at TP re ceptors in the pulmonary vascular bed of the rat in vivo.