IN-VIVO EFFECTS OF A NOVEL THROMBOXANE A(2) PROSTAGLANDIN H-2 (TXA(2)PGH(2)) PARTIAL AGONIST, LFONYLAMINO[2.2.1]-BICYCLOHEPT-2-EXO-YL]-HEPTENOIC ACID [(+)-S-145], ON VASCULAR, PLATELET AND CARDIAC-FUNCTION()5(Z))

A novel thromboxane A(2)/prostaglandin H-2 (TXA(2)/PGH(2)) receptor li gand, lfonylamino[2.2.1]-bicyclohept-2-exo-yl]-heptenoic acid [(+)-S-1 45], was evaluated in guinea pigs to assess the in vivo pharmacodynami c profile of this compound at vascular, cardiac and platelet TXA(2)/PG H(2) receptors. Comparison was made to the TXA(2)/PGH(2) receptor anta gonist SQ29548. Upon i.v. injection, (+)-S-145, but not SQ29548, elici ted transient(approximate to 1 min) increases in mean arterial blood p ressure (ED(50) +/- 95% confidence limit = 6.1 + 4.0, - 2.2 mu g/kg). The potency of i.v. (+)-S-145 (ID50 = 6.3 + 2.3, - 2.3 mu g/kg) agains t the presser response to subsequent i.v. TXA(2)/PGH(2) mimetic, U4406 9, was 9.5-fold greater than that of SQ29548 (ID50 = 59.1 + 52.9, - 52 .9 mu g/kg). intravenous (+)-S-145 inhibited U44069-induced decreases in circulating platelet count (ID50 = 4.2 + 4.1, - 2.0 mu g/kg). In th oracotomized guinea pigs, i.v. (+)-S-145 (31.6 mu g/kg) and increasing i.v. doses of U44069 increased mean arterial blood pressure, total pe ripheral resistance, left ventricular end-diastolic pressure and left ventricular peak positive dP/dt (LV+dP/dt) and depressed cardiac outpu t (P < .05). Pretreatment with i.v. (+)-S-145 (31.6 mu g/kg) abolished these U44069-induced effects. In thoracotomized guinea pigs in which left ventricular end-diastolic pressure and HR were held constant, U44 069 again increased LV+dP/dt (P < .05), but (+)-S-145 decreased LV+dP/ dt (P < .05), which indicates the lack of an (+)-S-145 direct inotropi c effect. We conclude that functioning as a partial agonist, (+)-S-145 elicited agonist responses in vascular smooth muscle, but not in card iac tissue. With similar potencies, (+)-S-145 antagonized TXA(2)/PGH(2 ) receptors in arteries and platelets.