Abstract

A novel thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor ligand, (+)5(Z)-7-[3-endo-phenylsulfonylamino[2.2.1]-bicyclohept-2-e xo- yl]-heptenoic acid [(+)-S-145], was evaluated in guinea pigs to assess the in vivo pharmacodynamic profile of this compound at vascular, cardiac and platelet TXA2/PGH2 receptors. Comparison was made to the TXA2/PGH2 receptor antagonist SQ29548. Upon i.v. injection, (+)-S-145, but not SQ29548, elicited transient (approximately 1 min) increases in mean arterial blood pressure (ED50 +/- 95% confidence limit = 6.1 + 4.0, -2.2 micrograms/kg). The potency of i.v. (+)-S-145 (ID50 = 6.3 + 2.3, -2.3 micrograms/kg) against the pressor response to subsequent i.v. TXA2/PGH2 mimetic, U44069, was 9.5-fold greater than that of SQ29548 (ID50 = 59.1 + 52.9, - 52.9 micrograms/kg). Intravenous (+)-S-145 inhibited U44069-induced decreases in circulating platelet count (ID50 = 4.2 + 4.1, - 2.0 micrograms/kg). In thoracotomized guinea pigs, i.v. (+)-S-145 (31.6 micrograms/kg) and increasing i.v. doses of U44069 increased mean arterial blood pressure, total peripheral resistance, left ventricular end-diastolic pressure and left ventricular peak positive dP/dt (LV + dP/dt) and depressed cardiac output (P < .05). Pretreatment with i.v. (+)-S-145 (31.6 micrograms/kg) abolished these U44069-induced effects. In thoracotomized guinea pigs in which left ventricular end-diastolic pressure and HR were held constant, U44069 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 inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)