Effect of (+)-S-145 calcium salt dihydrate, an orally active antagonist of the thromboxane A2/prostaglandin endoperoxide receptor, on platelet aggregation.

Transient agonist‐like action of the thromboxane A2 receptor antagonist S‐1452 (d‐s‐145 Ca) and its reduction by gradual injection or oral administration

“…The apnea observed in the present study appears to be due to the transient contraction of pulmonary smooth muscles by the compounds used via stimulating TXA, receptors, as pointed out already in previous studies [Hanasaki et al, 1989;Otani et al, 1989;Kakushi et al, 1991). This possibility is supported b y the fact that the apnea is observed as a stereoselective response to different enan tiomers of s-145.…”

“…The apnea observed in the present study appears to be due to the transient contraction of pulmonary smooth muscles by the compounds used via Agonist-like action of S-1452 and its diminution after gradual injection or oral administration. The experiment was done using the method of Konzett and Rossler [19401. The test compound was given to guinea pigs through the left jugular vein at the time indicated with an arrow: via bolus iniection in the left stimulating TXA, receptors, as pointed out already in previous studies [Hanasaki et al, 1989;Otani et al, 1989;Kakushi et al, 1991). This possibility is supported b y the fact that the apnea is observed as a stereoselective response to different enan tiomers of s-145.…”

Intrinsic activity of the non‐prostanoid thromboxane A2 receptor antagonist, daltroban (BM 13,505), in human platelets in vitro and in the rat vasculature in vivo

“…Thus is might be argued that sulotroban possessed insufficient efficacy to evoke any response in the latter blood vessels or smooth muscle cells. The prostanoid compound S-1452, transiently induced platelet shape change, as previously mentioned, evoked smooth muscle contraction in vitro (Hanasaki et al, 1989;Nakajima & Ueda, 1989;Otani et al, 1989;Kakushi et al, 1991) and caused a transient increase in airway resistance in guinea-pigs in vivo (Asanuma et al, 1993). In cat cerebral arteries, the intrinsic activity of S145 represented about one third of that of the high efficacy agonist (Nakajima & Ueda, 1989).…”

“…Like U-46619, daltroban concentration-dependently induced platelet shape change with a maximal response representing about half of that evoked by the full agonist. The prostanoid TxA2/PGH2 receptor antagonist S-1452 transiently altered platelet shape change, whereas other prostanoid TxA2/PGH2 receptor antagonists such as GR 32191 (vapiprost), BMS 180,291 (ifetroban sodium Misra et al, and AH 23848 were devoid of any effect (Brittain et al, 1985;Humphrey et al, 1990;Kakushi et al, 1991;Ogletree et al, 1992). No conclusion can be drawn from these observations regarding an eventual structure (i.e., prostanoid versus non-prostanoid)intrinsic activity relationship of these compounds on platelet shape change.…”

“…Intrinsic activity at TxA2/ PGH2 or other receptors could limit the therapeutic use of certain TxA2 receptor antagonists (Terres et al, 1987). Based on biochemical and pharmacological in vitro studies, intrinsic activities have been suspected for several, if not most of the non-prostanoid TxA2/PGH2 receptor antagonists described to date (Janssens et al, 1985;Lumley et al, 1988;Kakushi et al, 1991;Miki et al, 1992). In contrast, a number of prostanoid compounds seem to be devoid of intrinsic activity (Ogletree et al, 1985;Darius et al, 1995).…”