2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and sulotroban

Differential effects on human platelet function of thromboxane A2 (TXA2) synthetase inhibition singly and of TXA2 synthetase inhibition combined with TXA2/prostaglandin endoperoxide receptor antagonism were revealed, using ridogrel as a probe. Ridogrel combines selective TXA2 synthetase inhibition with TXA2/prostaglandin receptor antagonism in one molecule: in washed human platelets, the compound reduces the production of TXB2 (IC50 = 1.3 X 10(-8) M) and increases that of PGF2 alpha, PGE2, PGD2 from [14C]arachidonic acid. Additionally, at higher concentrations (Ki = 0.52 X 10(-6) M), it selectively antagonizes the breakdown of inositol phospholipids, subsequent to stimulation of TXA2/prostaglandin endoperoxide receptors with U 46619. The latter happens in a competitive way with fast receptor association-dissociation characteristics. At low concentrations (1 X 10(-9)-1 X 10(-7) M) producing single TXA2 synthetase inhibition, ridogrel reduces the collagen-induced formation of TXB2 by washed platelets, but enhances [32P]phosphatidic acid (PA) accumulation and [3H]5-hydroxytryptamine (5-HT) release. At higher concentrations (1 X 10(-6)-1 X 10(-5) M) which additionally block U 46619-induced [32P]PA accumulation, ridogrel inhibits the [32P]PA accumulation and release of [3H]5-HT by human platelets stimulated with collagen. These observations, corroborated by results obtained with OKY 1581, sulotroban, indomethacin and human serum albumin, suggest a causal role for prostaglandin endoperoxides in the stimulation by TXA2 synthetase inhibition of platelet reactions to collagen. They reinforce the concept that TXA2 synthetase inhibition-induced reorientation of cyclic endoperoxide metabolism, away from TXA2 into inhibitory prostanoids, requires additional TXA2/prostaglandin endoperoxide receptor antagonism to achieve optimal anti-platelet effects.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Blood Platelets; Collagen; Humans; In Vitro Techniques; Indomethacin; Inositol Phosphates; Methacrylates; Platelet Activating Factor; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

The effect of KW-3049, (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride on myocardial infarction in rats was examined, in comparison with some other drugs. Extension of myocardial infarction was assessed by separately determining the tissue creatine kinase (CK) activity of left ventricular free wall (LVFW) and that of interventricular septum. Loss of CK activity was limited to LVFW until 6 h after the ligation of the left main coronary artery, while 24 h after the ligation, it extended to the septum. Therefore, the effects of drugs were examined mainly in rats following 6 h of coronary artery ligation. Pretreatments with KW-3049 at 1 and 3 mg/kg (p.o.), given 1 h before coronary artery ligation, significantly reduced the loss of CK activity of LVFW by 45.3 and 39.7%, respectively. Also, posttreatment with KW-3049 at 30 micrograms/kg (i.p.), given 10 min after the ligation, significantly reduced the loss of CK activity by 30.6%. On the other hand, nifedipine (3, 10 mg/kg, p.o.), propranolol (100 mg/kg, p.o.), OKY-1581 (100 mg/kg, p.o.) and BM 13.177 (100 mg/kg, p.o.), each of which was given 1 h before coronary ligation, did not significantly reduce the loss of CK activity. Coronary artery ligation for 6 h significantly decreased the myocardial contents of adenosine triphosphate (ATP) and creatine phosphate (CP). Pretreatments with KW-3049 at 1 and 3 mg/kg (p.o.) reduced the decrease in ATP and CP. These results suggest that KW-3049 possesses a superior cardioprotective effect in comparison with the other drugs examined. The possible implications for the protection by KW-3049 are discussed.

Topics: Adenosine Triphosphate; Animals; Calcium Channel Blockers; Coronary Circulation; Creatine Kinase; Ligation; Male; Methacrylates; Myocardial Infarction; Myocardium; Nifedipine; Phosphates; Phosphocreatine; Propranolol; Rats; Rats, Inbred Strains; Sulfonamides