PHARMACOLOGIC CHARACTERIZATION OF HUMAN AND CANINE THROMBOXANE-A2 PROSTAGLANDIN H2-RECEPTORS IN PLATELETS AND BLOOD-VESSELS - EVIDENCE FOR DIFFERENT RECEPTORS

Abstract

Thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors in platelets and blood vessels were characterized. Both human and canine platelet aggregation and saphenous vein contractions were induced by the stable TXA2/PGH2 mimetics (15S)-hydroxy-11.alpha.,9.alpha.-(epoxymethano)prosta-5Z, 13E-dienoic acid (U46619) and 9,11-epithio-11,12-methano-TXA2 (ONO-11113). ONO-11113 was a more potent agonist than .+-.6619 in the human saphenous vein but less potent in the platelet. These agonists were equipotent in the canine platelet but ONO-11113 was more potent in the saphenous vein. Platelet aggregation and saphenous vein contraction induced by U46619 were blocked in a dose-dependent manner by the TXA2/PGH2 receptor agonists 9,11-dimethylmethano-11,12-methano-16-phenyl-13,14-dehydro-13-aza-15.alpha..beta.-.omega.-tetranor-TXA2 (ONO-11120), 9,11-dimethylmethano-11,12-methano-16-(4-hydroxyphenyl)-13,14-dihydro-13-aza-15.alpha..beta.-.omega.-tetranor-TXA2 (PTA-OH), 9,11-dimethylmethano-11,12-methano-16-(4-methoxyphenyl)-13,14-dihydro-13-aza-15.alpha..beta.-.omega.-tetranor-TXA2 (PTA-OM), 9,11-dimethylmethano-11,12-methano-16-(3-iodo-4-hydroxyphenyl-13,14-dihydro-13-aza-15.alpha..beta.-.omega.-tetranor-TXA2 (I-PTA-OH) and 9,11-dimethylmethano-11,12-methano-15-phenyl-13,14-dihydro-13-aza-15.alpha..beta.-.omega.-pentanor-TXA2 [PTA-(.omega.-1)]. The rank order potency for the antagonists in human platelets was ONO-11120 = I-PTA-OH > PTA-OH = PTA-(.omega.-1)> PTA-OM, which was significantly different (P < 0.05) compared to the saphenous veins [I-PTA-OH > ONO-11120 > PTA-(.omega.-1) = I-PTA-OM > PTA-OH]. The rank order potency for the antagonists in the canine saphenous vein was the same as that for the human saphenous vein but was significantly different from that observed in canine platelets. The TXA2/PGH2 receptor in platelets is different from that in blood vessels.