The effect of a new thromboxane receptor blocking drug GR32191 ([1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1"-biphenyl)-4-yl]methoxy] -3-hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoic acid,hydrochloride) has been examined upon platelets and vascular smooth muscle. In human platelet-rich plasma (PRP), aggregation to thromboxane(Tx) A2, PGH2, arachidonic acid, collagen andU-46619 was antagonised by GR32191 (IC50 range 2-36 nM).Primary aggregation (PRP treated with aspirin 10 pM) to ADP, 5-HT and adrenaline were unaffected by concentrations of GR32191 up to 10 pM. In human PRP, U-46619-induced aggregation and 5-HT release were antagonised by GR32191(10-100 nM). In contrast, in theabsence of aspirin, ADP-induced 5-HT release,but not aggregation, was antagonised by the compound implicating a role for TXA2 in the release process. In human PRP GR32191 (up to 30μM) did not itself induce aggregation or, in the presence of EGTA (4 mM), induce detectable shape change. Up to 10 μM GR32191 was without effect upon the inhibitory activity of PGI2 or PGD2 and at 1μMhad no significant inhibitory activity upon fatty acid cyclooxygenase, thromboxane synthase, prostacyclin synthase, 12-lipoxygenase orphosphodiesterase. The effect of GR32191was quantified further in human platelets suspended in whole blood or physiological salt solution. Aggregation to U-46619 was antagonised byGR32191 with a pA2 (slope of the Schild regression) of 8.2 (1.3) in whole blood and 8.8 (1.3) in resuspended platelets. The compound competitively and specifically antagonised the contractions of strips of human isolatedpulmonary blood vessels and rat and guinea-pig aortic strips produced by U-46619 with pA2 (slope) values of 8.2 (1.1), 7.9 (0.9) and 8.7(0.9) respectively. In contrast contractions induced by KC1 and 5-HT (rat) orKC1and histamine (guinea-pig) were unaffectedbyconcentrations of GR32191 up to 30 μM.Thus GR32191 is a potent and specific thromboxane receptor blocking drug on platelets and vascular smooth muscle in vitro. It is orally active and long lasting in man (Thomas, M et al.,this meeting).
The actions of azelnidipine, a dihydropyridine-derivative Ca antagonist, on voltage-dependent Ba2+
currents in guinea-pig vascular smooth muscle