Selective inhibition of adrenaline-induced human platelet aggregation by the structurally related Paf antagonist Ro 19-3704.
1. Two non-lipid antagonists of platelet-activating factor acether (Paf), BN 52021 and WEB 2086, at concentrations which completely blocked Paf-induced platelet aggregation, failed to interfere with aggregation by adrenaline. In contrast, Ro 19-3704, a structurally related antagonist of Paf, inhibited concentration-dependently aggregation induced by adrenaline or by the simultaneous addition of submaximal concentrations of adrenaline and Paf. Reversal of aggregation was obtained when Ro 19-3704 was added to the platelet suspension after adrenaline. 2. Ro 19-3704 was selective for Paf and adrenaline since it failed to interfere with platelet aggregation induced by arachidonic acid or ADP. CV-3988, an antagonist of Paf structurally similar to Ro 19-3704, also inhibited adrenaline-induced aggregation. However, a morpholine analogue (MA) of Paf, which has no anti-Paf activity, failed to interfere with the aggregation induced by adrenaline. This suggests that the effect of Ro 19-3704 and CV-3988 on adrenaline is not simply due to their lipid structure. 3. Experiments on plasma membrane preparations showed that Ro 19-3704 inhibited [3H]-yohimbine binding with an inhibition constant (Ki) of 7 +/- 3 microM. In contrast, BN 52021 and MA did not interfere with [3H]-yohimbine binding. Equilibrium binding experiments showed that Ro 19-3704 increased the apparent KD of [3H]-yohimbine binding from 2.02 +/- 0.15 to 7.3 +/- 0.4 nM. The Paf antagonist Ro 19-3704 interacts specifically with the alpha 2-adrenoceptor and may thus prevent the early steps involved in the mechanism of adrenaline-induced platelet activation.
Schattner
M
M
Academia Nacional de Medicina de Buenos Aires, Instituto de Investigaciones Hematologicas Mario R. Castex, Argentina.
Parini
A
A
Fouque
F
F
Vargaftig
B B
BB
Touqui
L
L
D006916:5-Hydroxytryptophan / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D004224:Diterpenes; D004357:Drug Synergism; D004837:Epinephrine / Q000037:antagonists & inhibitors*; D046934:Ginkgolides; D005995:Glyceryl Ethers; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D015016:Yohimbine / Q000378:metabolism
D004224:Diterpenes; D046934:Ginkgolides; D005995:Glyceryl Ethers; D007783:Lactones; D009025:Morpholines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D013844:Thiazoles; C053235:Ro 19-3704; D015016:Yohimbine; D006916:5-Hydroxytryptophan; C045856:ginkgolide B; D004837:Epinephrine