Interference of a PAF-acether antagonist with adrenaline-induced activation of human platelets

FOUQUE F; SCHATTNER M; SHAW A; TOUQUI L; VARGAFTIG B B

Londres, Inglaterra

Congreso; Annual Meeting of the British Society of Pharmacology; 1986

INTERFERENCE OF A PAF-ACETHER ANTAGONIST W!TH ADRENALINE-INDUCED ACTIVATION OF HUMAN PLATELETS. F.  Fouque, M. Schattner*, A. Shaw, L. Touqui and B.B. Vargaftig, Unité Associée Institut Pasteur/INSERM. no 285, 25, Rue du Dr. Roux, 75015 Paris, France Adrenaline associated to PAF-acether triggers aggregation of human platelets st A r which are inactive when used alone (Fouque and Vargaftig, 1984). This synergism is not mediated by cyclooxygenase metabolites of arachidonate but is suppressed, as well as the direct effects of adrenaline, by alpha2 adrenoreceptor antagonists. The possibility that adrenaline and PAF-acether share pathways for platelet activation was now investigated. Human citrated plate1et_rich plasma was aggregated with ADP (2.5 uM), arachidonate (0.4 mM), PAF-acether (0.1-1 uM) or adrenaline (0.5- 5 uM), antagonists being added 1 min beforehand. To evaluate secretion, platelets were labeled with 14C-5HT or secreted ATP was rneasured. The PAF-acether antagonist BN 52021 suppressed activation by PAF-acether (Braquet et al., 1985; Nunez et al., 1986), and was totally inactive against arachidonate, ADP and adrenaline when used up to 0.1 mM. In contrast, the PAF-acether antagonist and analogue Ro 19-3704 (3-4 (R)-2- (methoxycarbonyl) oxy-3- (octadecylcarbamoyl) oxy= propoxy butyl thiazolium lodide; Burri et al., 1985) was not only effective against PAF-acether itself (IC50 of 0.4 + 0.05 uM) but also antagonized dose-dependently platelet aggregation and secretion by adrenaline, with an lC50 of 5 + 2 uM. This antagonism differed from that due to aspirin-like drugs, since primary aggregation, which persists   in spite of cyclooxygenase inhibition, was also suppressed. Furthermore, inhibition was restricted to PAF-acether and adrenaline, since Ro 19-3704 failed to interfere with ADP or arachidonate up to 0.1 mM. A chemical analogue of PAF-acether (1-0-octadecyl-2-0-acetyl-glyceryl-3-phosphoryl-morpholino-ethanol) which is not an antagonist (Coeffier et al.,in press), added to PRP up to 0.1 mM was inactive against adrenaline, whereas the reference PAF-acether antagonist compound CV-3988 (a phospholipid analogue of Ro 19-3704; Terashita et al., 1983) at 0.1 mM antagonized altogether the effects of PAF-acether and adrenalíne. Finally, alpha2 adrenoceptor antagonists which suppress the first and the second wave of aggregation by adrenaline are inactive against PAF-acether (Hydergine, dihydroergotamine) or only marginally efective (yohimbine) (Fouque and Vargaftig, 1985). Our results indicate that endogenous PAF-acether does not account for adrenaline-induced human platelet activation and the PAF-acether and adrenaline do not share a common receptor, since neither BN S2021 nor alpha2 adrenoceptor antagonists antagonized adrenaline and PAF-acether, respectively. They also suggest that a component of the adrenaline receptor or pathway is affected by PAF-acether antagonist structurally related to the agonists.