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Effects of 2‐methylthioadenosine 5′‐β,γ‐methylenetriphosphonate and 2‐ethylthioadenosine 5′‐monophosphate on human platelet activation induced by adenosine 5′‐diphosphate
Author(s) -
Hourani Susanna M.O.,
Welford Laurence A.,
Cusack Noel J.
Publication year - 1996
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199605)38:1<12::aid-ddr2>3.0.co;2-o
Subject(s) - adenylate kinase , adenosine , cyclase , adenosine diphosphate , chemistry , adenosine monophosphate , platelet , arachidonic acid , adenine nucleotide , prostaglandin , endocrinology , biochemistry , medicine , biology , nucleotide , enzyme , platelet aggregation , gene
Adenosine 5′‐diphosphate (ADP) induces human platelet aggregation, increases intracellular levels of free calcium, and inhibits stimulated adenylate cyclase. These effects of ADP are mediated by P 2T ‐purinoceptors that are inhibited specifically and competitively by adenosine 5′‐triphosphate (ATP). Inhibition of ADP‐induced aggregation and increases in calcium by 2‐alkylthio analogs of ATP and of adenosine 5′‐monophosphate (AMP) are also specific, but the inhibition is non‐surmountable. To examine further the nature of inhibition of ADP‐induced platelet activation by 2‐alkylthio analogs, the effects of 2‐methylthioadenosine 5′‐β,γ‐methylenetriphosphonate (2‐MeS‐AMP‐PCP) and 2‐ethylthioadenosine 5′‐monophosphate (2‐EtS‐AMP) were tested on ADP‐induced platelet aggregation and inhibition of adenylate cyclase. 2‐MeS‐AMP‐PCP inhibited platelet aggregation induced by ADP but not by epinephrine, arachidonic acid, 5‐hydroxytryptamine (5‐HT), platelet activating factor (PAF), or 11α,9α‐epoxymethano‐prostaglandin H 2 (U46619). Inhibition of ADP‐induced platelet aggregation by 2‐MeS‐AMP‐PCP was non‐surmountable, and it achieved only 50% inhibition of ADP (5 μM)‐induced aggregation. 2‐MeS‐AMP‐PCP achieved 100% inhibition of ADP (5 μM)‐induced inhibition of prostaglandin E 1 ‐stimulated adenylate cyclase, and Schild analysis showed the inhibition to be potent (pA 2 7.3) and competitive (slope 1.12). 2‐MeS‐AMP‐PCP inhibited platelet aggregation induced by adenosine 5′‐O‐2‐thiodiphosphate (ADP‐β‐S), which inhibited stimulated adenylate cyclase activity, but did not inhibit aggregation induced by adenosine 5′‐O‐1‐thiodiphosphate (ADP‐α‐S), which does not inhibit stimulated adenylate cyclase. 2‐EtS‐AMP behaved similarly to 2‐MeS‐AMP‐PCP. These results suggest that ADP may induce aggregation by interacting with two forms of the calcium‐mobilizing P 2T ‐purinoceptor, only one of which is coupled to inhibition of adenylate cyclase and at which 2‐alkylthio analogs of ATP and AMP are specific competitive antagonists. © 1996 Wiley‐Liss, Inc.