Effect of 1-aminoadamantanes on adenine nucleotide and serotonin storage in blood platelets.
The platelet release reaction, the liberation of adenine nucleotides and serotonin (5-HT) from osmiophilic dense granules, can be induced in human platelets by C-alkyl-derivatives of the antiviral and anti-Parkinson drug 1-aminoadamantane (D 1). The release-inducing activity is enhanced with increasing chain length and with the number of C-alkylsubstituents, respectively. The parent compound, D 1, liberates only 5-HT. Analyses of LDH activity in the incubation medium of the platelets and electron micrographs of platelets treated with 1-aminoadamantanes support the assumption that ATP, ADP, and 5-HT are released from the organelles by an exocytosis-like process rather than by destruction of the plasma and organelle membranes. The number of osmiophilic dense granules in platelets isolated from human and rabbit blood is decreased by the action of the drugs. This is in contrast to other subcellular structures where no morphological changes can be observed. The ADP-stimulated platelet aggregation is inhibited by preincubation with 1-aminoadamantanes. The inhibitory activity of the drugs on platelet aggregation parallels the effects observed after induction of the release reaction: the inhibition of platelet aggregation is enhanced with increasing C-alkylation. Hence, the inhibition of ADP-induced platelet aggregation can be used to screen for the releasing activity of 1-aminoadamantanes which have, as far as tested, similar effects on 5-HT storage in blood platelets and in the CNS. The time-, temperature, and concentration-dependent 5-HT uptake by platelets (K = 0.75 micro M; V max = 0.22 nmoles/min X 10 9 cells) is noncompetitively inhibited by the drugs with K1-values varying from 10 to 100 micro M depending on the degree of C-alkylation.
D000244:Adenosine Diphosphate / Q000097:blood* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000097:blood*; D000328:Adult; D000547:Amantadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D012701:Serotonin / Q000097:blood*
D012701:Serotonin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000547:Amantadine