Inhibition of agonist-induced rise in platelet Ca2+ by antithrombotic nipecotamides.
The effects of three structural types of nipecotamides and their stereoisomers on collagen-induced aggregation and intraplatelet ionized calcium ([Ca2+]i) rise in human platelets were evaluated using aequorin as the [Ca2+]i indicator. The orders of potencies of racemic nipecotamides were different when collagen was the agonist compared with those obtained using ADP. It is suggested that in addition to their earlier hypothesized interactions with platelet anionic phospholipids of the plasma and organelle membranes, nipecotamides may, in addition, act at other receptor sites. In general, the inhibition of collagen-induced aggregation paralleled their inhibitory effects on the rise of [Ca2+]i. The compounds were stereoselective in inhibiting aggregation as well as [Ca2+]i rise. The meso diastereomers of I and II were more potent than the corresponding enantiomeric pairs. A single [Ca2+]i peak was noticed when the incubate contained 1.0 mM extracellular calcium [Ca2+]o. On the other hand a biphasic [Ca2+]i rise was noticed when the nominally Ca(2+)-free buffer contained 75 microM ethylene glycol tetraacetate (EGTA). The first peak corresponded with platelet shape change, suggesting Ca2+ discharge from internal stores, and the second, with aggregation. The second peak may reflect either Ca2+ flux across the plasma membrane or aequorin leak from internal cellular locations or from the canicular system. Inhibition of the rise in intraplatelet Ca2+ appears to be associated with the platelet aggregation-inhibitory actions of nipecotamides.
Gollamudi
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Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee-Memphis 38163.
Dillingham
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Bond
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D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D003094:Collagen / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013237:Stereoisomerism
D005343:Fibrinolytic Agents; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D004533:Egtazic Acid; D000244:Adenosine Diphosphate; D003094:Collagen; D002118:Calcium