Inhibition of calcium influx in thrombin-stimulated platelets by SIN-1, an activator of soluble guanylate cyclase.
A previous study revealed that elevation of platelet cyclic GMP induced by a pharmacological activator of soluble guanylate cyclase, 3-morpholinosydnonimine (SIN-1), induced a major inhibition of Ca2+ influx caused by thrombin, as detected by monitoring the fluorescence of the Ca2+ indicator quin-2. In contrast, activation of phospholipase C as well as Ca2+ mobilization presumably promoted by inositol-1,4,5-trisphosphate was less affected by SIN-1 treatment. In the present study, the effects of SIN-1 on Ca2+ influx have been investigated in more detail using platelets loaded with millimolar concentrations of quin-2. Under these conditions, Ca2+ entry from the medium into the platelet cytoplasm could be followed either by detecting fluorescence quenching by Mn2+ or by determination of 45Ca2+ uptake. Both events were inhibited by SIN-1 in a dose-dependent manner. Furthermore, the inhibition of 45Ca2+ uptake and of fluorescence increase observed in the presence of extracellular Ca2+ displayed remarkably parallel dose-response curves, suggesting that elevation of cyclic GMP brought about by SIN-1 inhibits the opening of "receptor-operated channels" whose precise nature remains to be determined.
Simon
M F
MF
INSERM Unité 101, Biochimie des Lipides, Hôpital Purpan, Toulouse, France.
Chap
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D001692:Biological Transport; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D006152:Cyclic GMP / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005453:Fluorescence; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; C002385:linsidomine; D008981:Molsidomine; D013917:Thrombin; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium