title: Inhibitors of inositol trisphosphate-induced Ca2+ release from isolated platelet membrane vesicles.
abstract: Platelet membrane vesicles accumulated Ca2+ in an ATP-dependent fashion, and 25-50% of the accumulated Ca2+ was released by the addition of 10 microM inositol 1,4,5-trisphosphate (IP3). The concentration of IP3 required for half-maximal Ca2+ release was approximately 0.5 microM. The inhibition of IP3-induced Ca2+ release from these membrane vesicles by various agents was examined. Of the plasma membrane Ca2+ channel blockers, cinnarizine and flunarizine were found to be potent inhibitors of IP3-induced Ca2+ release while having no effect on ATP-dependent Ca2+ uptake. The IC50 value for both cinnarizine and flunarizine as inhibitors of IP3-induced Ca2+ release was below 10(-6) M. Nifedipine, verapamil, bepridil, and diltiazem did not significantly inhibit IP3-induced Ca2+ release at the highest concentration tested (50 microM). The "intracellular Ca2+ antagonists" ryanodine, TMB-8 (8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate), dantroline, trifluoperazine and chlorpromazine were not inhibitors of IP3-induced Ca2+ release at 50 microM. The local anesthetics benzocaine and lidocaine weakly inhibited the IP3-induced Ca2+ release with IC50 values of approximately 5 and 50 microM, respectively, whereas other local anesthetics tested were less potent inhibitors. The potent inhibitors described may prove useful as probes of the IP3-induced Ca2+ release channels.
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002936:Cinnarizine / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005444:Flunarizine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000494:pharmacology*; D012433:Ryanodine / Q000494:pharmacology; D013403:Sugar Phosphates / Q000494:pharmacology*
chemical_list: D000779:Anesthetics, Local; D007295:Inositol Phosphates; D013403:Sugar Phosphates; D012433:Ryanodine; D002936:Cinnarizine; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D003620:Dantrolene; D005444:Flunarizine; D002118:Calcium