Cyclosporine increases platelet aggregation as well as the risk of thromboembolism. To test the hypothesis that CsA stimulates platelets by activating cytosolic calcium [Ca2+]i and related mechanisms, we measured the effects of CsA on [Ca2+]i, protein kinase C (PKC), and sodium/proton (Na+/H+) exchange. [Ca2+]i was measured in human platelets with fura 2, PKC was determined by the phosphorylation of the endogenous 47 kDa protein, and Na+/H+ exchange was measured with BCECF after acidification of the platelets with propionic acid. CsA alone did not influence basal PKC activity in platelets. However, CsA augmented the thrombin-induced phosphorylation of the specific PKC substrate p47 in platelets in a dose-dependent fashion. CsA did not affect basal [Ca2+]i--however, it increased thrombin-induced calcium influx. The effect of CsA on PKC was not dependent on the CsA-induced calcium influx. CsA increased Na+/H+ exchange, which was blocked completely by a PKC inhibitor. Our results demonstrate that CsA directly augments PKC-dependent cellular mechanisms in platelets.
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Haller et al. (1994) studied this question.