THE INHIBITORY EFFECT OF CINCHONINE ON HUMAN PLATELET-AGGREGATION DUETO BLOCKADE OF CALCIUM INFLUX

The Cinchona bark contains alkaloids like quinine, quinidine, cinchoni ne and cinchonidine. These agents are effective antimalarial drugs and have been used clinically in malaria caused by Plasmodium falciparum. Previous studies show that quinine and quinidine exert effects on car diovascular system. This study was conducted to examine the effect of cinchonine on human platelet aggregation. The results show that cincho nine inhibited platelet aggregation mediated by platelet agonists, epi nephrine (200 mu M), ADP (4.3 mu M), platelet activating factor (PAF; 800 nM) and collagen (638 nM) but had no effect on arachidonic acid (A PI; 0.75 mM). Cinchonine was most effective in inhibiting aggregation induced by platelet activating factor and epinephrine with IC50 values of 125 and 180 mu M respectively, however, higher concentrations of c inchonine were required to inhibit aggregation mediated by ADP or coll agen (IC50; 300 mu M). Pretreatment of platelets with cinchonine inhib ited aggregation caused by Ca2+ ionophore, A-23187 (6 mu M), in a dose -dependent manner (Ic(50); 300 mu M) indicating an inhibitory effect o n Ca2+-signaling cascade. This was supported by measuring [Ca2+]i in p latelets loaded with Fura-2AM where cinchonine inhibited the rise in c ytosolic Ca2+ mediated by A-23187 (6 mu M) or collagen (638 nM). Resul ts show that cinchonine (20 mu M) also inhibited aggregation when plat elets were pretreated with protein kinase C (PKC) activator, phorbol m yristate acetate (PMA; 0.1 mu M) in combination with low doses of plat elet activating factor (80 nM). Cinchonine, however, had no effect on AA-induced platelet aggregation and thromboxane A(2) (TXA(2)) synthesi s in platelets. These results suggest that antiplatelet effects of cin chonine are mediated mainly through inhibition of Ca2+-influx and prot ein kinase C pathways in platelets. (C) 1998 Elsevier Science Inc.