The mechanism(s) of the antiaggregatory effects of cryptolepine: the role of cyclic adenosine monophosphate and cellular Ca2+.

1. In this investigation, the properties and possible mechanisms of the antiaggregatory effects of cryptolepine were evaluated. 2. Cryptolepine had no effect on platelet shape change but inhibited aggregation in a time-dependent manner. The inhibition of aggregation lacks agonist specificity, the IC50 values (x 10(-5) M) being 2.79 +/- 0.7 ADP 3.05 +/- 0.2 (U46619), 2.89 +/- 0.6 (A23187), 2.41 +/- 0.6 (thrombin), 4.05 +/- 0.9 (arachidonic acid) and 47.3 +/- 3.9 (PAF). 3. The antiaggregatory effects were fully reversible and surmountable at concentrations < or = 75 microM but unsurmountable at concentrations > or = 100 microM. 4. The coincubation of cryptolepine (25 and 50 microM) with cpt-cAMP (50 microM) resulted in increased inhibition of aggregation from 24.2 +/- 2.1% (25 microM) and 45.1 +/- 3.4% (50 microM) to 69.5 +/- 5.8% and 84.2 +/- 6.4%, respectively. 5. Cryptolepine (10 microM) synergized with stimulants of platelet adenylate cyclase, prostacyclin (0.5 and 1 nM) and forskolin (2.5 and 5 microM) to inhibit aggregation induced by adenosine diphosphate (ADP). The inhibition of aggregation by cryptolepine (10 microM; 18.2 +/- 1.5%) or prostacyclin (0.5 nM; 23.4 +/- 2.0%) increased to 62.6 +/- 3.8% (P < 0.01) on combined administration. 6. Following pretreatment with IBMX (50 microM), a phosphodiesterase (PDE) inhibitor, the inhibitory effect of cryptolepine (25 microM) increased from 21.5 +/- 2.1% to 42.3 +/- 3.7% (P < 0.01). In the presence of imidazole (2.5 mM), an activator of PDE, the inhibitory effects of cryptolepine reduced from 63.2 +/- 5.4% (50 microM) and 84.7 +/- 4.4% (75 microM) to 1.4 +/- 0.2% and 21.3 +/- 2.4%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)