Comparison of the effects of cilostazol and milrinone on intracellular cAMP levels and cellular function in platelets and cardiac cells

Cilostazol is a potent cyclic nucleotide phosphodiesterase (PDE) type 3 (PD E3) inhibitor that was recently approved by the Food and Drug Administratio n (FDA) for the treatment of intermittent claudication. Its efficacy is pre sumed to be due to its vasodilatory and platelet activation inhibitory acti vities. Compared with those treated with placebo, patients treated with cil ostazol showed a minimal increase in cardiac adverse events. Because of its PDES inhibitory activity, however, the possibility that cilostazol exerts positive cardiac inotropic effects is a safety concern. Therefore we compar ed the effects of cilostazol with those of milrinone, a selective PDE3 inhi bitor, on intracellular cyclic adenosine monophosphate (cAMP) levels in pla telets, cardiac ventricular myocytes, and coronary smooth muscle cells. We also compared the corresponding functional changes in these cells. Cilostaz ol and milrinone both caused a concentration-dependent increase in the cAMP level in rabbit and human platelets with similar potency. Furthermore, cil ostazol and milrinone were equally effective in inhibiting human platelet a ggregation with a median inhibitory concentration (IC50) of 0.9 and 2 mu M, respectively. In rabbit ventricular myocytes, however, cilostazol elevated cAMP levels to a significantly lesser extent (p < 0.05 vs. milrinone). By using isolated rabbit hearts with a Langendorff preparation, we showed that milrinone is a very potent cardiotonic agent; it concentration-dependently increased left ventricular developed pressure (LVDP) and contractility. Ci lostazol was less effective in increasing LVDP and contractility (p < 0.05 vs, milrinone), which is consistent with the cardiac cAMP levels. The cardi ac effect of OPC-13015, a metabolite of cilostazol with about sevenfold hig her PDE3 inhibition, was similar to cilostazol. Whereas milrinone concentra tion-dependently increased cAMP in rabbit coronary smooth muscle cells, cil ostazol did not have such an effect. However, both compounds increased coro nary flow equally in rabbit hearts, Our results show that although cilostaz ol and milrinone both inhibit PDES, cilostazol preferentially acts on vascu lar elements (platelets and flow). This unique profile of cilostazol is con sistent with its beneficial and safe clinical outcomes in patients with int ermittent claudication.