Cilostazol's Effect on the Response to Perivascular Nerve Stimulation in Isolated Dog Cerebral and Mesenteric Arteries

Abstract

Clinical studies have demonstrated that cilostazol (CZ), an antiplatelet agent with type 3 phosphodiesterase inhibition, reduces the risk of secondary stroke. To analyze CZ's vascular action, especially in relation to endothelial and perivascular nerve functions, we examined CZ's effects on the responses to endothelial and nerve stimulation in dog cerebral arteries, and on the response to nerve stimulation in dog mesenteric arteries. Low concentrations of CZ (10(-8) and 10(-7) mol/L) failed to relax the cerebral arteries, but a higher concentration (10(-6) mol/L) relaxed them in an endothelium-independent manner. Substance P-induced relaxation was endothelium-dependent in the cerebral arteries, whereas transmural electrical stimulation (TES) and nicotine-induced relaxation were endothelium-independent. This relaxation was abolished by N(G)-nitro-L-arginine, an NO synthase (NOS) inhibitor. A lower concentration (10(-7) mol/L) of CZ enhanced the relaxation caused by nerve-derived NO but did not affect the relaxation caused by endothelium-derived NO in the cerebral arteries; moreover, it did not affect the contractions caused by nerve-derived noradrenaline in the mesenteric arteries under treatment with the NOS inhibitor. It is concluded that CZ may selectively enhance nitrergic nerve function, possibly via the activation of neuronal NOS, in dog cerebral arteries, since it does not affect the function of the noradrenergic nerve or that of endothelial NOS. Therefore, this novel vasodilatory effect of CZ may explain the reduction in the risk of secondary stroke in addition to the antiplatelet action and the direct vasodilatory action on smooth muscle.