Effects of Cilostazol, a Selective cAMP Phosphodiesterase Inhibitor on the Contraction of Vascular Smooth Muscle

Abstract

The effects of cilostazol (OPC-13013, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone) on cyclic nucleotide metabolism and Ca²⁺-induced contraction of intact and skinned rabbit arterial smooth muscles were investigated. The concentrations of cilostazol producing 50% inhibition of cyclic adenosine monophosphate phosphodiesterase and Ca²⁺-dependent cyclic nucleotide phosphodiesterase were 0.4 μM and above 100 μM, respectively. This compound has no significant effect on adenylate cyclase in concentrations of up to 100 μM. Addition of cilostazol increased significantly the cAMP content without significant effect on cyclic guanosine monophosphate level of rabbit thoracic aorta in the presence of forskolin. Moreover, the ED₅₀ value of cilostazol in relaxation of rabbit mesenteric arterial strips was decreased selectively by addition of 0.01 μM forskolin, which alone at this concentration has no effect on vascular contraction. Cilostazol of up to 30 μM did not suppress the Ca²⁺-induced contraction of the chemically skinned rabbit mesenteric artery. Therefore, cilostazol may produce the relaxation of intact vascular smooth muscle by its inhibition of cyclic adenosine monophosphate hydrolysis.

Hypertension and Endothelial Dysfunction in Apolipoprotein E Knockout Mice

“…Cilostazol has been shown to induce vasodilation via increasing cyclic adenosine monophosphate (cAMP) rather than nitric oxide release. [25][26][27][28] A preliminary study showed that cutaneous blood perfusion in response to cilostazol was maximally increased at 15 to 20 minutes in mice. The procedure was the same as before except 2 measurements were performed 15 minutes after topical administration of 1% cilostazol and averaged.…”

“…Consistent with this hypothesis, a parallel experiment using cilostazol, a selective cAMP phosphodiesterase inhibitor that has been shown to increase blood flow in the skin after topical administration, 25 showed no difference in the blood flow response between the 2 groups at 7.5 months of age. Cilostazol blocks cAMP hydrolysis, elevates vascular smooth muscle cell cAMP levels, and produces vasodilation in vitro and in vivo 26,27 with no effect on nitric oxide production. 28 These results observed in Apoe -/-mice showed a deficit of nitric oxide-mediated vasodilation associated with extensive atherosclerosis and elevated blood pressure, which is consistent with endothelial dysfunction.…”

Pharmacological Profile of Gastric Mucosal Protection by Marmin and Nobiletin from a Traditional Herbal Medicine, Aurantii Fructus Immaturus

“…Nobiletin has been reported to show inhibitory effects against cAMP phosphodiesterase and possess an inhibitory effect on histamine release from peritoneal mast cells (6,7). In addition, in the case of smooth muscle, it has been proposed that the inhibition of cAMP phosphodiesterase is closely related to the relax ation of smooth muscle (38). Hence, the relaxatory effect of nobiletin on smooth muscle may be due to the inhibi tion of cAMP phosphodiesterase.…”

Pharmacokinetic characteristics of cilostazol 200 mg controlled-release tablet compared with two cilostazol 100 mg immediate-release tablets (Pletal) after single oral dose in healthy Korean male volunteers

“…[4] In a 12-week, double-blind clinical trial in patients with intermittent claudication, initial claudication distance and absolute claudication distance were significantly improved by 35% and 41%, respectively, in the participants who received cilostazol 100 mg twice daily (n = 52) compared with participants who received placebo (n = 25) (P < 0.01). [5] In a 24-week, double-blind clinical trial in patients with peripheral arterial disease, absolute claudication distance was significantly improved by 54% in the participants who received cilostazol 100 mg twice daily (n = 227) compared with participants who received pentoxifylline (n = 232) (P < 0.001).…”