title: Effects of cilostazol, a selective cyclic AMP phosphodiesterase inhibitor on isolated rabbit spinal arterioles.
abstract: Cilostazol, a potent inhibitor of guanosine 3':5'-cyclic monophosphate (cGMP)-inhibited adenosine 3':5'-cyclic monophosphate (cAMP) phosphodiesterase (PDE3), has been used clinically for the treatment of chronic peripheral arterial occlusive disease. The beneficial effect of cilostazol is attributed to both anti-platelet aggregating activity and vasodilation. However, the effect of cilostazol on resistance-sized vasculature is not well documented. Furthermore, mechanisms of vasodilation and influence on endothelium function are not fully understood. Thus, we investigated the vasodilator action of cilostazol using isolated, pressurized rabbit spinal arterioles with special reference to the functional endothelium. Cilostazol, acetylcholine (ACh), isocarbacyclin (prostacyclin analogue), and sodium nitroprusside (SNP) all produced concentration-dependent vasodilations of isolated spinal arterioles with endogenous myogenic tone. The order of potency of these agonists was isocarbacyclin>ACh>SNP>cilostazol. Indomethacin (10 micro M, a cyclo-oxygenase inhibitor), N(omega)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 30 micro M), or chemical denudation of the endothelial cells did not significantly alter the cilostazol-induced arteriolar dilation. Furthermore, stimulating the release of endothelium-derived relaxing factors by administering ACh (100 nM), or treating with isocarbacyclin (1 nM) or SNP (3 nM) did not significantly modify the cilostazol-induced vasodilation. These results suggest that cilostazol produces the vasodilation of isolated, pressurized rabbit spinal arterioles independent of the functional endothelium. We infer that the vasodilator action of cilostazol in the spinal arterioles may be attributed to a yet unknown mechanism that is independent of the PDE3 inhibition.
authors.affiliation: 1st Department of Physiology, Shinshu University School of Medicine, Matsumoto, 390-8621 Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Yashiro
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohhashi
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D002317:Cardiovascular Agents / Q000494:pharmacology; D000077407:Cilostazol; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D013116:Spinal Cord / Q000098:blood supply*; D013777:Tetrazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002317:Cardiovascular Agents; D010726:Phosphodiesterase Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000077407:Cilostazol