EFFECT OF CILOSTAZOL, A PHOSPHODIESTERASE TYPE-III INHIBITOR, ON HISTAMINE-INDUCED INCREASE IN [CA2-ARTERY OF THE RABBIT(](I) AND FORCE IN MIDDLE CEREBRAL)

1 The effect of cilostazol, an inhibitor of phosphodiesterase type III (PDE III), on the contraction induced by histamine was studied by mak ing simultaneous measurements of isometric force and the intracellular concentration of Ca2+ ([Ca2+](i)) in endothelium-denuded muscle strip s from the peripheral part of the middle cerebral artery of the rabbit . 2 High K+ (80 mM) produced a phasic, followed by a tonic increase in both [Ca2+](i) and force. Cilostazol (10 mu M) did not modify the res ting [Ca2+](i), but it did significantly decrease the tonic contractio n induced by high K+ without a corresponding change in the [Ca2+](i) r esponse. 3 Histamine (3 mu M) produced a phasic, followed by a tonic i ncrease in both [Ca2+](i) and force. Cilostazol (3 and 10 mu M) signif icantly reduced both the phasic and tonic increases in [Ca2+](i) and f orce induced by histamine, in a concentration-dependent manner. 4 Rp-a denosine-3':5'-cyclic monophosphorothioate (Rp-cAMPS, 0.1 mM), a PDE-r esistant inhibitor of protein kinase A (and as such a cyclic AMP antag onist), did not modify the increases in [Ca2+](i) and force induced by histamine alone, but it did significantly decrease the cilostazol-ind uced inhibition of the histamine-induced responses. 5 In Ca2+-free sol ution containing 2 mM EGTA, both histamine (3 mu M) and caffeine (10 m M) transiently increased [Ca2+](i) and force. Cilostazol (1-10 mu M) ( i) significantly reduced the increases in [Ca2+](i) and force induced by histamine, and (ii) significantly reduced the increase in force but not the increase in [Ca2+](i) induced by caffeine. 6 In ryanodine-tre ated strips, which had functionally lost the histamine-sensitive Ca2storage sites, histamine (3 mu M) slowly increased [Ca2+](i) and force . Cilostazol (3 and 10 mu M) lowered the resting [Ca2+](i), but did no t modify the histamine-induced increase in [Ca2+](i), suggesting that functional Ca2+ storage sites are required for the cilostazol-induced inhibition of histamine-induced Ca2+ mobilization. 7 The [Ca2+](i)-for ce relationship was obtained in ryanodine-treated strips by applying a scending concentrations of Ca2+ (0.16-2.6 mM) in Ca2+-free solution co ntaining 100 mM K+. Histamine (3 mu M) shifted the [Ca2+](i)-force rel ationship to the left and increased the maximum Ca2+-induced force. Un der the same conditions, whether in the presence or absence of 3 mu M histamine, cilostazol (3-10 mu M) shifted the [Ca2+](i)-force relation ship to the right without producing a change in the maximum Ca2+-induc ed force. 8 It is concluded that, in smooth muscle of the peripheral p art of the rabbit middle cerebral artery, cilostazol attenuates the hi stamine-induced contraction both by inhibiting histamine-induced Ca2mobilization and by reducing the myofilament Ca2+ sensitivity. It is s uggested that the increase in the cellular concentration of cyclic AMP that will follow the inhibition of PDE III may play an important role in the cilostazol-induced inhibition of the histamine-contraction.