Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine‐induced increase in [Ca 2+ ] i and force in middle cerebral artery of the rabbit

1 The effect of cilostazol, an inhibitor of phosphodiesterase type III (PDE III), on the contraction induced by histamine was studied by making simultaneous measurements of isometric force and the intracellular concentration of Ca 2+ ([Ca 2+ ] i ) in endothelium‐denuded muscle strips from the peripheral part of the middle cerebral artery of the rabbit. 2 High K + (80 m M ) produced a phasic, followed by a tonic increase in both [Ca 2+ ] i and force. Cilostazol (10 μ M ) did not modify the resting [Ca 2+ ] i , but it did significantly decrease the tonic contraction induced by high K + without a corresponding change in the [Ca 2+ ] i response. 3 Histamine (3 μ M ) produced a phasic, followed by a tonic increase in both [Ca 2+ ] i and force. Cilostazol (3 and 10 μ M ) significantly reduced both the phasic and tonic increases in [Ca 2+ ] i and force induced by histamine, in a concentration‐dependent manner. 4 Rp‐adenosine‐3′ : 5′‐cyclic monophosphorothioate (Rp‐cAMPS, 0.1 m M ), a PDE‐resistant inhibitor of protein kinase A (and as such a cyclic AMP antagonist), did not modify the increases in [Ca 2+ ] i and force induced by histamine alone, but it did significantly decrease the cilostazol‐induced inhibition of the histamine‐induced responses. 5 In Ca 2+ ‐free solution containing 2 m M EGTA, both histamine (3 μ M ) and caffeine (10 m M ) transiently increased [Ca 2+ ] i and force. Cilostazol (1–10 μ M ) (i) significantly reduced the increases in [Ca 2+ ] i and force induced by histamine, and (ii) significantly reduced the increase in force but not the increase in [Ca 2+ ] i induced by caffeine. 6 In ryanodine‐treated strips, which had functionally lost the histamine‐sensitive Ca 2+ storage sites, histamine (3 μ M ) slowly increased [Ca 2+ ] i and force. Cilostazol (3 and 10 μ M ) lowered the resting [Ca 2+ ] i , but did not modify the histamine‐induced increase in [Ca 2+ ] i , suggesting that functional Ca 2+ storage sites are required for the cilostazol‐induced inhibition of histamine‐induced Ca 2+ mobilization. 7 The [Ca 2+ ] i ‐force relationship was obtained in ryanodine‐treated strips by applying ascending concentrations of Ca 2+ (0.16–2.6 m M ) in Ca 2+ ‐free solution containing 100 m M K + . Histamine (3 μ M ) shifted the [Ca 2+ ] i ‐force relationship to the left and increased the maximum Ca 2+ ‐induced force. Under the same conditions, whether in the presence or absence of 3 μ M histamine, cilostazol (3–10 μ M ) shifted the [Ca 2+ ] i ‐force relationship to the right without producing a change in the maximum Ca 2+ ‐induced force. 8 It is concluded that, in smooth muscle of the peripheral part of the rabbit middle cerebral artery, cilostazol attenuates the histamine‐induced contraction both by inhibiting histamine‐induced Ca 2+ mobilization and by reducing the myofilament Ca 2+ sensitivity. It is suggested 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.British Journal of Pharmacology (1998) 123 , 869–878; doi: 10.1038/sj.bjp.0701699