Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine‐induced increase in [Ca²⁺]_i and force in middle cerebral artery of the rabbit

Abstract

1 The e ect 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 mM) produced a phasic, followed by a tonic increase in both [Ca 2+ ] i and force. Cilostazol (10 mM) did not modify the resting [Ca 2+ ] i , but it did signi®cantly decrease the tonic contraction induced by high K + without a corresponding change in the [Ca 2+ ] i response. 3 Histamine (3 mM) produced a phasic, followed by a tonic increase in both [Ca 2+ ] i and force. Cilostazol (3 and 10 mM) signi®cantly 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 mM), 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 signi®cantly decrease the cilostazol-induced inhibition of the histamine-induced responses. 5 In Ca 2+ -free solution containing 2 mM EGTA, both histamine (3 mM) and ca eine (10 mM) transiently increased [Ca 2+ ] i and force. Cilostazol (1 ± 10 mM) (i) signi®cantly reduced the increases in [Ca 2+ ] i and force induced by histamine, and (ii) signi®cantly reduced the increase in force but not the increase in [Ca 2+ ] i induced by ca eine. 6 In ryanodine-treated strips, which had functionally lost the histamine-sensitive Ca 2+ storage sites, histamine (3 mM) slowly increased [Ca 2+ ] i and force. Cilostazol (3 and 10 mM) 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 mM) in Ca 2+ -free solution containing 100 mM K + . Histamine (3 mM) 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 mM histamine, cilostazol (3 ± 10 mM) 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 myo®lament 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.

Neuroprotective Effects of Cilostazol on Retinal Ganglion Cell Damage in Diabetic Rats

“…These inhibitory effects on platelet functions are due to decreased intracellular Ca 21 concentration caused by elevated cyclic AMP levels. An arterial vasodilation by cilostazol is mediated through its direct action on vascular smooth muscle cells (Shiraishi et al, 1998). Those antiplatelet, antithrombotic, and vasodilation effects of cilostazol may support its protective effects on diabetic retinopathy, which is characterized by retinal microvascular alterations and subsequent ischemia.…”

The Phosphodiesterase 3 Inhibitor Cilostazol Dilates Large Cerebral Arteries in Humans Without Affecting Regional Cerebral Blood Flow

“…Cilostazol dilates cerebral arteries in vitro (Birk et al, 2004a;Shiraishi et al, 1998), and the effect is not dependent on a functional vascular endothelium or nitric oxide tone (Birk et al, 2004a). This is important, because dysfunction of the endothelium or of the nitric oxide-cyclic GMP pathway has been proposed to participate in the pathogenesis of DCV (Sobey, 2001).…”

Effects of Cilostazol, a Selective Cyclic AMP Phosphodiesterase Inhibitor on Isolated Rabbit Spinal Arterioles.

“…Vasodilator prostaglandins, on the other hand, may potentiate the vasodilator action of cilostazol by increasing cAMP in the smooth muscles via activating adenylate cyclase [15][16][17]. Thus, although cilostazol and other PDE3 inhibitors are shown to exert vasodilation even in the absence of intact endothelium [10,13,18,19], it is of particular interest whether or not endothelium or endotheliumderived factors can modulate the vasodilator action of cilostazol.…”