Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine‐induced increase in [Ca2+]i and force in middle cerebral artery of the rabbit
Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine‐induced increase in [Ca2+]i and force in middle cerebral artery of the rabbit
复制标题
III 型磷酸二酯酶抑制剂西洛他唑对组胺诱导的兔大脑中动脉 [Ca2+]i 和力量增加的影响
DOI：
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发表时间：
1998
影响因子：
7.3
通讯作者：
T. Itoh
中科院分区：
文献类型：
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作者：
Y. Shiraishi;Y. Kanmura;T. Itoh
1通过同时测定家兔大脑中动脉外周去内皮肌条的等长收缩力和细胞内Ca 2+浓度（[Ca 2 +]i），研究了磷酸二酯酶III（PDE III）抑制剂西洛他唑对组胺引起的收缩的影响。 2高K+（80 mM）引起[Ca 2 +]i和力的阶段性增加，随后是紧张性增加。 西洛他唑（10 μM）不改变静息[Ca 2 +]i，但可显著降低高K+诱导的强直性收缩，而[Ca 2 +]i反应无相应变化。 3组胺（3 μM）引起[Ca 2 +]i和力的阶段性增加，随后是紧张性增加。 西洛他唑（3和10 μM）以浓度依赖性方式显著降低组胺诱导的[Ca 2 +]i和力的阶段性和强直性增加。 4 Rp-腺苷-3 ′：5′-环硫代磷酸（Rp-cAMPS，0.1 mM）是一种蛋白激酶A的PDE抗性抑制剂（也是一种环AMP拮抗剂），未改变组胺单独诱导的[Ca 2 +]i和力的增加，但它显著降低了西洛他唑诱导的组胺诱导反应的抑制作用。 5在含有2 mM EGTA的无钙溶液中，组胺（3 μM）和咖啡因（10 mM）均短暂增加[Ca 2 +]i和力。 西洛他唑（1-10 μM）（i）显著降低组胺诱导的[Ca 2 +]i和力的增加，（ii）显著降低咖啡因诱导的力的增加，但不降低[Ca 2 +]i的增加。 6在ryanodine处理的试纸中，功能上失去了组胺敏感的Ca 2+储存位点，组胺（3 μM）缓慢增加[Ca 2 +]i和力。 西洛他唑（3和10 μM）可降低静息[Ca 2 +]i，但不能改变组胺诱导的[Ca 2 +]i升高，表明西洛他唑对组胺诱导的Ca 2+动员的抑制作用需要功能性Ca 2+储存位点。 [7]通过在含有100 mM K+的无Ca 2+溶液中应用递增浓度的Ca 2+（0.16-2.6 mM），在ryanodine处理的试纸中获得[Ca 2 +]i-力关系。 组胺（3 μM）使[Ca 2 +]i-力关系向左移动，并增加最大Ca 2+诱导力。 在相同条件下，无论是否存在3 μM组胺，西洛他唑（3-10 μM）均使[Ca 2 +]i-力关系向右移动，而不会导致最大Ca 2+诱导力发生变化。 8可以得出结论，在家兔大脑中动脉外周部分的平滑肌中，西洛他唑通过抑制组胺诱导的Ca 2+动员和降低肌丝Ca 2+敏感性来减弱组胺诱导的收缩。这表明，PDE III抑制后环AMP细胞浓度的增加可能在西洛他唑诱导的组胺收缩抑制中发挥重要作用。
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 Ca2+ ([Ca2+]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 [Ca2+]i and force. Cilostazol (10 μM) did not modify the resting [Ca2+]i, but it did significantly decrease the tonic contraction induced by high K+ without a corresponding change in the [Ca2+]i response. 3 Histamine (3 μM) produced a phasic, followed by a tonic increase in both [Ca2+]i and force. Cilostazol (3 and 10 μM) significantly reduced both the phasic and tonic increases in [Ca2+]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 [Ca2+]i and force induced by histamine alone, but it did significantly decrease the cilostazol‐induced inhibition of the histamine‐induced responses. 5 In Ca2+‐free solution containing 2 mM EGTA, both histamine (3 μM) and caffeine (10 mM) transiently increased [Ca2+]i and force. Cilostazol (1–10 μM) (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‐treated strips, which had functionally lost the histamine‐sensitive Ca2+ storage sites, histamine (3 μM) slowly increased [Ca2+]i and force. Cilostazol (3 and 10 μM) lowered the resting [Ca2+]i, but did not 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‐force relationship was obtained in ryanodine‐treated strips by applying ascending concentrations of Ca2+ (0.16–2.6 mM) in Ca2+‐free solution containing 100 mM K+. Histamine (3 μM) shifted the [Ca2+]i‐force relationship to the left and increased the maximum Ca2+‐induced force. Under the same conditions, whether in the presence or absence of 3 μM histamine, cilostazol (3–10 μM) shifted the [Ca2+]i‐force relationship to the right without producing a change in the maximum Ca2+‐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 Ca2+ mobilization and by reducing the myofilament Ca2+ 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.