The vasodilator papaverine stimulates L-type Ca2+ current in rat tail artery myocytes via a PKA-dependent mechanism
The vasodilator papaverine stimulates L-type Ca2+ current in rat tail artery myocytes via a PKA-dependent mechanism
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DOI：
10.1016/j.vph.2015.11.041
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Saponara, Simona
中科院分区：
文献类型：
--
作者：
Fusi, Fabio;Manetti, Fabrizio;Saponara, Simona
罂粟碱是一种鸦片生物碱，主要用作抗痉挛药物和脑和冠状动脉扩张剂。其磷酸二酯酶抑制活性主要促进细胞质中cAMP水平的升高。由于已知cAMP可以调节l型Ca2+通道活性，因此我们在这里测试了罂粟碱可以影响血管通道功能的命题。在大鼠尾动脉肌细胞中，采用全细胞或穿孔膜片钳方法，深入分析了罂粟碱通过L型Ca2+通道[I-Ba(L)或I-Ca(L)]对Ba2+或Ca2+电流的影响，并对大鼠主动脉环进行了功能研究。罂粟碱增加了穿孔或全细胞结构下的电流振幅。罂粟碱对电流的刺激是浓度、V-h、频率和电荷载流子相关的，并通过药物冲洗完全恢复。PICA抑制剂H89，而不是PKG抑制剂Rp-8-Br-cGMPS，可以拮抗罂粟碱和IBMX（另一种磷酸二酯酶抑制剂）诱导的I-Ba(L)刺激。在用IBMX预处理的细胞中，应用罂粟碱不能增加电流振幅。罂粟碱加速了I-Ba(L)的失活动力学，尽管只有在浓度>= 30 μ M时，并且将失活曲线的电压依赖性转移到更多的负电位。在环中，以前用硝苯地平治疗后，罂粟碱的血管舒张活性增强。总之，罂粟碱通过pka依赖性机制刺激血管l型Ca2+通道，从而拮抗其主要的血管舒张活性。(C) 2015 Elsevier Inc .版权所有
Papaverine is an opium alkaloid, primarily used as an antispasmodic drug and as a cerebral and coronary vasodilator. Its phosphodiesterase inhibitory activity promotes increase of cAMP levels mainly in the cytosol. As cAMP is known to modulate L-type Ca2+ channel activity, here we tested the proposition that papaverine could affect vascular channel function. An in-depth analysis of the effect of papaverine on Ba2+ or Ca2+ current through L-type Ca2+ channel [I-Ba(L) or I-Ca(L)], performed in rat tail artery myocytes using either the whole-cell or the perforated patch-clamp method, was accompanied by a functional study on rat aorta rings. Papaverine increased current amplitude under both the perforated or whole-cell configuration. Stimulation of the current by papaverine was concentration-, V-h-, frequency-, and charge carrier-dependent, and fully reverted by drug washout. The PICA inhibitor H89, but not the PKG inhibitor Rp-8-Br-cGMPS, antagonised papaverine- as well as IBMX- (another phosphodiesterase inhibitor) induced I-Ba(L) stimulation. In cells pre-treated with IBMX, application of papaverine failed to increase current amplitude. Papaverine sped up the inactivation kinetics of I-Ba(L), though only at concentrations >= 30 mu M, and shifted the voltage dependence of the inactivation curve to more negative potentials. In rings, the vasorelaxing activity of papaverine was enhanced by previous treatment with nifedipine. In conclusion, papaverine stimulates vascular L-type Ca2+ channel via a PKA-dependent mechanism, thus antagonising its main vasodilating activity. (C) 2015 Elsevier Inc All rights reserved.