John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, Australian Capital Territory, Australia.
J Cereb Blood Flow Metab. 2010 Jun;30(6):1226-39. doi: 10.1038/jcbfm.2010.11. Epub 2010 Feb 3.
Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (Ca(V)1.2) and T-type (Ca(V)3.1 and Ca(V)3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L- and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised approximately 20% of current in SMCs of the main arteries and approximately 45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.
尽管二氢吡啶类药物被广泛用于治疗血管痉挛,但它们的疗效存在疑问,这表明其他电压依赖性钙通道(VDCC)有助于控制脑血管张力。因此,本研究探讨了二氢吡啶类药物不敏感的 VDCC 在脑血管功能中的作用。通过定量 PCR 和免疫组织化学,我们在成年大鼠基底动脉和大脑中动脉及其分支中发现了 L 型(Ca(V)1.2)和 T 型(Ca(V)3.1 和 Ca(V)3.2)通道的 mRNA 和蛋白。免疫电子显微镜显示 L 型和 T 型通道均存在于平滑肌细胞(SMC)膜中。通过膜片钳电生理学,我们发现一种高电压激活的钙电流,具有 T 型通道动力学特征,对硝苯地平和尼莫地平不敏感,约占主动脉 SMC 电流的 20%,约占分支 SMC 电流的 45%。这两种成分均被 T 型拮抗剂米贝地尔、NNC 55-0396 和依福地平所消除。尽管硝苯地平完全阻断了加压基底动脉的血管收缩,但在分支中发现了一种硝苯地平不敏感的收缩,并且随着血管尺寸的减小,这种收缩的幅度增加。我们得出结论,异质的 VDCC 群体有助于脑血管功能,二氢吡啶类药物不敏感的通道在较小的血管中具有更大的作用。这些电流对非选择性 T 型通道拮抗剂的敏感性表明,这些药物可能为治疗难治性脑血管收缩提供更有效的治疗方法。