A novel ionic current contributing to spasm of small blood vessels

血管平滑肌会产生强烈的收缩或痉挛，严重限制血流。这种痉挛引起的疾病包括猝死、神经功能障碍、视力和听力丧失或损害、雷诺现象(手指和脚趾阵发性疼痛收缩)和肠道坏死。共同的机制可能是与这些不同的疾病相关的痉挛的基础。在最近的一项血管平滑肌电生理研究中，我们发现了一种新的膜电流，我们称之为平台电流。这种电流具有强烈的去极化影响，很可能对痉挛做出重大贡献，特别是在更依赖于去极化收缩的小动脉和小动脉。阻断这一电流有望最大限度地减少去极化，从而防止或缓解血管痉挛。因此，高原电流代表了一个治疗潜力的新领域，用于解决具有重大健康影响的血管问题。然而，对电流的治疗操作需要了解其特性。在这个项目中，我们将使用电压钳技术来确定该电流的生物物理和药理学特性。然后，我们将利用这些信息，通过同时记录细胞内微电极的膜电位和收缩活动来评估其功能意义。我们还将比较患有或不患有雷诺现象的血管痉挛障碍的志愿者的小血管。我们以前使用这些技术的工作在《J Physiol》杂志上被描述为最高质量和最高技术难度的微电极、膜片钳和肌电研究，并获得了前十名的命中率。由于我们是唯一记录高原流的人，我们处于独特的地位，可以在我们对小血管收缩(包括痉挛)的理解方面取得重大进展。

Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow. Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In a recent electrophysiological study of vascular smooth muscle, we discovered a novel membrane current which we refer to as the plateau current. This current has a strong depolarizing influence that is likely to make a major contribution to the spasms, particularly in arterioles and small arteries which are more dependent on depolarization for contraction. Block of this current is expected to minimize the depolarization and therefore prevent or ameliorate spasm of the vessels. Thus the plateau current represents a new field of therapeutic potential for addressing vascular problems that have significant health implications. However, therapeutic manipulation of the current requires knowledge of its properties. In this project we will determine the biophysical and pharmacological properties of this current using voltage-clamp techniques. We will then use this information to assess its functional significance by recording membrane potential with intracellular microelectrodes simultaneously with contractile activity. We will also compare small vessels obtained from volunteers with or without the vasospastic disorder of Raynaud's phenomenon. Our previous work using these techniques was described in J Physiol as a microelectrode, patch clamp and myograph study of the highest quality and of supreme technical difficulty and scored a Top-Ten hit rate. Since we are the only ones to record the plateau current, we are in a unique position to make significant progress to our understanding of contraction, including spasm, in small blood vessels.