Arterial 5-HT Transporter Function

5-羟色胺(5-羟色胺，5-羟色胺)浓度或受体刺激的改变有 治疗抑郁症、进食障碍和肥胖症。5-羟色胺也是一种血管 有丝分裂原和血管收缩因子，但已经产生了大量的工作 5-羟色胺改善体内动脉张力在控制全身血液方面的结果不明确 压力。重要的是，5-羟色胺与外周动脉功能的相关性一直受到质疑 因为5-羟色胺的动脉处理和代谢机制尚不清楚。我们的整体 假设5-羟色胺转运体(SERT)存在于外周动脉中，并具有 对动脉功能的生理影响。我们将使用一套集成的技术- 隔离组织浴和肌层摄影术，免疫组织化学，Western胶片，细胞培养， 转运蛋白活性分析和遥测--在大鼠和小鼠身上--以解决两个特定目标： 具体目标#1：检验5-羟色胺被动脉摄取和释放的假设 用SERT检测平滑肌。我们假设5-羟色胺被积极吸收、释放和 可能储存在外周动脉，功能依赖于SERT。这些发现建立了一个 动脉局部5-羟色胺能系统的情况，一个系统应该被调节和 如果生理上重要的话是可以修改的。因此，这一目标的工作是为了理解 SERT的功能调节和检测是否存在可形成 局部5-羟色胺系统：合成、摄取、储存和释放。 具体目标2：验证SERT通过以下途径改变动脉功能的假设 生理后果。这个目标建立在目标1的基础上，通过研究SERT的两个模型 功能具有生理学相关性，因此能够说明 5-羟色胺/SERT与调节动脉收缩功能和血压有关。第一个型号是 亚阈值浓度的5-羟色胺使动脉收缩增强到 去甲肾上腺素和内皮素，第二种为高血压模型。 总的来说，这些研究很重要，因为它们强调了5-羟色胺在 外周心血管系统，揭示了SERT的新功能。此外， 因为SERT是常用的5-羟色胺再摄取抑制剂的靶点，例如 百忧解，这些研究为心血管并发症提供了潜在的洞察力 那些服用SERT抑制剂的人。

Modification of 5-hydroxytryptamine (5-HT, serotonin) concentration or receptor stimulation has resulted in treatments for depression, feeding disorders and obesity. 5-HT is also a vascular smooth muscle cell mitogen and vasoconstrictor but a significant amount of work has produced equivocal results in terms of 5-HT modifying arterial tone in vivo in the control of systemic blood pressure. Importantly, the relevance of 5-HT to peripheral arterial function has been questioned because mechanisms for arterial handing and metabolism of 5-HT are unknown. Our overall hypothesis is that the serotonin transporter (SERT) is present in peripheral arteries and has physiological consequence in arterial function. We will use an integrated set of techniques - isolated tissue baths and myographs, immunohistochemistry, Westerns, cell culture, transporter activity assays, and telemetry -- in rats and mice to address two specific Aims: Specific Aim #1: To test the hypothesis that 5-HT is taken up and released from arterial smooth muscle by SERT. We hypothesize that 5-HT is actively taken up, released and potentially stored in peripheral arteries, functions dependent on SERT. Such findings build a case for a local serotonergic system in the artery, a system which should be regulated and modifiable if physiologically important. Thus, work in this aim is directed towards understanding functional regulation of SERT and testing for the presence of components that would form a local 5-HT system: synthesis, uptake, storage and release. Specific Aim #2: To test the hypothesis that SERT modifies arterial function with physiological consequence. This aim builds on Aim 1 by studying two models in which SERT function has physiological relevance and thus enables illustration of the importance of 5-HT/SERT as it relates to modifying arterial contractility and blood pressure. The first model is the artery in which subthreshpld concentrations of 5-HT potentiate arterial contraction to norepinephrine and endothelin, the second a model of hypertension. Collectively, these studies are important because they highlight the role of 5-HT in the peripheral cardiovascular system, and reveal a new functional role for SERT. Moreover, because SERT is a target for the commonly prescribed serotonin reuptake inhibitors such as Prozac¿, these studies provide potential insight into cardiovascular complications experienced by those taking SERT inhibitors.