MELATONIN AND CEREBRAL BLOOD FLOW AUTOREGULATION

褪黑激素和脑血流自动调节

• 批准号: 6026896
• 负责人: MOHAN VISWANATHAN
• 金额: $ 10.91万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6026896
• 关键词: autoradiography; cerebral artery; hemorrhage; hormone receptor; hormone regulation /control mechanism; hypercapnia; laboratory rat; melatonin; ultrasound blood flow measurement; vasomotion

Melatonin, a neuroendocrine transducer of photoperiod, is used by mammals to establish and maintain circadian rhythms. Melatonin receptors which mediate these functions are believed to be located in the hypothalamus. Recent studies demonstrate that high affinity melatonin receptors are also present in cerebral arteries and that melatonin is capable of causing constriction of these arteries. However, our understanding of the functional role of melatonin receptors in cerebral arteries is lacking. Therefore, the major goal of the proposed research is to define the physiological role of these receptors in cerebral blood flow. The proposed project will focus on functional studies and signal transduction mechanisms of melatonin receptors in the cerebral arteries of rats, and pharmacological characterization of melatonin binding sites that the applicant has recently identified in human cerebral arteries. The specific aims of this proposal are: (1) Evaluation of the physiological role of melatonin in cerebral circulation. We will test the hypothesis that melatonin modulates cerebral vasodilation during experimental hypotension and hypercapnia, conditions where vasodilators are known to be active. (2) Evaluation of the pharmacological properties and receptor signaling mediated by melatonin receptors in cerebral arteries. We will test the hypothesis that: (a) melatonin causes vasoconstriction by potentiating the stimulating action of calcium-mobilizing agents on phosphoinositide phospholipid hydrolysis; (b) melatonin inhibits cAMP accumulation stimulated by vasodilators; and (c) a changes in density and affinity of melatonin receptors in the artery will be reflected in a significant change in melatonin-induced contraction. (3) Localization and characterization of melatonin receptors in human cerebral arteries. Using quantitative autoradiography we will perform the pharmacological characterization of melatonin receptors in various human cerebral arteries. These studies will (a) further our understanding of the role of melatonin receptors in cerebral arterial contraction and cerebral blood flow, and the biochemical processes by which these effects are produced, and (b) pave the way for future studies on the physiology of vascular melatonin receptors in health and disease.

褪黑激素是光周期的神经内分泌转换器，被哺乳动物用来建立和维持昼夜节律。调节这些功能的褪黑激素受体被认为位于下丘脑中。最近的研究表明，高亲和力褪黑激素受体也存在于脑动脉中，褪黑激素能够引起这些动脉的收缩。然而，我们对脑动脉中褪黑激素受体的功能作用缺乏了解。因此，拟议研究的主要目标是确定这些受体在脑血流中的生理作用。拟开展的项目将侧重于大鼠脑动脉中褪黑激素受体的功能研究和信号转导机制，以及申请人最近在人类脑动脉中发现的褪黑激素结合位点的药理学表征。本研究的具体目的是：（1）评价褪黑素在脑循环中的生理作用。我们将检验褪黑激素在实验性低血压和高碳酸血症时调节脑血管舒张的假设，在这种情况下血管舒张剂是活跃的。(2)脑动脉中褪黑激素受体介导的药理学特性和受体信号传导的评价。我们将检验以下假设：（a）褪黑激素通过增强钙动员剂对磷酸肌醇磷脂水解的刺激作用而引起血管收缩;（B）褪黑激素抑制血管扩张剂刺激的cAMP积累;（c）褪黑激素诱导的收缩的显著变化将反映动脉中褪黑激素受体密度和亲和力的变化。(3)人脑动脉褪黑素受体的定位和特征。利用定量放射自显影术，我们将进行各种人类脑动脉褪黑激素受体的药理学特性。这些研究将（a）进一步了解褪黑激素受体在脑动脉收缩和脑血流中的作用，以及产生这些作用的生化过程，（B）为未来研究健康和疾病中血管褪黑激素受体的生理学铺平道路。