内源性大麻素系统对心房钠尿肽分泌的调节作用及机制

Atrial natriuretic peptide (ANP) is a peptide hormone synthesized and secreted predominantly from the atrial cardiomyocytes. ANP has been known to play a crucial role in maintaining homeostasis of cardiovascular system through the potent diuretic, natriuretic, vasorelaxant and antihypertensive actions. Recently, we have found that second messengers, ion channels and autonomic nervous system, which could modulate the cardiac myocyte contraction, are involved in the regulation of atrial ANP secretion. It has been known that the endocannabinoid system (ECS) is widely distributed in the body, and the ECS modulates the cardiac contractility. However, the effect of the ECS on atrial ANP secretion has not yet been defined. .This study will be performed in normal and hypertensive rats, using radioimmunoassay and molecular biology techniques. In order to explore the role of the ECS in the regulation of atrial ANP secretion and its signal transduction mechanisms in physiological/hypertensive pathological conditions, different drugs are infused into the atria, and also atrial dynamics, atrial ANP secretion and second messengers are measured. In order to explore the molecular mechanisms of the ECS in the regulation of atrial ANP secretion, the atrial tissue levels of ANP, cannabinoid and their receptor genes and protein expressions are measured. .We believe that the study will disclose the role of the ECS in the regulation of atrial ANP secretion, and modulation of cardiovascular function. Therefore, the results are expected to provide new ideas and theoretical basis for the prevention and treatment of cardiovascular diseases.

心房钠尿肽(ANP)是主要由心房肌细胞合成和分泌的肽类激素，具有利尿、扩血管和降压效应，在维持心血管稳态中发挥重要作用。我们前期研究表明，能影响心肌收缩的第二信使、离子通道和自主神经系统参与心房ANP分泌调节。已知体内广泛分布的内源性大麻素系统(ECS)亦能引起心肌收缩的改变，然而ECS对心房ANP分泌的调节作用如何目前尚不清楚。为此，本项目拟采用正常/高血压大鼠模型，利用放免和分子生物学技术，以大麻素及其代谢产物和不同工具药处理心房后，通过观测大麻素对心房动力、ANP分泌和第二信使的影响，探讨生理/高血压病理状态下ECS对心房ANP分泌的调节作用及胞内信号传导机制；通过观测心房中ANP、大麻素水平以及大麻素受体基因和蛋白表达，进而探讨高血压病理状态下ECS调节心房ANP分泌变化的分子机制，揭示ECS是否通过心房ANP分泌调节来参与心血管功能调控，为心血管疾病的防治提供新的思路和理论依据。

体内广泛分布的内源性大麻素系统(ECS)能引起心肌收缩的改变，然而ECS对心房ANP分泌的调节作用如何目前尚不清楚。为此，本项目拟采用正常/高血压大鼠模型，利用放免和分子生物学等技术，以大麻素及其代谢产物和不同工具药处理心房后，通过观测大麻素对心房动力、ANP分泌和第二信使的影响，探讨生理/高血压病理状态下ECS对心房ANP分泌的调节作用及胞内信号传导机制；通过观测心房中ANP、大麻素水平以及大麻素受体基因和蛋白表达，进而探讨高血压病理状态下ECS调节心房ANP分泌变化的分子机制。通过本课题实施获得了以下结果：（1）大麻素可促进心房钠尿肽分泌的同时降低心房动力。CB1受体阻断剂SR141716能阻断上述效应，而CB2受体阻断剂SR144528未能阻断上述效应。大麻素转运阻断剂AM 404对心房钠尿肽分泌的调节作用类似于大麻素的效应。（2）分别用乙酰胆碱、蛋白激酶G预处理后观察到大麻素的促进心房钠尿肽分泌的效应增强。但是，分别用异丙肾上腺素、蛋白激酶A和内皮素-1预处理后观察到大麻素的促进心房钠尿肽分泌的效应减弱。（3）大麻素的代谢产物花生四烯酸能促进心房钠尿肽的分泌，同时抑制心房动力。（4）高血压病理状态下ECS调节心房ANP分泌的作用增强，其机制与心房CB1受体的基因和蛋白表达上调有关。. 本研究探讨了生理/高血压病理状态下ECS调节心房ANP分泌变化的分子机制，揭示了ECS通过心房ANP分泌调节来参与心血管功能的调控作用，为心血管疾病的防治提供了新的思路和理论依据。