CENTRALLY MEDIATED CARDIOVASCULAR EFFECTS OF ETHANOL

乙醇的中枢介导的心血管作用

• 批准号: 2045969
• 负责人: GEORGE KUNOS
• 金额: $ 15.59万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045969
• 关键词: GABA receptor; afferent nerve; alcoholic beverage consumption; antihypertensive agents; baroreceptors; centrally acting drug; endorphins; ethanol; genetic strain; heart rate; hypertension; hypothalamus; inhibitor /antagonist; laboratory rat; neuroanatomy; proopiomelanocortin; solitary tract nucleus

The results of numerous epidemiological and controlled clinical studies indicate that chronic ethanol consumption increases both the prevalence and severity of hypertension. The pressor and tachycardiac effects of ethanol have been also documented in experimental animals, but the mechanisms underlying these effects are not clear. Ethanol can influence the cardiovascular system not only by a direct action on the heart and vasculature, but also by an action at sites of cardiovascular regulation in the central nervous system. The baroreceptor reflex is the most important homeostatic mechanism for maintaining blood pressure and heart rate within normal, physiological limits. Recent studies in the rat have demonstrated that both acute and chronic treatment with ethanol inhibit baroreflex bradycardia by acting at one or more sites in the brainstem. The nucleus tractus solitarii (NTS) is the site of the first synapse of the baroreflex arc and, together with the adjacent dorsal motor nucleus of the vagus (DVN) and nucleus ambiguous, are also sites of integration for additional afferent input that modulates, inhibits or facilitates, the baroreflex. Our working hypothesis is that ethanol inhibits baroreflex bradycardia by potentiating an endogenous inhibitory mechanism, and/or by inhibiting an endogenous facilitatory mechanism in the brainstem. The main inhibitory mechanism in the NTS/DVN is GABAergic, while endorphinergic input from the hypothalamus can facilitate baroreflex bradycardia. Our previous studies indicate that ethanol inhibits baroreflex bradycardia in part by potentiating the similar action of endogenous GABA in the NTS/DVN, and we have also shown that ethanol inhibits the activity of the hypothalamic endorphinergic neuronal system. The present proposal is to further clarify the role of GABA and beta-endorphin in the baroreflex inhibitory action of ethanol. We will examine the effects of ethanol on the cardiovascular responses to stimulation of various neural pathways that are known to impinge on and activate GABAergic interneurons in the NTS/DVN and nucleus ambiguous. We will test the effect of ethanol on the baroreflex in selectively bred rats that display differential sensitivity to the acute effects of ethanol, including the potentiation of GABA-gated chloride fluxes. Finally, we will examine the possible role of endorphinergic neural input to the NTS in the baroreflex inhibitory effect of ethanol.

大量流行病学和对照临床研究的结果 表明长期摄入乙醇会增加患病率 和高血压的严重程度。升压和心动过速作用 实验动物中也有乙醇的记录，但 这些影响背后的机制尚不清楚。乙醇会影响 心血管系统不仅通过直接作用于心脏 脉管系统，但也通过心血管调节部位的作用 在中枢神经系统中。压力感受器反射是最 维持血压和心脏的重要稳态机制 速率在正常的生理限度内。最近对大鼠的研究表明 表明急性和慢性乙醇治疗都会抑制 通过作用于脑干的一个或多个部位而引起压力反射性心动过缓。 孤束核（NTS）是第一个突触的位置 压力反射弧，以及邻近的背运动核 迷走神经 (DVN) 和核模糊不清，也是整合位点 调节、抑制或促进的额外传入输入 压力反射。我们的工作假设是乙醇抑制压力反射 通过增强内源性抑制机制和/或通过 抑制脑干内源性促进机制。主要 NTS/DVN 中的抑制机制是 GABA 能的，而内啡肽能的 来自下丘脑的输入可以促进压力反射性心动过缓。我们的 先前的研究表明，乙醇可抑制压力反射性心动过缓 部分是通过增强 NTS/DVN 中内源性 GABA 的类似作用， 我们还发现乙醇会抑制 下丘脑内啡能神经系统。目前的建议是 进一步阐明GABA和β-内啡肽在压力反射中的作用 乙醇的抑制作用。我们将研究乙醇对 心血管对各种神经通路刺激的反应 已知会影响并激活 GABA 能中间神经元 NTS/DVN 和核心不明确。我们将测试乙醇对 选择性繁殖的大鼠的压力反射表现出不同的敏感性 乙醇的急性作用，包括 GABA 门控的增强 氯化物通量。最后，我们将研究可能的作用 内啡肽能神经输入 NTS 的压力感受反射抑制作用 乙醇。