Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38103, United States.
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38103, United States.
Alcohol. 2018 Dec;73:45-55. doi: 10.1016/j.alcohol.2018.04.002. Epub 2018 Apr 26.
Alcohol (ethyl alcohol; ethanol) and caffeine are the two most widely used psychoactive substances in the world. Caffeine and ethanol have both been reported to constrict cerebral arteries in several species, including humans. We have recently shown that application of 10-μM caffeine mixed with 50 mM ethanol to in vitro pressurized cerebral arteries of rats reduced ethanol-induced constriction. This effect was dependent on the presence of nitric oxide (NO) and could be observed in de-endothelialized arteries supplied with the NO donor sodium nitroprusside (SNP). The molecular target(s) of ethanol-caffeine interaction in cerebral arteries has remained unknown. In the present work, we used rat and mouse middle cerebral arteries (MCA) to identify the extra-endothelial effectors of NO-mediated, caffeine-induced protection against ethanol-evoked arterial constriction. Constriction of intact MCA of rat by either 50 mM ethanol or 10 μM caffeine was ablated in the presence of a selective TRPV1 pharmacological blocker. TRPV1 pharmacological block, but not block of TRPA1, PKG, or BK channels, removed caffeine-induced protection against ethanol-evoked rat MCA constriction, whether evaluated in arteries with intact endothelium or in SNP-supplemented, de-endothelialized arteries. In mouse arteries, caffeine-induced protection against ethanol-induced MCA constriction was significantly amplified, resulting in actual vasodilation, upon pharmacological block of TRPV1, and in TRPV1 knock-out arteries. Despite some species-specific differences, our study unequivocally demonstrates the presence of functional, extra-endothelial TRPV1 that participates in both endothelium-independent MCA constriction by separate exposure to ethanol or caffeine and caffeine-induced protection against ethanol-evoked MCA constriction.
酒精（乙基酒精；乙醇）和咖啡因是世界上使用最广泛的两种精神活性物质。据报道，咖啡因和乙醇都能使包括人类在内的几种物种的脑动脉收缩。我们最近表明，将 10-μM 咖啡因与 50mM 乙醇混合应用于体外加压大鼠脑动脉，可减少乙醇诱导的收缩。这种作用依赖于一氧化氮（NO）的存在，并且可以在用 NO 供体硝普钠（SNP）供应的去内皮化动脉中观察到。乙醇-咖啡因相互作用在脑动脉中的分子靶标（s）仍然未知。在本工作中，我们使用大鼠和小鼠大脑中动脉（MCA）来鉴定 NO 介导的咖啡因对乙醇诱导的动脉收缩的保护作用的血管外效应器。在选择性 TRPV1 药理学阻滞剂存在的情况下，50mM 乙醇或 10μM 咖啡因对完整大鼠 MCA 的收缩作用被消除。TRPV1 药理学阻断，但不是 TRPA1、PKG 或 BK 通道阻断，消除了咖啡因对乙醇诱导的大鼠 MCA 收缩的保护作用，无论是在完整内皮的动脉中还是在 SNP 补充的去内皮化动脉中评估。在小鼠动脉中，TRPV1 药理学阻断后，咖啡因对乙醇诱导的 MCA 收缩的保护作用显著放大，导致实际的血管舒张，并且在 TRPV1 敲除动脉中也是如此。尽管存在一些种间差异，但我们的研究明确表明存在功能性的血管外 TRPV1，它参与了分别暴露于乙醇或咖啡因引起的非内皮依赖性 MCA 收缩以及咖啡因对乙醇诱导的 MCA 收缩的保护作用。
