Grant Abstract: Ethanol actions on slo channels from arteries vs. brain

Grant Number: 5R37AA011560-18
PI Name: Dopico
Project Title: Ethanol actions on slo channels from arteries vs. brain

Abstract: We submitted this proposal in response to a call from the Office of Dietary Supplements (ODS) to provide administrative supplements for research on Dietary Supplements (PAR-14-201), including caffeine-containing supplements/food, caffeine-containing energy drinks (CCED) in particular. The proposal is linked to the NIAAA-funded project “Ethanol actions on slo channels from arteries vs. brain” (PI: Dopico; R37-AA11560; current period: 07/14-06/19). Intake of CCED and energy supplements containing caffeine as main active compound continue to rise. They are particularly targeted at males to boost physical energy and mental alertness. One-two CCED matches 200 mg of caffeine, and abuse leads to poor health outcomes, in particular when interacting with alcohol. Despite the increased consumption of alcohol and CCED, the molecular targets underlying caffeine-alcohol interactions remain in most cases unknown.
Episodic drinking (such as during binge drinking) with blood alcohol levels of 35-80 mM is associated with an increased risk for cerebrovascular ischemia, stroke, and death from ischemic stroke. Cerebrovascular ischemia may result from impaired dilation and/or enhanced constriction of cerebral arteries. In our study of ethanol targets involved in ethanol-induced cerebral constriction, however, we discovered a protective effect of caffeine against ethanol-induced cerebral artery constriction, both in vivo and in vitro. Caffeine does not significantly alter alcohol metabolism in the body. Thus, caffeine protection against alcohol action must occur at the cerebral artery itself. While caffeine targets in vascular beds have been studied extensively, the initial targets and mechanisms of this protection are unknown. Based on solid Supporting data and key Preliminary findings, we will utilize selective pharmacology on pressurized cerebral arteries of rat and endothelial nitric oxide synthase (eNOS) knock-out mouse to complete following Specific Aims: 1) determine whether it is eNOS activity that is required for the caffeine protection against ethanol-induced cerebral artery constriction; 2) detect distinct nitric oxide (NO•) targets present in the vascular smooth muscle that mediate caffeine-induced protection against deleterious constriction of cerebral arteries by ethanol. Based on recognized targets of NO• within smooth muscle cells, we will test non-mutually exclusive targets: TRPV1-mediated (sub-aim 2.1) and PKG-mediated (2.2) pathways, and a direct NO•-BK channel interaction (2.3).
Our proposal will unveil for the first time the primary targets of the caffeine-alcohol interaction in cerebral arteries. Newly acquired data will provide critical information that is necessary for designing small agents that may modulate specific targets involved in such interaction and thus, obtain therapeutic benefit on the detrimental effects of widely used psychoactive drugs on brain circulation.

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