title: Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction.
abstract: Despite preventive education, the combined consumption of alcohol and caffeine (particularly from "energy drinks") continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied. Using intravital microscopy on a closed-cranial window and isolated, pressurized vessels, we investigated the in vivo and in vitro action of ethanol-caffeine mixtures on cerebral arteries from rats and mice, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation after ingestion of one to two cups of coffee (10 µM) antagonized the endothelium-independent constriction of cerebral arteries evoked by ethanol concentrations found in blood during moderate-heavy alcohol intoxication (40-70 mM). Caffeine antagonism against alcohol was similar whether evaluated in vivo or in vitro, suggesting independence of systemic factors and drug metabolism, but required a functional endothelium. Moreover, caffeine protection against alcohol increased nitric oxide (NO•) levels over those found in the presence of ethanol alone, disappeared upon blocking NO• synthase, and could not be detected in pressurized cerebral arteries from endothelial nitric-oxide synthase knockout (eNOS(-/-)) mice. Finally, incubation of de-endothelialized cerebral arteries with the NO• donor sodium nitroprusside (10 µM) fully restored the protective effect of caffeine. This study demonstrates for the first time that caffeine antagonizes ethanol-induced cerebral artery constriction and identifies endothelial NO• as the critical caffeine effector on smooth muscle targets. Conceivably, situations that perturb endothelial function and/or NO• availability will critically alter caffeine antagonism of alcohol-induced cerebrovascular constriction without significantly disrupting endothelium-independent, alcohol-induced cerebral artery constriction itself.
authors.affiliation: Department of Pharmacology (J.C., G.K., A.N.B., A.M.D.) and Department of Physiology (A.L.F., C.W.L.), College of Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pharmacology (J.C., G.K., A.N.B., A.M.D.) and Department of Physiology (A.L.F., C.W.L.), College of Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Fedinec
authors.affiliation: Department of Pharmacology (J.C., G.K., A.N.B., A.M.D.) and Department of Physiology (A.L.F., C.W.L.), College of Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee.
authors.forename: Guruprasad
authors.initials: G
authors.lastname: Kuntamallappanavar
authors.affiliation: Department of Pharmacology (J.C., G.K., A.N.B., A.M.D.) and Department of Physiology (A.L.F., C.W.L.), College of Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Leffler
authors.affiliation: Department of Pharmacology (J.C., G.K., A.N.B., A.M.D.) and Department of Physiology (A.L.F., C.W.L.), College of Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Bukiya
authors.affiliation: Department of Pharmacology (J.C., G.K., A.N.B., A.M.D.) and Department of Physiology (A.L.F., C.W.L.), College of Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee adopico@uthsc.edu.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Dopico
mesh_terms: D000818:Animals; D002110:Caffeine / Q000097:blood / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D002492:Central Nervous System Depressants; D000697:Central Nervous System Stimulants; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D002110:Caffeine; D000431:Ethanol; D052250:Nitric Oxide Synthase Type III