Despite preventative education, the combined consumption of alcohol and caffeine (particularly with "energy drinks") continues to rise. Physiological perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biological actions of 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 rat and mouse, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation following ingestion of 1-2 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 raised NO· above those levels found with alcohol alone, disappeared upon block of NO· synthase, and could not be detected in pressurized cerebral arteries from eNOS-/- mouse. 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.
- The American Society for Pharmacology and Experimental Therapeutics