Preconditioning with ethanol prevents postischemic leukocyte-endothelial cell adhesive interactions

Abstract

Long-term ethanol consumption at low to moderate levels exerts cardioprotective effects in the setting of ischemia and reperfusion (I/R). The aims of this study were to determine whether 1) a single orally administered dose of ethanol [ethanol preconditioning (EtOH-PC)] would induce a biphasic temporal pattern of protection (early and late phases) against the inflammatory responses to I/R and 2) adenosine and nitric oxide (NO) act as initiators of the late phase of protection. Ethanol was administered as a bolus to C57BL/6 mice at a dose that achieved a peak plasma concentration of ~45 mg/dl 30 min after gavage and returned to control levels within 60 min of alcohol ingestion. The superior mesenteric artery was occluded for 45 min followed by 60 min of reperfusion beginning 10 min or 1, 2, 3, 4, or 24 h after ethanol ingestion, and the numbers of fluorescently labeled rolling and firmly adherent (stationary) leukocytes in single postcapillary venules of the small intestine were quantified using intravital microscopic approaches. I/R induced marked increases in leukocyte rolling and adhesion, effects that were attenuated by EtOH-PC 2-3 h before I/R (early phase), absent when assessed after 10 min, 1 h, and 4 h of ethanol ingestion, with an even more powerful late phase of protection reemerging when I/R was induced 24 h later. The anti-inflammatory effects of late EtOH-PC were abolished by treatment with adenosine deaminase, an adenosine A(2) (but not A(1)) receptor antagonist, or a NO synthase (NOS) inhibitor during the period of EtOH-PC. Preconditioning with an adenosine A(2) (but not an A(1)) receptor agonist in lieu of ethanol 24 h before I/R mimicked the protective actions of late phase EtOH-PC. Like EtOH-PC, the effect of preconditioning with an adenosine A(2) receptor agonist was abrogated by coincident NOS inhibition. These findings suggest that EtOH-PC induces a biphasic temporal pattern of protection against the proinflammatory effects of I/R. In addition, our observations are consistent with the hypothesis that the late phase of EtOH-PC is triggered by NO formed secondary to adenosine A(2) receptor-dependent activation of NOS during the period of ethanol exposure.

Hydrogen sulfide preconditioning or neutrophil depletion attenuates ischemia-reperfusion-induced mitochondrial dysfunction in rat small intestine

“…Indeed, even after systemic administration at doses that produce pharmacological effects (as in our study), plasma concentrations only briefly rise above the normal range (46). A more likely explanation is that NaHS-dependent BK Ca channel activation initiates a downstream signaling cascade that culminates in increased expression and/or stimulation of effectors such as protein kinase C and heme oxygenase-1 to mediate its protective actions during I/R 24 h later, as has been shown for other forms of preconditioning (2,9,10,13,14,17,18,33,38,57,58,67). It is also unclear how H 2 S activates BK Ca channels, although H 2 S is known to elicit an oxidative stress (secondary to its effect to inhibit cytochrome oxidase), which may activate BK Ca channels (48).…”

“…preconditioning occur over two distinct temporal phases (2,13,14,17,58). An initial, relatively short-lived phase arises within minutes of exposure to the preconditioning stimulus and then disappears after 1-4 h (acute, early phase, or classical preconditioning).…”

Hydrogen sulfide triggers late-phase preconditioning in postischemic small intestine by an NO- and p38 MAPK-dependent mechanism

“…In previous studies (16,22,43,52,53), we have demonstrated that a variety of late-phase preconditioning stimuli, including antecedent ethanol ingestion, short bouts of ischemia, adenosine A 2 receptor agonists, exogenous calcitonin gene-related peptide (CGRP) or bradykinin, and AMP-activated protein kinase (AMPK) activators, induce the development of an anti-inflammatory phenotype that is triggered by eNOS-dependent NO release. Although we found no data to support NOS-dependent H 2 S vasodilation, the inverse relationship has been shown: H 2 S can enhance the vasorelaxant effects of NO (21).…”

Low-Dose Ethanol Preconditioning Protects Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury By Activating Large Conductance, Ca2+-Activated K+ Channels In Vitro

“…However, increasing evidence suggests that low to moderate ethanol ingestion (1-2 beverages per day or *30 g ethanol) may protect against the harmful effects of subsequent ischemia/reperfusion (I/R) Electronic supplementary material The online version of this article (doi:10.1007/s12264-016-0080-3) contains supplementary material, which is available to authorized users. [14,15], an effect known as ethanol preconditioning (EtOH-PC). For example, a meta-analysis indicated that light (\12 g/day) or moderate (12-24 g/day) ethanol consumption reduces the relative risk of ischemic stroke [16].…”

“…The prompt benefits of ethanol preconditioning last for about 2 h after ingestion. However, after the plasma ethanol level has returned to baseline, a delayed phase of further EtOH-PC emerges [14], leading researchers to postulate that ethanol ingestion may trigger a downstream signaling cascade which induces the protective effect against I/R injury. However, the underlying mechanisms of the neuroprotective effect of EtOH-PC remain to be elucidated.…”