Inhibitory Actions Of Ethanol Research Articles

Inhibition by Ethanol of Shear Stress-Induced Formation of Platelet Thrombi in Whole Blood.

The risk of thromboatherosclerotic disease is lower in moderate drinkers than in non-drinkers. We investigated the effects of ethanol on platelet aggregation under a condition with shear stress. Shear stress-induced formation of platelet thrombi is inhibited by ethanol at its attainable concentrations after drinking. This effect is prominent at the early stage of thrombus formation, being in agreement with inhibitory actions of ethanol on the initial steps of platelet activation such as Ca2+ entry and phospholipase A2 activation. Platelet aggregation was evaluated by using a total thrombus-formation analysis system, and shear rates of 1000 s-1 (low), 1500 s-1 (middle) and 2000 s-1 (high) were loaded to whole blood. The times required to generate increases in flow pressure of 10 kPa (T10), 30 kPa (T30) and 50 kPa (T50) in microchips containing the blood, which depend on the degree of thrombus generation, were recorded. Under the conditions of the low-grade and middle-grade shear rates, T10 and T30 were significantly longer in the presence of ethanol at 0.25-1% than in the absence of ethanol. T10 under the condition of the low-grade shear rate and T30 under the conditions of the low-grade and middle-grade shear rates were also significantly longer in the presence of ethanol at 0.125% than in the absence of ethanol. On the other hand, T50 under the conditions of the low-grade and middle-grade shear rates was not significantly different in the absence and presence of ethanol at 0.125, 0.25 and 0.5%. Under the condition of the high-grade shear rate, T10, T30 and T50 were not significantly different in the absence and presence of ethanol at its lower concentrations. Ethanol at attainable concentrations inhibits platelet thrombus formation induced by shear stress, and the inhibitory effect of ethanol is prominent at the early stage of thrombus formation.

Inhibition of recombinant GluN1/GluN2A and GluN1/GluN2B N-methyl-D-aspartate receptors by single malt whiskies

NMDARs (N-methyl-D-aspartate receptors) are considered to be a target for the inhibitory actions of ethanol. While profound inhibition of both native and recombinant NMDARs can be observed following the application of high concentrations of ethanol the levels of inhibition seen with lower concentrations of ethanol are more modest. Here, we report the effects of inhibiting NMDAR-mediated responses with ethanol concentrations that are experienced during the social consumption of alcohol comparing levels of inhibition seen with 'pure' ethanol with those produced by ethanol contained in three popular single malt whiskies.

Modulation of the anti-apoptotic transcription factor NF-κB by an endoplasmic reticulum-generated signal

The effects of ethanol on N-methyl-d-asparate (NMDA) and non-NMDA receptor agonist-stimulated activator protein-1 (AP-1) DNA binding activity in primary cultures of rat cerebellar granule cells were investigated. The application of intoxicating concentrations of ethanol produced a concentration-dependent inhibition of NMDA-enhanced AP-1 binding with a significant reduction obtained at 50 mM ethanol. The inhibitory actions of ethanol on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-stimulated AP-1 binding were considerably weaker as compared to the effects seen following administration of NMDA. The AMPA-induced enhancement of AP-1 DNA binding activity was demonstrated both in the absence and presence of cyclothiazide, a drug, which is known to block the desensitization of AMPA receptors. Our data suggest that moderate concentrations of ethanol modulate glutamate-induced alterations of gene expression in brain neurons.

Developmental changes in the inhibitory actions of ethanol on glutamate-induced translocation of protein kinase C in cerebellar granule neurons

The effects of increasing concentrations of ethanol (25–200 mM) on the enhancement of [ 3H]phorbol-12,13-dibutyrate ([ 3H]PDBu) binding produced by different glutamate receptor agonists, indicative of a translocation of the intracellular enzyme protein kinase C (PKC), were studied in rat cerebellar granule cells at 2, 4, 8, and 12 days in vitro (DIV). Glutamate-produced stimulation of [ 3H]PDBu binding was inhibited by 50 mM ethanol at 2 DIV, whereas higher ethanol concentrations (> 100 mM) were needed to reduced the increase of [ 3H]PDBu binding in cells grown for 4, 8, and 12 DIV. Ethanol significantly inhibited NMDA-stimulated [ 3H]PDBu binding in a concentration-dependenf fashion in cells maintained in culture for 4 and 8 days, respectively, with a slightly less pronounced inhibition by ethanol (50 mM) seen in cells kept for 2 and 12 DIV. Application of higher ethanol concentrations (> 100 mM), inhibited the NMDA-induced stimulation in all cell preparations. Following kainic acid-induced enhancement of [ 3H]PDBu binding, ethanol (100 mM) reduced the binding only in cells maintained for 2 DIV. Even higher ethanol concentrations (200 mM) inhibited the effects of kainic acid only in cells maintained for 2 and 4 DIV, respectively. Our data suggest that various subclasses of glutamate receptors display a developmentally determined differential sensitivity to ethanol at least in cerebellar granule cells in vitro.

N-Methyl- d-aspartate-induced enhancement of activator protein-1 DNA binding activity is blocked by ethanol in cerebellar granule cells

The effects of ethanol on N-methyl- d-asparate (NMDA) and non-NMDA receptor agonist-stimulated activator protein-1 (AP-1) DNA binding activity in primary cultures of rat cerebellar granule cells were investigated. The application of intoxicating concentrations of ethanol produced a concentration-dependent inhibition of NMDA-enhanced AP-1 binding with a significant reduction obtained at 50 mM ethanol. The inhibitory actions of ethanol on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-stimulated AP-1 binding were considerably weaker as compared to the effects seen following administration of NMDA. The AMPA-induced enhancement of AP-1 DNA binding activity was demonstrated both in the absence and presence of cyclothiazide, a drug, which is known to block the desensitization of AMPA receptors. Our data suggest that moderate concentrations of ethanol modulate glutamate-induced alterations of gene expression in brain neurons.

Blockade of l-glutamate receptors in the rostral ventrolateral medulla contributes to ethanol-evoked impairment of baroreflexes in conscious rats

This study investigated the effect of ethanol microinjected into the rostral ventrolateral medulla on the cardiovascular responses to in6arostral ventroleteal medulla administration of the excitatory amino acids l-glutamate and N-methyl- d-aspartate (NMDA) and on baroreflex-mediated heart rate responses (baroreflex sensitivity) in conscious freely moving Sprague-Dawley rats. l-Glutamate (5 nmol) or NMDA (25, 50, and 100 pmol) microlrjected into the rostral ventrolateral medulla elicited pressor and bradycardic responses. The cardiovascular responses elicited by both l-glutamate and NMDA were significantly ( p < 0.05) attenuated by intrarostrel ventrolateral medulla ethanol (10 μg) or 2-amino-5 acid (2 nmoq, a selective NMDA receptor antagonist, but not by ACSF. Enhancement of the cardiovascular responses to l-glutamate by intrarostra ventrolateral medulla p-chloromercuriphenylsulfonic acid (0.1 nmol), a glutamate uptake inhibitor, was reversed by subsequent ethanol, but not ACSF, microinjection. None of the treatments influenced baseline blood pressure or heart rate. Ethanol or 2-amino-5-phosphonopentanoic acid microinjected into the rostral ventrolateral medulla significantly ( p < 0.05) attenuated baroreflex sensitivity tested by phenylephrine. In contrast, p-chloromercuriphenylsulfonic acid significantly ( p < 0.05) enhanced baroreflex sensitivity (−2.14 ± 0.09 vs. −3.08 ± 0.18); subsequent ethanol micoinjection reversed this enhancement (−290 ± 0.21 vs. −1.86 ± 0.24). Equal volume of ACSF had no effect on baroreftex sensitivity of pretreated rats (−3.22 ± 0.31 vs. −2.98 ± 0.34). These results suggest that ethanol exerts a marked inhibitory action on glutamatergic pathways within the rostral ventrolateral medulla that act to enhance baroreftex sensitivity. The similarities between the inhibitory actions of ethanol and the selective NMDA receptor Mocker 2-amino-5-phosphonopentanoic acid on the cardiovascular responses to NMDA and on baroreflex sensitivity suggest that ethanol attenuates baroreflex sensitivity, at least in part, by blocking the NMDA receptors in the rostral ventrolateral medulla. This evidence is presented, for the first time, in the absence of the confounding effects of anesthetics.