calcimycin and Alcoholism

We investigated the mechanism underlying increased relaxation of aortic strips to acetylcholine in rats chronically treated with ethanol. Rats were divided into three groups and maintained on liquid diets containing ethanol (35% of total calories) as the ethanol-fed group or an equicaloric volume of sucrose instead of ethanol as the sucrose-fed group for 10 weeks. The control group was also maintained on modified American Institute of Nutrition diet for the same period. Vascular strips of isolated rat aortas were mounted in organ chambers to record isometric tension. The endothelium-dependent relaxation responses to acetylcholine and calcium ionophore A23187 were greater in ethanol-fed rats than in control and sucrose-fed rats. However, the relaxation response to sodium nitroprusside or nifedipine did not differ among the three groups. Acetylcholine, calcium ionophore A23187, and sodium nitroprusside caused an increase in the cGMP contents of rat aortic strips that was similar among the three groups. These results suggest that a cGMP-independent relaxation mechanism is involved in the increased relaxation response to acetylcholine after chronic treatment with ethanol.

Topics: Acetylcholine; Alcoholism; Animals; Aorta, Thoracic; Calcimycin; Culture Techniques; Endothelium, Vascular; Male; Nifedipine; Nitroprusside; Rats; Rats, Wistar; Vasodilation

The effect of short-term (15 days) and long-term (60 days) ethanol treatment and withdrawal on agonist-stimulated phosphoinositide (Pl) hydrolysis, serotonin receptor subtypes (5HT1A and 5HT2), and alpha 1-adrenergic receptors were studied in rat cerebral cortex. Short-term ethanol treatment had no significant effect on serotonin (5HT), norepinephrine (NE), and calcium ionophore (A23187)-stimulated [3H]-inositol-1-phosphate ([3H]-IP1) formation and 5-HT2 receptors as measured by 125I-lysergic acid diethylamide (125I-LSD) binding, in rat cerebral cortex. However, 15 days of ethanol treatment, followed by 24 hr of withdrawal resulted in a decrease in Bmax of 125I-LSD binding without significant change in KD, as well as a decrease in 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. 5HT1A and alpha 1-adrenergic receptors were determined by using [3H]-8-hydroxy-2-(di-N-propylamino)tetralin and [3H]-prazosin as radioligand, respectively. We also observed that long-term ethanol treatment had no significant effect on Bmax and KD of 5HT2, 5HT1A, and alpha 1-adrenergic receptors, as well as NE and A23187-stimulated [3H]-IP1 formation, but significantly decreased the 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. It is possible that a decrease in 5HT-induced PI turnover after long-term ethanol exposure may be due to a decrease in coupling of 5HT2 receptors to G protein or PLC enzyme, whereas the decrease in 5HT-induced PI turnover after withdrawal may be due to a decrease in functional 5HT2 receptor number.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Alcohol Withdrawal Delirium; Alcoholism; Animals; Calcimycin; Cerebral Cortex; Hippocampus; Hydrolysis; Lysergic Acid Diethylamide; Male; Norepinephrine; Phosphatidylinositols; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Receptors, Serotonin; Serotonin; Signal Transduction

The cutaneous vasodilation produced by ethanol is exaggerated when acetaldehyde levels are increased after aldehyde dehydrogenase inhibition, producing a flushing reaction, the mechanism of which is unknown. The authors investigated whether ethanol and its metabolites affect the vascular release of prostacyclin, a potent vasodilator, and whether such an effect might be modified by chronic alcohol consumption. Aortic rings from rats fed Chow ad libitum or pair-fed liquid diets containing either ethanol (36% of energy) or isocaloric carbohydrate for 4 to 5 weeks were incubated in Krebs-Ringer bicarbonate supplemented with saturating amounts of arachidonate (10-20 microM) in the presence of ethanol (10-100 mM), acetaldehyde (10-100 microM) or acetate (1.25-5 mM). Prostacyclin was measured by the radioimmunoassay of 6-keto-prostaglandin F1 alpha. Acetaldehyde produced a concentration-dependent stimulation of prostacyclin production both in alcohol-fed and control rats, whereas acetate did not. This effect was associated with increased conversion of arachidonate (either exogenous or released with A23187) and of prostaglandin endoperoxide H2 to prostacyclin. Ethanol did not affect prostacyclin release in control rats, but, in aortas from alcohol-fed animals, 50 mM ethanol did stimulate prostacyclin formation. These effects may contribute to the cardiovascular responses associated with high blood acetaldehyde levels in flushers and with high ethanol levels in alcoholics. In conclusion, acetaldehyde is a potent stimulant of vascular prostacyclin production. This effect is due, at least in part, to enhanced activity of prostacyclin synthase. Ethanol acquires such a stimulatory effect on prostacyclin formation after chronic alcohol consumption.

Topics: Acetaldehyde; Acetates; Acetic Acid; Alcohol Dehydrogenase; Alcoholism; Animals; Arachidonic Acid; Arachidonic Acids; Calcimycin; Dietary Carbohydrates; Epoprostenol; Ethanol; Male; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred Strains; Vasodilation

Topics: Alcoholism; Animals; Brain; Calcimycin; Cell Membrane; Drug Tolerance; Ethanol; Humans; Membrane Lipids; Neurons; Neurotransmitter Agents; Platelet Aggregation; Synaptic Membranes