UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
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Alcoholic cardiomyopathy is characterized by impaired ventricular function although its toxic mechanism is unclear. This study examined the impact of cardiac overexpression of alcohol dehydrogenase (ADH), which oxidizes ethanol into acetaldehyde (ACA), on ethanol-induced cardiac contractile defect. Mechanical and intracellular Ca(2+) properties were evaluated in ventricular myocytes from ADH transgenic and wild-type (FVB) mice. ACA production was assessed by gas chromatography. ADH myocytes exhibited similar mechanical properties but a higher efficiency to convert ACA compared with FVB myocytes. Acute exposure to ethanol depressed cell shortening and intracellular Ca(2+) in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular Ca(2+) was significantly augmented in the ADH group, with maximal inhibitions of 43.7% and 40.6%, respectively. Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP) or the aldehyde dehydrogenase inhibitor cyanamide prevented or augmented the ethanol-induced inhibition, respectively, in the ADH but not the FVB group. The ADH transgene also substantiated the ethanol-induced inhibition of maximal velocity of shortening/relengthening and unmasked an ethanol-induced prolongation of the duration of shortening/relengthening, which was abolished by 4-MP. These data suggest that elevated cardiac ACA exposure due to enhanced ADH expression may play an important role in the development of alcoholic cardiomyopathy.
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PMID:Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes. 1189 54

1,4-Butanediol (1,4-BD) is the dihydroxy precursor of gamma-hydroxybutyrate (GHB), a popular recreational drug that has been banned by the United States Food and Drug Administration (FDA) and controlled as a federal schedule I drug. 1,4-BD is enzymatically converted in vivo to GHB by alcohol dehydrogenase (ADH), and overdoses can result in coma, severe respiratory depression, bradycardia, hypothermia, seizures, and death. Presently, there is no antidote. We pretreated CD-1 mice with the ADH antagonist, 4-methylpyrazole (4-MP), to determine if blocking ADH can prevent or decrease toxicity from 1,4-BD overdose. Pretreatment with 4-MP increased the Toxic Dose-50 (TD(50)) of 1,4-BD for the righting reflex from 585 mg/kg (95% CI, 484-707 mg/kg) in control mice to 5,550 mg/kg (95% CI, 5,353-5,756 mg/kg) in pretreated mice. Pretreatment with 4-MP also increased the TD(50) of 1,4-BD for the rotarod test from 163 mg/kg (95% CI, 136-196 mg/kg) in control mice to 4,900 mg/kg (95% CI, 4,812-4,989 mg/kg) in pretreated mice. Pretreatment with 4-MP significantly decreased the toxicity of 1,4-BD in CD-1 mice, presumably by inhibiting its ADH biotransformation to GHB. 4-MP warrants further investigation as a potential antidote for this increasingly abused drug.
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PMID:Pretreatment of CD-1 mice with 4-methylpyrazole blocks toxicity from the gamma-hydroxybutyrate precursor, 1,4-butanediol. 1207 36

Our previous studies in rats have suggested a role for renomedullary hyaluronan (HA) in water homeostasis. The gerbil is known for its unique ability to conserve water. In the present study renal papillary and intestinal HA were compared between groups of anaesthetized gerbils and rats before and after up to 6 h of I.V. water loading. Baseline papillary HA in gerbils was only 37 % of that in the rat. Water loading in rats increased the papillary HA content. Elevation was maximal (+27 %, P < 0.05) after 2 h of water loading and then declined to control levels after 6 h of water loading (+3 %, n.s.). In contrast, the gerbil responded with a decreased papillary HA content during water loading. The depression was maximal after 2 h (-49 %, P < 0.05) and was still 41 % below the control values after 6 h (P < 0.05). The urine flow rate increased rapidly in the rat and its maximum, 21 times above the control level (P < 0.05), occurred at the HA peak, i.e. after 2 h of water loading while in the gerbil, the urine flow rate increased slowly and slightly and was only six times above control values after 6 h of water loading (P < 0.05). The HA content along the intestine was similar in the two species: lowest in the duodenum and jejunum and highest in the distal colon. To conclude, in the rat, the elevation of papillary interstitial HA during acute water loading would counteract water reabsorption by changing the physico-chemical characteristics of the interstitial matrix favouring rapid water diuresis. This would work as a complement to the powerful regulation by ADH. The gerbil has a diametrically different regulation of papillary HA turnover during water loading. The decreased papillary HA level during water loading and the slow and small diuretic response may represent a genetic difference in adaptation to enhance the ability to conserve water in an arid environment.
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PMID:Renomedullary and intestinal hyaluronan content during body water excess: a study in rats and gerbils. 1209 72

Even though the number of alcohol-dependent women is only about 1/3 of the number of alcoholic men, the alcoholism in women, by its clinical features and its course, is the source of therapeutic and economic stakes, particularly in young women among whom an increase of alcohol consumption related problems is reported. Another specificity of the female alcoholism is the lack of care seeking, whereas women have tendency globally to solicit more often care structures than men. Women represent only 1/4 of the overall treated alcoholic patients. The main explanation for this phenomenon is the pejorative social and moral connotation of the female alcoholism, with frequent feelings of shame and deep guilt, that also account for the frequency of hidden and lonely alcohol intakes. The female alcoholism is essentially characterized by an increased vulnerability to the toxic effects of the alcohol, whereas the pathological consumption starts later and with smaller daily amounts. Most studies have revealed a higher vulnerability in women to somatic complications directly attributable to the alcohol organs toxicity, such as hepatic cirrhosis and cardiovascular complications (high blood pressure, non obstructive cardiomyopathy). The reported brain morphological abnormalities could also occur more precociously in alcoholic women than in men. A decreased corpus callosum size among alcoholic women, but not in alcoholic men, was thus found in a recent study, compared with healthy controls. Among the different hypothesis proposed to explain this increased alcohol toxicity, the most incriminated is higher alcohol blood rates for the same ingested amount, mainly of the fact of a lower size with a weaker proportion of the bodily total water, but also of weaker concentrations of gastro-intestinal tract ADH, or of a longer metabolism during some menstrual phases. Indeed, some experimental studies on animal showed that the alcohol toxic effects may occur only from a threshold of alcohol blood rate. More recent studies suggest that the explanation to keep is more related to the lower gastric metabolism in women (lower ADH activity), than the difference of gastric volume or alcohol hepatic oxidation. Regarding to comorbidity, in the Epidemiologic Catchment Area survey, 65% of women, versus 44% of men, with abuse and/or dependence to alcohol had at least one another life-time psychiatric disorder (mainly depression and anxiety disorders), compared to 36% of the overall women of the studied sample. On the other hand, the alcohol dependence is, more often than in men, secondary to other psychiatric disorders, essentially depressive episodes, but less associated to antisocial behaviours. Among the different etiopathogenic factors involved in the alcohol dependence occurrence, genetic factors seem to have a determinant impact. According to the previous family, separation/adoption and twins studies performed, genetic factors could explain 50 to 60% of the alcoholism vulnerability in both men and women. In this context, and whereas we assist to the development of etiopathogenic models with new therapeutic perspectives in alcohol dependence, it seems necessary not to neglect female alcoholism specificities.
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PMID:[Clinical and biological specificities of female alcoholism]. 1250 62

Acute ethanol exposure depresses ventricular contractility and contributes to alcoholic cardiomyopathy in both men and women chronically consuming ethanol. However, a gender-related difference in the severity of myopathy exists with female being more sensitive to ethanol-induced tissue damage. Acetaldehyde (ACA), the major oxidized product of ethanol, has been implicated to play a role in the pathogenesis and gender-related difference of alcoholic cardiomyopathy, possibly due to its direct cardiac effect and interaction with estrogen. This study was designed to compare the effects of cardiac overexpression of alcohol dehydrogenase (ADH), which converts ethanol into ACA, on the cardiac contractile response to ethanol in ventricular myocytes isolated from age-matched adult male and female transgenic (ADH) and wild-type (FVB) mice. Mechanical properties were measured with an IonOptix SoftEdge system. ACA production was assessed by gas chromatography. The ADH myocytes from both genders exhibited similar mechanical properties but a higher efficacy to produce ACA compared to FVB myocytes. Exposure to ethanol (80-640 mg/dl) for 60 min elicited concentration-dependent decrease of cell shortening in both FVB and ADH groups. The ethanol-induced depression on cell shortening was significantly augmented in female but not male ADH group. ADH transgene did not exacerbate the ethanol-induced inhibition of maximal velocity of shortening/relengthening in either gender. In addition, neither ethanol nor ADH transgene affect the duration of shortening and relengthening in male or female mice. These data suggest that females may be more sensitive to ACA-induced cardiac contractile depression than male, which may attribute to the gender-related difference of alcoholic cardiomyopathy.
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PMID:Influence of gender on ethanol-induced ventricular myocyte contractile depression in transgenic mice with cardiac overexpression of alcohol dehydrogenase. 1260 Jun 69

Alcoholism is one of the major causes of non-ischemic heart damage. The myopathic state of the heart due to alcohol consumption, namely alcoholic cardiomyopathy, is manifested by cardiac hypertrophy, compromised ventricular contractility and cardiac output. Several mechanisms have been postulated for alcoholic cardiomyopathy including oxidative damage, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament Ca(2+ )sensitivity, and impaired protein synthesis. Despite intensive efforts to unveil the mechanism and ultimate toxin responsible for alcohol-induced cardiac toxicity, neither has been clarified thus far. Primary candidates for the specific toxins are ethanol, its first and major metabolic product - acetaldehyde (ACA) and fatty acid ethyl esters. Evidence from our lab suggests that ACA directly impairs cardiac function and promotes lipid peroxidation resulting in oxidative damage. The ACA-induced cardiac contractile depression may be reconciled with inhibitors of Cytochrome P-450 oxidase, xanthine oxidase and lipid peroxidation Unfortunately, the common methods to investigate the toxicity of ACA have been hampered by the fact that direct intake of ACA is toxic and unsuitable for chronic study, which is unable to provide direct evidence of direct cardiac toxicity for ACA. In order to overcome this obstacle associated with the chemical properties of ACA, our laboratory has used the chronic ethanol feeding model in transgenic mice with cardiac over-expression of alcohol dehydrogenase (ADH) and an in vitro ventricular myocyte culture model. The combination of both in vivo and in vitro approaches allows us to evaluate the role of ACA in ethanol-induced cardiac toxicity and certain cellular signaling pathways leading to alcoholic cardiomyopathy.
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PMID:Experimental Assessment of the Role of Acetaldehyde in Alcoholic Cardiomyopathy. 1273 61

2-Butoxyethanol (BE) is a one member of a family of ethylene glycol monoalkyl ethers that are used in a variety of industrial and household products. The clinical features of human and animal BE intoxications mainly include metabolic acidosis, CNS depression and coma, hemolytic anemia, hematuria, and renal injury. It is believed that metabolic activation of BE to butoxyacetic acid (BAA) is responsible for these pathologic changes. The treatment of BE poisoning have been based on an inhibition of the metabolic pathway enzymes which convert BE to toxic metabolites. Therefore, a comparison was made between antidotal properties of pyrazole (PY) and 4-methylpyrazole (MP) in rats subcutaneously intoxicated with BE. It was found that both antidotes effectively protected animals against appearance of hemolytic anemia signs induced by BE. MP appears to be more efficient than PY. These data confirm the beneficial role of alcohol dehydrogenase (ADH) inhibitors in BE intoxication.
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PMID:Pyrazole and methylpyrazole for the treatment of 2-butoxyethanol poisoning. 1766 57

Heterotrophic carbon metabolism has been demonstrated to be limited by oxygen availability in a variety of plant tissues, which in turn inevitably affects the adenylate status. To study the effect of altering adenylate energy metabolism, without changing the oxygen supply, we expressed a plastidially targeted ATP/ADP hydrolyzing phosphatase (apyrase) in tubers of growing potato (Solanum tuberosum) plants under the control of either inducible or constitutive promoters. Inducible apyrase expression in potato tubers, for a period of 24 h, resulted in a decrease in the ATP-content and the ATP-ADP ratio in the tubers. As revealed by metabolic profiling, this was accompanied by a decrease in the intermediates of sucrose to starch conversion and several plastidially synthesized amino acids, indicating a general depression of tuber metabolism. Constitutive tuber-specific apyrase expression did not lead to a reduction of ATP, but rather a decrease in ADP and an increase in AMP levels. Starch accumulation was strongly inhibited and shifted to the production of amylopectin instead of amylose in these tubers. Furthermore, the levels of almost all amino acids were decreased, although soluble sugars and hexose-Ps were highly abundant. Respiration was elevated in the constitutively expressing lines indicating a compensation for the dramatic increase in ATP hydrolysis. The increase in respiration did not affect the internal oxygen tensions in the tubers. However, the tubers developed a ginger-like phenotype having an elevated surface-volume ratio and a reduced mass per tuber. Decreased posttranslational redox activation of ADP-glucose pyrophosphorylase and a shift in the ratio of soluble starch synthase activity to granule-bound starch synthase activity were found to be partially responsible for the alterations in starch structure and abundance. The activity of alcohol dehydrogenase was decreased and pyruvate decarboxylase was induced, but this was neither reflected by an increase in fermentation products nor in the cellular redox state, indicating that fermentation was not yet induced in the transgenic lines. When taken together the combined results of these studies allow the identification of both short- and long-term adaptation of plant metabolism and development to direct changes in the adenylate status.
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PMID:Metabolic and developmental adaptations of growing potato tubers in response to specific manipulations of the adenylate energy status. 1830 7

We recently reported that the maturation of whisky prolongs the exposure of the body to a given dose of alcohol by reducing the rate of alcohol metabolism and thus lowers the blood acetaldehyde level (Alcohol Clin Exp Res. 2007;31:77s-82s). In this study, administration of the nonvolatile fraction of whisky was found to lower the concentration of acetaldehyde in the blood of mice by depressing alcohol metabolism through the inhibition of liver alcohol dehydrogenase (ADH). Four of the 12 phenolic compounds detected in the nonvolatile fraction (caffeic acid, vanillin, syringaldehyde, ellagic acid), the amounts of which increase during the maturation of whisky, were found to strongly inhibit mouse ADH 1 (class I). Their inhibition constant values for ADH 1 were 0.08, 7.9, 15.6, and 22.0 mumol/L, respectively, whereas that for pyrazole, a well-known ADH inhibitor, was 5.1 mumol/L. The 2 phenolic aldehydes and ellagic acid exhibited a mixed type of inhibition, whereas caffeic acid showed the competitive type. When individually administered to mice together with ethanol, each of these phytophenols depressed the elimination of ethanol, thereby lowering the acetaldehyde concentration of blood. Thus, it was demonstrated that the enhanced inhibition of liver ADH 1 due to the increased amounts of these phytophenols in mature whisky caused the depression of alcohol metabolism and a consequent lowering of blood acetaldehyde level. These substances are commonly found in various food plants and act as antioxidants and/or anticarcinogens. Therefore, the intake of foods rich in them together with alcohol may not only diminish the metabolic toxicity of alcohol by reducing both the blood acetaldehyde level and oxidative stress, but also help limit the amount of alcohol a person drinks by depressing alcohol metabolism.
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PMID:Phytophenols in whisky lower blood acetaldehyde level by depressing alcohol metabolism through inhibition of alcohol dehydrogenase 1 (class I) in mice. 1937 27

The present study sought to determine whether an association exists between alcohol dependence and select affective and anxiety disorders in patients presenting at substance abuse centres in Trinidad and Tobago (TT). The participants in this study were 143 alcohol dependents, of either East Indian ancestry (Indo-TT) or African ancestry (Afro-TT) and 109 controls matched by age, gender and ethnicity. A structured interview was used to gather information on demographics, psychiatric diagnoses and personal drinking and drug use. A blood sample was obtained and used to genotype for the presence of ADH and ALDH1 polymorphisms and serum levels of hepatic enzymes. Forty-one per cent of Indo-TT and 37% of Afro-TT with alcohol dependence had co-morbid major depressive disorders independent of alcohol and/or drug use. Thirty-nine per cent of Indo-TT and 37% of Afro-TT with alcohol dependence had co-morbid major depression induced by alcohol or drug use. The severity of depression was significantly associated with severity of alcohol dependence. Neither major depression nor the severity of depressive episodes was associated with values of any liver function test or the presence of ALDH1*2 or ADH1C*2 alleles. However in participants of African descent elevated alanine transaminase ALT was associated (p = 0.038) with not having substance-induced major depression. Co-morbidity of major depressive disorder with alcohol dependence is common in the two major ethnic groups in Trinidad and Tobago and appears to be as likely the consequence of drinking and/or drug use, as the cause. Clinicians should solicit a history of depression from patients with alcohol dependence.
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PMID:Co-morbidity of alcohol dependence and select affective and anxiety disorders among individuals of East Indian and African ancestry in Trinidad and Tobago. 2095 17

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