Aminotriazole (1 g/kg IP) pretreatment resulted in higher ethanol blood levels during the first hour after 90 mmole/kg IP ethanol administration and at 1 hour after when rats received 60 mmole/kg IP, than the respective controls receiving the same doses of ethanol. No difference in the blood levels at time higher than 1 hour were observed, in spite of the fact that the inhibitory effect of aminotriazole lasted more than 7 hours. These results are consistent with the idea that hepatic catalase may play a significant role in liver first pass effect when portal blood levels are expected to be rather high, but not when distribution balance is established.

Amitrole↗

PubMedDate not supplied

Absence of effect of 3-amino-1,2,4-triazole pretreatment on blood ethanol levels after oral administration, in rats.

Blood ethanol levels registered in rats receiving 90 mmole/kg by gavage were not different in rats pretreated with aminotriazole (1 g/kg IP) 1 hour before, than in untreated controls. Results are consistent with the idea that no measurable gastrointestinal catalase first pass effect is present in rats.

Administration, Oral↗

PubMedDate not supplied

Effect of different treatment regimens with ethanol and p-chlorophenylalanine on tolerance development in UChA and UChB rats.

Since we have previously observed a genetic difference in the development of tolerance to the narcotic effect of ethanol in UChA and UChB rats when providing them with a 10% v/v ethanol solution as sole drinking fluid, experiments were performed in order to know whether the resistance to development of tolerance to ethanol in UChB rats was also exhibited after other regimens of ethanol administration, namely, a 2.76 g/kg ethanol IP injection 24 hr before the experiment, only 10% v/v ethanol solution as sole drinking fluid for 21 days, or receiving acutely a daily dose of 2.76 g/kg ethanol by gavage for seven days. Participation of serotoninergic neurons was tested by treating rats with p-chlorophenylalanine (p-CPA), a known serotonin depletor. Results show that UChA rats developed tolerance to ethanol-induced narcosis and hypothermia, while UChB rats developed it to narcosis only when they received acute oral doses of ethanol for 7 days and did not develop tolerance to hypothermia with any of the treatment regimens. p-CPA pretreatment did prevent the development of tolerance in both strains of rats, confirming the participation of serotoninergic neurons in ethanol tolerance in rats.

Animals↗

PubMedDate not supplied

Effect of 3-amino-1,2,4-triazole on narcosis time and lethality of ethanol in UChA rats.

The capacity of rat brain homogenates to oxidize ethanol by catalase peroxidative system, previously reported, was reevaluated in experiments using lower ethanol concentration, showing that the effect of this system can be observed even with a concentration of 50 mM, equivalent to non lethal blood level. The involvement of catalase was confirmed by its blocking by aminotriazole (AT) or methanol but not by pyrazole or butanol. Evidence for a functional role of ethanol oxidation by brain catalase in the action of this substance was given by the fact that rats pretreated with AT (1 g/kg IP) exhibited a significant shorter narcosis than untreated controls, strongly suggesting the mediation of acetaldehyde in this effect. Previous results with doses of 60 mmole/kg IP were confirmed with 70 mmole/kg IP, but not with 90 mmole/kg IP. A significant prolonging of narcosis time was observed when AT was administered after any of these doses by an unknown mechanism. Furthermore it was observed that AT pretreatment reduced significantly the lethal effect of 110 mmole/kg IP ethanol; but when AT was given after ethanol (90 mmole/kg IP) it enhanced the lethality. These results suggest that catalase peroxidative pathway might play a role not only in narcosis time but also in ethanol toxicity.

Amitrole↗

PubMedDate not supplied

The effects of alpha-methyl-p-tyrosine pretreatment on ethanol-induced narcosis and hypothermia, as well as in the development of tolerance to these effects in UChA and UChB rats.

We have previously reported that UChA rats (genetically low ethanol consumer) develop tolerance to narcosis time easier than UChB rats (genetically high ethanol consumer). We also have reported that UChA rats develop tolerance to the hypothermic effect of ethanol, while in UChB rats the repeated administration of ethanol induces sensitization towards this effect. In the present paper the effects of alpha-methyl-p-tyrosine (AMPT)--a competitive inhibitor of norepinephrine synthesis--on ethanol-induced narcosis and hypothermia, as well as in the development of tolerance to these effects, were studied in both strains of rats. Results obtained show that AMPT pretreatment induced a significantly higher increase in narcosis time and hypothermia, as well as, greater susceptibility to ethanol toxicity in UChB than UChA rats. Furthermore, the simultaneous treatment with AMPT and ethanol did not change the development of tolerance to narcosis time in both strains and to hypothermia and sensitization in UChA and UChB rats respectively.

Alcohol Drinking↗

PubMedDate not supplied

Effect of 3-amino-1,2,4-triazole on the hypothermic effect of ethanol and on ethanol tolerance development.

The effect of aminotriazole (AT), inhibitor of catalase activity, on hypothermia and narcosis induced by ethanol and on the acquisition of tolerance to the ethanol hypothermic and narcotic effect was studied. Rats were pretreated with AT (1 g/kg IP) 1 hour before the test dose of ethanol (2.76 g/kg IP) and narcosis time, hypothermia and ethanol blood levels evaluated (first test). For studies on tolerance to ethanol, rats of the first test received daily (for 7 days) a dose of AT (1 g/kg IP) 1 hour before ethanol (2.76 g/kg) given by gavage, and the same parameters evaluated (8th day test). Results were compared to similar groups of rats without AT pretreatment (controls, 1st and 8th day test). Rats pretreated with AT exhibited a shorter narcosis time induced by ethanol but this treatment did not alter the hypothermic effect of ethanol nor ethanol disposal rate. Chronic ethanol treatment induced tolerance to the narcotic and hypothermic effect of ethanol as well as a metabolic tolerance. AT administered daily before the dose of ethanol produced a partial blockade of the development of tolerance to the narcotic effect of ethanol, but did not alter the development of hypothermic or metabolic tolerance. The brain catalase system seems to play a role in narcosis and on the development of tolerance to this effect of ethanol, but not in the hypothermic effect or in the development of tolerance to this ethanol effect. Since the inhibition of liver catalase activity by AT treatment was not correlated with changes in ethanol disposal rate, the liver catalase system appears not to play a role in the metabolic tolerance.

Amitrole↗

PubMedDate not supplied

Ethanol intake: effect on liver and brain mitochondrial function and acetaldehyde oxidation.

The effect of a chronic ethanol consumption by forcing rats to drink a 20% v/v ethanol solution as sole drinking fluid, for 3 months, was evaluated on: liver and brain mitochondrial function, the capacity of isolated mitochondria to oxidize acetaldehyde, as well as on the low Km mitochondrial AlDH activity, in rats. The O2 uptake by liver and brain mitochondria in the presence of glutamate + malate, succinate or ascorbate + TMPD, was measured polarographically with a Clark electrode. Acetaldehyde oxidation was measured by the disappearance rate in presence of the intact or disrupted mitochondria (AlDH activity) by gas chromatography. Results indicate that an ethanol intake of 11 g/kg b.wt. per day produce a significant reduction of the liver mitochondrial respiration tested with all the substrates used, including acetaldehyde. In contrast, the activity of AlDH in disrupted mitochondria remained unchanged. These results are in accord with the idea that a progressive deterioration of liver mitochondrial function appears with the increase in amount of ethanol consumed, and that alterations of acetaldehyde oxidation by intact mitochondria can be detected before an alteration of the AlDH activity. Concerning the brain, this ethanol consumption regimen did not affect the brain mitochondrial respiration tested with glutamate + malate, succinate or ascorbate + TMPD, but it induces an increase in acetaldehyde oxidation rate by intact brain mitochondria. The imposed increase in the cerebral aldehyde oxidizing capacity could reflect a principal biochemical mechanism underlying neural adaptation to ethanol.

Acetaldehyde↗

PubMedDate not supplied

Effect of diet and disulfiram on acetaldehyde blood levels after ethanol in UChA and UChB rats.

Acetaldehyde (AcH) levels in blood samples taken from different zones of the vascular system 2 h after a p.o. dose of ethanol (2.76 g/kg) were studied in UChA (low ethanol consumer) and UChB (high ethanol consumer) rats fed a diet devoid of animal products, diet 1 (D1), and a diet containing fish meal, diet 2 (D2), and in rats pretreated with disulfiram (600 mg/kg p.o.). The results showed that, while there is no significant difference between UChA and UChB rats fed D1 with respect to blood AcH levels and the basal activity of the hepatic mitochondrial high-affinity aldehyde dehydrogenase (AIDH), a significant strain difference was observed in rats fed D2, which induced high blood AcH levels in UChA rats but not in UChB ones. No strain differences were observed in blood ethanol levels in the two groups of rats. When rats fed D1 were pretreated with disulfiram, the raising of AcH blood levels induced by ethanol after disulfiram was significantly higher in UChA than in UChB rats in suprahepatic vein, femoral vein, and tail blood. This difference was concomitant with a greater inhibition of the hepatic mitochondrial high-affinity ADH activity in UChA rats than in UChB ones, whether disulfiram was administered in vivo or in vitro, which excluded the possibility that the strain difference would be caused by a different bioavailability of disulfiram.

Acetaldehyde↗

PubMedDate not supplied

Metabolism of acetaldehyde by rat isolated aortic rings: does endothelial tissue contribute to its extrahepatic metabolism?

Acetaldehyde (AcH) metabolism in isolated aortic rings was studied by assessing in vitro-added AcH disappearing rate by head space gas chromatography. It was found that AcH was metabolized by aortic rings or by homogenates prepared in 0.1 M phosphate buffer containing Triton X-100, by an NAD-dependent enzyme with characteristics similar to those of aldehyde dehydrogenase (AIDH) present in mitochondria from rat liver and brain. This enzyme appears to be present in the vascular endothelium, since the action of aortic rings showed a remarkable decrease by its removal. Extrahepatic metabolism of AcH was assessed by the differences between AcH levels found in samples of blood obtained from the suprahepatic vein, carotid artery, femoral vein, and tail cut of rats. The in vitro activity of aortic rings, as well as the extrahepatic AcH metabolism, were significantly decreased by pretreatment of rats with disulfiram. The wide distribution of vascular endothelium throughout the body suggests that this tissue could contribute to AcH extrahepatic metabolism.

Acetaldehyde↗

PubMedDate not supplied

Effects of aminotriazole on ethanol, water, and food intake and on brain catalase in UChA and UChB rats.

Aminotriazole (AT), a catalase inhibitor, was administered to UChA (low ethanol consumer) and UChB (high ethanol consumer) rats. Ethanol, water, and solid food intake were measured during basic, treatment, and posttreatment periods. The effects of AT on brain catalase activity and acetaldehyde recovered during incubation of brain homogenates with ethanol were also studied in rats of both strains. Results showed that AT decreased voluntary ethanol intake in UChB rats, and also diminished the consumption of food by rats of both strains. No strain difference in brain catalase activity and acetaldehyde recovered during ethanol incubation was observed. The results suggest that AT effect on ethanol consumption is secondary to a reduction in the appetite for calories and not related to its catalase blocking effect.

Alcohol Drinking↗

PubMedDate not supplied

Acetaldehyde metabolism by brain mitochondria from UChA and UChB rats.

The acetaldehyde (AcH) oxidizing capacity of total brain homogenates from the genetically high-ethanol consumer (UChB) appeared to be greater than that of the low-ethanol consumer (UChA) rats. To gain further information about this strain difference, the activity of aldehyde dehydrogenase (AIDH) in different subcellular fractions of whole brain homogenates from naive UChA and UChB rat strains of both sexes has been studied by measuring the rate of AcH disappearance and by following the reduction of NAD to NADH. The results demonstrated that the higher capacity of brain homogenates from UChB rats to oxidize AcH when compared to UChA ones was because the UChB mitochondrial low Km AIDH exhibits a much greater affinity for NAD than that of the UChA rats, as evidenced by four-to fivefold differences in the Km values for NAD. But the dehydrogenases from both strains exhibited a similar maximum rate at saturating NAD concentrations. Because intact brain mitochondria isolated from UChB rats oxidized AcH at a higher rate than did mitochondria from UChA rats only in state 4, but not in state 3, this strain difference in AIDH activity might be restricted in vivo to NAD disposition.

Acetaldehyde↗