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Biomedical subjects

M Younes

Publications and source records attributed to M Younes.

At least 217 records · Page 12Linked to original sources
PubMed1984

Posthypotensive generation of superoxide free radicals--possible role in the pathogenesis of the intestinal mucosal damage.

Graded small intestinal ischemia was induced in cats by partial occlusion of the superior mesenteric artery. Specimens from the small intestine were studied at the end of the hypotensive period, 10 min and 60 min posthypotensively . Specimens obtained late during hypotension revealed characteristic mucosal damage in all cases. However, the intestinal mucosal damage was more pronounced in the specimens taken posthypotensively . This aggravation was prevented if the cats were given superoxide dismutase (SOD) during the hypotensive period. Further, the intestinal tissue concentration of total glutathione was reduced posthypotensively . It is suggested that the posthypotensive aggravation of the intestinal mucosal damage is caused by generation of cytotoxic oxygen free radicals. Data favouring the suggestion that the glutathione-glutathione peroxidase system is an important generator of free radicals in intestinal ischemia is presented.

Animals↗
PubMed1984

Lipid peroxidation and lysosomal enzyme release induced by vanadate in vitro.

Incubation of premitochondrial liver homogenate supernatants of phenobarbital-induced rats with sodium vanadate led to a time- and concentration-dependent formation of malondialdehyde and a parallel release of beta-glucuronidase from lysosomes. Both were inhibited in the presence of glutathione, (+)-catechin or dithiocarb, and took place after a lag phase of 30 min. In contrast, the glutathione content dropped immediately after addition of vanadate. Scavengers of reactive oxygen species had no effect on vanadate-induced lipid peroxidation. In liver homogenates of non-induced rats vanadate-promoted lipid peroxidation was 7.3 times lower than in those of phenobarbital-induced animals, suggesting the involvement of the microsomal mixed-function oxidase system. Thus, vanadate seems to act as a pro-oxidant of the enzymatically-promoted lipid peroxidation.

Animals↗
PubMed1984

Interpretation of clinical exercise testing in respiratory disease.

The usefulness of exercise tests is considerably enhanced if the treating physician becomes involved in interpretation of their results. Interpretation is facilitated through the use of a graphic approach that can be implemented with inexpensive desk-top computers. The relevant relations and the clinical and pathophysiologic significance of abnormalities in these graphs are discussed.

Adult↗
PubMed1983

Halothane hepatotoxicity in hyperthyroid rats as compared to the phenobarbital-hypoxia model.

Halothane hepatotoxicity was observed after exposing hyperthyroid rats to 0.625% halothane for 4 hr under hypoxic conditions (10% O2). In this model, increases in serum enzyme activities of the alanine aminotransferase (GPT) and the sorbitol dehydrogenase (SDH) were evident immediately following exposure and were six-fold higher than in the phenobarbital-hypoxic model. Plasma free-fluoride levels estimated immediately after exposure to halothane were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as compared to a sixfold increase in the phenobarbital-hypoxic model. The concentration of glutathione in liver was more markedly decreased in hyperthyroid rats than in phenobarbital-induced rats. The fact that no clear-cut correlation was found between defluorination and hepatotoxicity in both models may favor the hypothesis that a non-defluorinated metabolite of halothane, e.g., 2-chloro-1,1,1-trifluoroethyl radical, is the reactive intermediate responsible for the liver lesions. On the other hand, intracellular hypoxia due to hypermetabolism during the hyperthyroid state may be the reason for the higher sensitivity of hyperthyroid rats.

Animals↗
PubMed1983

Influence of alcohol, dithiocarb and (+)-catechin on the hepatotoxicity and metabolism of vinylidene chloride in rats.

Hepatotoxicity of vinylidene chloride (1, 1-dichloroethylene, VDC) in rats was evidenced by increases of serum enzyme activities of the aminotransferases (GOT, GPT) and sorbitol dehydrogenase (SDH). Simultaneous treatment with ethanol (4.8 g kg-1; p.o.) totally inhibited these hepatotoxic effects, whereas pretreatment with the same ethanol dose 24 h prior to VDC had no effect. Dithiocarb or (+)-catechin (0.2 g kg-1; p.o.), administered simultaneously with VDC, significantly reduced the VDC-induced increments of serum enzyme activities. Pretreatment with 5% ethanol for 7 days instead of drinking water increased the hepatotoxicity of a single dose of VDC. The combined treatment with VDC (0.125-0.2 g kg-1, twice weekly) and 5% ethanol for 4 weeks led to only small increases of serum enzyme activities as compared with controls treated with VDC alone. However, 60% lethality occurred in the VDC-ethanol group. Administration of either dithiocarb or (+)-catechin with VDC totally antagonized the observed lethality. Metabolic studies with VDC in a closed exposure system indicated that simultaneous treatment with ethanol or dithiocarb totally depressed the metabolic removal of VDC, whereas (+)-catechin had no effect.

Animals↗
PubMed1983

Formation of ethane in vitro by rat liver homogenates following glutathione depletion in vivo.

Depletion of hepatic glutathione (GSH) in rats by treatment with phorone (diisopropylidene acetone) in vivo led to a dramatic enhancement of spontaneous ethane production by liver post-mitochondrial fractions. Exogenous GSH added in vitro abolished this effect in a concentration-dependent manner. The same inhibitory action was seen with both dithiocarb or (+)-catechin. The concentrations yielding 50% inhibition (I50) were in the micromolar range for all three compounds.

Animals↗
PubMed1983

Clinical significance of the glutathione-conjugating system.

Glutathione displays important functions in living cells of many species, human included. Apart from its direct antioxidative activity, which supports the maintenance of the reduced state of proteinthiols, and its possible role in amino acid transport across membranes, it appears to exert several detoxification functions. These include the conjugation of electrophilic compounds and the reduction of H2O2 and lipid hydroperoxides. Disorders in GSH synthesis and metabolism are known and produce hemolysis in the first place. Little data exist concerning GSH and the GSH-dependent enzymes involved in its various functions in normal and diseased human tissues. The aim of this review is to stimulate research in this area.

Glutathione↗
PubMed1983

Influence of dithiocarb, (+)-catechin and silybine on halothane hepatotoxicity in the hypoxic rat model.

In phenobarbital (phenemalum NFN)-pretreated male rats exposed to 1% halothane for 2 hrs under hypoxic conditions (10% O2), significant increases in serum enzyme activities of alanine aminotransferase and sorbitol dehydrogenase were observed 24 and 48 hrs later indicating liver damage. In this known model of halothane hepatotoxicity, pretreatment with (+)-catechin (200 mg/kg orally) or silybine (150 mg/kg orally) protected against halothane-induced liver injury, whereas diethyldithiocarbamate (200 mg/kg orally) failed to be effective. Halothane decreased the concentration of reduced glutathione in liver only under hypoxic conditions indicating that glutathione might be involved in the non-oxidative metabolic pathways of halothane. Free fluoride in plasma was used as a measure of non-oxidative defluorination of halothane. Higher plasma fluoride levels were observed under conditions which led to hepatotoxicity but did not correlate with the protective effects of the antidotes. This further supports the assumption that 2-chloro-1,1,1-trifluoroethane might be the radical intermediate responsible for halothane hepatotoxicity.

Animals↗
PubMed1983

Effect of carbon tetrachloride--alcohol-induced liver fibrosis on microsomal mixed-function oxidases and the cytosolic glutathione-conjugating system in rat liver.

1. Subchronic treatment of male and female rats with CCl4 (0.2 ml/kg orally twice weekly) and drinking water containing 5% ethanol for four weeks led to a 20 to 40-fold increase in serum sorbitol dehydrogenase activity and to an augmentation of the liver triglyceride and hydroxyproline contents, indicating steatosis and fibrosis, respectively. Liver fibrosis was less pronounced in females than in male rats. 2. As a consequence of these alterations the hepatic microsomal mixed-function oxidase activity as measured by aminopyrine demethylation was decreased with concomitant loss of cytochrome P-450 in both sexes. Aniline hydroxylation as well as the activity of the NADPH-cytochrome c reductase showed no significant alterations. 3. While the hepatic glutathione content remained unchanged, the cytosolic glutathione S-transferase activities towards both an aryl and an epoxide substrate were markedly decreased following the development of liver fibrosis both in male and female rats.

Animals↗
PubMed1983

Interrelation between lipid peroxidation and lysosomal enzyme release in the presence of carbon tetrachloride, cumene hydroperoxide or thioacetamide.

To study the relationship between lipid peroxidation (LPO) and the release of lysosomal enzymes as markers of liver injury three compounds were chosen which evoke lipid peroxidation (cumene hydroperoxide, CHP), hepatocellular injury (thioacetamide, TAA) or both (carbon tetrachloride, CCl4). Premitochondrial supernatants of phenobarbital-induced rat liver homogenates were incubated in the presence of either agent and an NADPH-regenerating system. Then, lipid peroxidation was assessed by measurement of malondialdehyde (MDA) formation and, after centrifugation at 105 000 g, released beta-glucuronidase was measured in the supernatant. While CCl4 and CHP promoted both events in a time and concentration dependent manner, TAA did not evoke either LPO or lysosomal enzyme release. Glutathione, dithiocarb and (+)-catechin inhibited both effects. Though LPO and lysosomal enzyme release proved to be related events, no strict correlation with the hepatotoxicity was found.

Acetamides↗
PubMed1983

Interrelationship between in vivo lipid peroxidation, microsomal Ca2+-sequestration activity and hepatotoxicity in rats treated with carbon tetrachloride, cumene hydroperoxide or thioacetamide.

To study the relationship between lipid peroxidation and cellular damage we studied three compounds known to evoke lipid peroxidation (cumene hydroperoxide, CHP), hepatocellular injury (thioacetamide, TAA) or both (carbon tetrachloride, CCl4). Phenobarbital-induced male rats were treated with one of the three agents and lipid peroxidation was monitored via the measurement of exhaled ethane. Treatment with both, CCl4 and CHP resulted in an increased ethane expiration, whereas TAA did not. When liver-specific serum enzyme activities (GPT, SDH) were investigated 24 h later, however, hepatotoxicity was evident only in rats treated with either CCl4 or TAA. The ATP-dependent Ca2+-sequestration activity of microsomal membranes, suggested to be a final common pathway leading to cellular death, was studied in microsomes isolated from rats treated with either agent. 2 h after treatment with CCl4 or TAA a clear inhibition was seen which persisted after 24 h in the case of CCl4 only. CHP did not affect the Ca2- -pump activity. Thus, a clear correlation between cellular damage and lipid peroxidation cannot be expected in every case. An impairment of the microsomal calcium-pump, however, seems to be a crucial event which leads to hepatocellular injury.

Animals↗
PubMed1983

[Effect of diazepam and barbiturates on the in vivo metabolism of halothane and enflurane in rats].

The effect of pretreatment with barbiturates or diazepam on the in vivo metabolism of halothane or enflurane (92 ppm) was investigated upon application by inhalation. In male rats exposed to halothane the elimination half-life from the atmosphere of the closed exposure system amounted to 0.64 h; pretreatment with thiopental or methohexital (40 mg/kg i.p.) caused a small, but significant prolongation of the half-life (1.3 or 1.4-fold), whereas hexobarbital (75 or 100 mg/kg i.p.) had no effect in this respect. Much stronger and dose-dependent effects were seen in rats pretreated with pentobarbital (25 or 50 mg/kg i.p.; 2 or 3-fold) or diazepam (5 or 10 mg/kg i.p.; 3 or 5-fold increase). In control rats exposed to enflurane the elimination half-life was 4.77 h; pretreatment with hexobarbital, thiopental or methohexital at the above doses did not alter this value, whereas pentobarbital and diazepam again exerted marked and dose-dependent effects: a 1.5 or 1.7-fold prolongation of the half-life was observed after pentobarbital (25 or 50 mg/kg i.p.) and a 1.9 or 3.3-fold prolongation after diazepam (5 or 10 mg/kg i.p.), respectively. These different effects of the pretreatment drugs seems to correlate with their own pathways and rates of metabolism.

Animals↗
PubMed1983

Effects of phenobarbital, GSH-depletors, CCl4 and ethanol on the biliary efflux of glutathione in rats.

The efflux of reduced glutathione (GSH) into bile appears to be a major contribution to the hepatic glutathione homeostasis. In bile-fistula rats pretreatment with phenobarbital strongly enhanced the biliary export of GSH, whereas hepatic damage due to carbon tetrachloride markedly decreased the transport of GSH into bile. An oral load of ethanol, which was not hepatotoxic in rats, had the same effect in this respect. Depletion of hepatic GSH in response to the treatment with diethylmaleate, vinylidene chloride or paracetamol was followed by a decrease in the efflux of GSH into bile. Phorone which depleted the hepatic GSH nearly totally, in contrast, even enhanced its biliary output indicating a rapid decomposition of the phorone-GSH-adduct. Our experiments support recent findings of others that the canalicular transport of reduced GSH requires an active energy-dependent carrier mechanism.

Acetaminophen↗
PubMed1982

Effects of dithiocarb and (+)-catechin against carbon tetrachloride-alcohol-induced liver fibrosis.

Treatment of male rats with carbon tetrachloride (CCl4, 2 x weekly 0.2 ml/kg p.o.) and a 5% alcohol solution, instead of drinking water, for 4 weeks led to marked increases in serum enzyme activities (GOT, GPT, SDH), hepatic triglyceride and hydroxyproline content. Diethyl dithiocarbamate (dithiocarb, 200 mg/kg p.o.) simultaneously applied with CCl4 totally suppressed the elevation in serum enzyme activities and hepatic hydroxyproline concentration, and partially suppressed that of the triglyceride content. (+)-Catechin (50-300 mg/kg p.o.) simultaneously applied with CCl4 had no influence on the enhanced serum enzymes, but depressed the augmented content of both hepatic triglyceride and hydroxyproline in a dose-dependent way. The most effective dose with respect to the reduction of the hydroxyproline concentration was 100 mg/kg (+)-catechin; the highest dose (300 mg/kg), however, enhanced the CCl4-alcohol-induced hydroxyproline augmentation.

Animals↗
PubMed1982

The pathophysiological profile of the acute cardiovascular toxicity of sodium fluoride.

The intravenous infusion of sodium fluoride (2 mg/kg X min) into anesthetized rats caused a progressive fall in arterial blood pressure, cardiac output, heart rate and peripheral resistance. Respiratory rate increased during the first 20 min of infusion resulting in increased oxygen and decreased carbon dioxide blood concentrations. Total body oxygen consumption decreased after 30 min of NaF infusion by 29%, whereas the respiratory quotient (RQ) increased from 0.8 to 1.06. Death occurred after a mean dose of 79.6 +/- 4.6 mg/kg NaF. The terminal cardiac event before death was atrioventricular block followed immediately by asystole. Artificial ventilation did not influence the cardiovascular and the lethal effects of fluoride infusion. The plasma concentrations of total and ionized calcium decreased upon NaF infusion. The infusion of extra calcium did not prevent NaF-induced cardiovascular failure but decreased plasma fluoride levels and increased the lethal dose of NaF by 17% (not significant). In isolated atria and perfused hearts in vitro, NaF decreased the force of contraction in a dose-dependent manner. In conclusion, cardiovascular failure resulting from the direct cardiodepressive and vasodilatating effects of fluoride (and not from respiratory depression or hypocalcemia) accounts for the lethal outcome of fluoride intoxication.

Animals↗
PubMed1982

Effects of dithiocarb and (+)-catechin on microsomal enzyme activities of rat liver.

The effects of dithiocarb and (+)-catechin on the microsomal mixed-function oxidase system of rat liver were investigated after a single dose as well as after repeated treatment for 7 and for 28 days. Dithiocarb (200 mg/kg p.o.) significantly reduced the microsomal cytochrome P-450 content, aniline hydroxylase and aminopyrine demethylase activities; maximum decrease was observed at 4 hrs, return to normal values after 24 hrs. (+)-catechin (200 mg/kg p.o.) had no effects in this respect. Both agents did not affect microsomal enzyme activities when applied orally for 7 days. After 28 days treatment only dithiocarb (50 - 100 - 200 mg/kg p.o.) exerted a dose-dependent depression of the aniline hydroxylase activity. In vitro experiments confirmed the in vivo observations: a concentration-dependent inhibition of the aniline hydroxylation and aminopyrine demethylation were seen from the addition of dithiocarb, the I50-values were 5.4 X 10(-6) M and 9.6 X 10(-5) M, respectively. (+)-catechin showed no inhibitory activity on both enzyme activities in vitro. Both dithiocarb and (+)-catechin depressed the activity of the NADPH-cytochrome C-reductase only in the 10(-4) M concentration range, these effects should be therefore evaluated as non-physiological without relevance in vivo.

Animals↗