Benjamin Highman

Enhanced hepatotoxicity of carbon tetrachloride, thioacetamide, and dimethylnitrosamine by pretreatment of rats with ethanol and some comparisons with potentiation by isopropanol

Abstract Elevated plasma glutamic-pyruvic transaminase (GPT) activity induced by carbon tetrachloride (CCl 4 ), thioacetamide, or dimethylnitrosamine in male rats was increased by pretreatment with four doses (each 5 ml/kg) of ethanol orally 48, 42, 24, and 18 hr before the hepatotoxic agent. The potentiated hepatotoxicity of CCl 4 was confirmed by histologic evaluation. During the pretreatment, blood ethanol concentrations fluctuated between 0 and 300 mg/100 ml, but were less than 5 mg/100 ml when a hepatotoxic agent was injected ip. Pretreatment with ethanol did not affect the hepatic concentrations of CCl 4 or its metabolite, chloroform (CHCl 3 ), at 1 hr after administration of CCl 4 . The CCl 4 -induced diene conjugation tended to increase after ethanol pretreatment and was significantly potentiated by pretreatment with isopropanol or pyrazole and a single dose of ethanol. In rats pretreated with ethanol, covalent binding of 14 CCl 4 to liver protein and lipid in vivo was significantly greater at 6 and 24 hr, but not during the first 3 hr, than in control rats. The in vitro binding of 14 CCl 4 , 14 CHCl 3 , and 14 CBrCl 3 to hepatic microsomal protein was increased by ethanol pretreatment. Ethanol pretreatment also doubled the in vitro rate of demethylation of dimethyl-nitrosamine by liver microsomes, but did not affect the amount of microsomal protein and cytochrome P-450, NADPH c reductase activity nor the rate of N-demethylation of ethylmorphine. The similarities in microsomal effects of pretreatment with isopropanol and pretreatment with four doses of ethanol suggest that similar mechanisms are involved in their potentiation of CCl 4 -induced hepatotoxicity. The potentiation by pretreatment with ethanol, but not with isopropanol, of the hepatotoxicity of thioacetamide and dimethylnitrosamine suggests that ethanol pretreatment also activates some additional mechanisms.

Some similar effects after large doses of catecholamines and myocardial infarction in dogs

Abstract In dogs, both myocardial infarction and administration of large doses of catecholamines produce sustained ventricular hypersensitivity, as indicated by exaggerated ectopic responses to administration of small doses of norepinephrine. This hypersensitivity is associated with myocardial fatty changes. The triglyceride content of the heart is elevated the day after an infusion of a large amount of norepinephrine. Both myocardial infarction and administration of large doses of catecholamines cause marked elevations in serum glutamic oxalacetic and glutamic pyruvic transaminases, lactic dehydrogenase and alkaline phosphatase. The adrenergic blocking agent, phenoxybenzamine, prevents the triglyceride deposition in the heart, the prolonged ventricular hypersensitivity and the elevations in serum transaminases and lactic dehydrogenase after large doses of catecholamines; it does not prevent these changes, however, after coronary occlusion.

THE INFLUENCE OF PHENOXYBENZAMINE AND ISOPROPYLMETHOXAMINE (BW 61-43) ON SOME CARDIOVASCULAR, METABOLIC, AND HISTOPATHOLOGIC EFFECTS OF NOREPINEPHRINE INFUSIONS IN DOGS.

SummaryThe effects of intravenous norepinephrine infusion (0.5 mg/kg in two hours) in conscious dogs can be classified according to the influence of pretreatment with phenoxybenzamine (2 or 5 mg/kg intravenously one hour before norepinephrine) or isopropylmethoxamine (BW 61-43) (8 mg/kg intravenously 20 to 30 minutes before infusion). Effects blocked or reduced by phenoxybenzamine, but not by BW 61-43, include the rise in arterial pressure, electrocardiographic changes, accumulation of pericardial fluid rich in lactic dehydrogenase, the rise in hematocrit, presence of inclusion bodies in liver cells, and necrosis of the adrenal cortex. Effects blocked by BW 61-43, but not by phenoxybenzamine, include the rises in plasma FFA and glucose and the accumulation of triglycerides in liver. Both phenoxybenzamine and BW 61-43 block, at least partially, the accumulation of triglycerides in heart. Neither phenoxybenzamine nor BW 61-43 prevents the norepinephrine-induced depletion of glycogen in liver.

Effect of Environmental Temperature on the Response of Mice to Whole-Body Roentgen Radiation

Summary The net effect of a sufficiently cold environment is to lower the resistance of mice to the lethal action of X-rays. Subjection to a 10° or 30°C environment for 2 weeks prior to irradiation favors survival of irradiated mice maintained in those environments. Mice kept in a 30° environment that die following irradiation frequently show fatty changes in the liver.

Effects of dimethyl sulfoxide on serum enzymes and tissues in exercised rats

Abstract Five hours exercise of rats increased as much as four-fold serum levels of glutamic oxalacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), aldolase (SAld), lactic dehydrogenase (SLDH), malic dehydrogenase (SMDH) and urea nitrogen (SUN). Exercise also caused virtually complete depletion of liver glycogen, and a moderate intensification of the 5 isoenzyme bands of SLDH. Nineteen hours after exercise was terminated, approximately half of the rats showed slight to moderate fatty changes in the liver and thigh muscles. Administration of 4.5 mg/kg dimethyl sulfoxide (DMSO) i.p., without exercise increased slightly serum transaminase levels within 24 hours. DMSO combined with exercise (5 hours) increased serum enzymes as much as nine-fold and intensified all 5 isoenzyme bands of SLDH. In addition the isoenzyme band of malic dehydrogenases associated with the mitochondria was found in the serum. Nineteen hours after terminating exercise, fatty changes in the liver and thigh muscles occured in all 6 rats given DMSO and in only 3 of 6 untreated rats. These results suggest that DMSO in exercised rats enhances the permeability of cellular and mitochodrial membrane, facilities the release of tissue enzymes into the circulation, and may increase the incidence of fatty changes in the liver and in thigh muscles.

Reduction by pretreatment with dibenamine of hepatotoxicity induced by carbon tetrachloride, thioacetamide or dimethylnitrosamine

Abstract Pretreatment with dibenamine (25 mg/kg sc 48 and 24 hr before the administration of a hepatotoxic agent) protected rats against the hepatotoxicity of CCl4, thioacetamide, or dimethylnitrosamine, but not against allyl alcohol or bromobenzene. Protection was evident from reduced activity of plasma glutamic-pyruvic transaminase and reduced liver necrosis as demonstrated by histologic evaluations. In rats pretreated with dibenamine, LD50 values for CCl4 and thioacetamide were elevated and liver triglycerides after CCl4 and dimethylnitrosamine were reduced. Dibenamine protection against hepatotoxicity did not correlate with alpha-adrenergic receptor blockade. Similar pretreatment with 3 other alpha-adrenergic blocking agents, tolazoline, phenoxybenzamine, and EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), failed to protect rats against CCl4-induced hepatotoxicity.

Alterations in serum enzymes and isoenzymes in various species induced by epinephrine

Abstract 1. 1. The administration of epinephrine to rats, rabbits, guinea pigs and dogs leads to an elevation of several serum enzyme levels. 2. 2. Serum lactic dehydrogenase isoenzyme patterns and histological examination indicate that several tissues may contribute to this increase, but that there is a relatively greater contribution from cardiac tissue and/or erythrocytes. 3. 3. Adrenergic blocking agents prevent the serum enzyme alterations, the tissue changes and the abnormal isoenzyme patterns induced by epinephrine. 4. 4. A likely cause of the serum elevations is an increase in cellular permeability.

Induction of Hypothermia by Dimethyl Sulfoxide in Rats Exposed to Gold Tissue and Enzyme Changes.

Summary Topical and intraperitoneal treatment of rats with DMSO produced a 1 to 2°C drop in body temperature in 5 hours at 23°C; however, those treated topically showed an early transient rise of as much as 0.7°C. No serum enzyme, urea nitrogen, or sugar changes were produced by DMSO at 23°C. The only serum enzyme changes noted during a 5-hour exposure to 1.7°C was a fall in SAkP levels, but 19 hours later a rise in serum transaminases became evident. DMSO given intraperitoneally prior to cold exposure caused a marked decrease in body temperature and a marked increase within 5 hours in all serum enzymes studied, including SGOT, SGPT, SAld, SLDH, and SMDH. DMSO did not influence SAkP values. Also, the DMSO-treated rats exposed to cold showed intensification of all 5 SLDH iso-enzyme bands and the isoenzyme band of SMDH associated with mitochondria and an increased elevation in SUN, serum glucose and hematocrit. At 5 hours, all rats exposed to cold showed marked depletion of hepatic glycogen, but repletion was delayed in the DMSO-treated group. Nineteen hours after exposure to cold, only depletion of liver glyco-gen and fatty changes in the liver, heart, or muscle persisted. Topicaly DMSO before exposure to cold did not alter the serum enzyme values or tissue changes produced by cold exposure alone. These findings show that intraperitoneal injection of DMSO in rats exposed to cold induces marked hyper-glycemia, a severe hypothermia accompanied by a marked rise in serum enzyme values and glycogen depletion, and an increased incidence of fatty changes in the liver and muscle.

Effect of Altitude and Cobalt Polycythemia, Hypoxia, and Cortisone on Susceptibility of Rats to Endocarditis

Rats with polycythemia induced by exposures to simulated high altitudes developed a significantly higher incidence of endocarditis following intravenous bacterial injections than rats with cobalt polycythemia or ground level controls. No increase occurred in altitude rats when polycythemia was prevented by repeated bleedings. These findings suggest that both polycythemia and hypoxia are necessary to explain increased susceptibility of altitude rats. Cortisone increased susceptibility of ground level rats injected with Streptococcus faecalis. Unlike altitude exposures, however, cortisone did not render rats susceptible to endocarditis due to Hemophilus parainfluenza.

Serum enzyme and tissue changes in shaven rabbits exposed to cold

Abstract Shaven rabbits were exposed to −5 °C from 6 to 16 hr. With maximum exposure 50% became severely hypothermic, and the rest either became moderately hypothermic or remained normothermic. In severely hypothermic rabbits, marked elevations in serum concentrations of glutamic oxalacetic transaminase, glutamic pyruvic transaminase, aldolase, creatine phosphotransferase, and lactic dehydrogenase developed within 10–16 hr. Serum enzyme concentrations reached peak levels within 1 day after removal from cold and returned to normal within 6 days. Serum levels of isoenzyme lactic dehydrogenase 5 (SLDH 5 ) greatly increased and SLDH 1 decreased in severely hypothermic rabbits. This indicated that striated muscle tissue contributed to serum concentration of lactic dehydrogenase. About one-half of the rabbits showed foci of cardiac necrosis multiple pulmonary hemorrhages, and fatty changes in the liver, kidney, and striated and heart muscles. It is apparent that serum enzymes reached peak concentrations within the first day after cold exposure at a time when fatty changes and necrosis were found in the heart and other organs. The tissue changes were most frequent and severe in the hypothermic rabbits with the highest serum enzyme concentrations. Within 3–6 days fatty changes had largely disappeared, but the myocardial lesions persisted in the form of granulation and scar tissue.