S. Schenker

Cerebral acetylcholine in thiamine deficiency.

Summary This study assesses the hypothesis that severe thiamine deficiency may lead to a depletion of cerebral ACh, which, in turn, may be responsible for the cerebral dysfunction seen in this condition. Acetylcholine assays were carried out in rats with diet-induced thiamine deficiency resulting in overt neurologic signs and in asymptomatic pair-fed and normally fed controls. The brainstem and cerebellum were assayed, in addition to the cortex, since the former sites exhibit the most significant biochemical alterations in thiamine deficiency. Acetylcholine was assayed by a modification of a specific and accurate fluorometric procedure. For every brain area studied the cerebral ACh concentrations in thiamine-deficient rats exhibiting overt neurologic signs were comparable to values seen in asymptomatic pair-fed controls. This study indicates that thiamine deficiency does not cause an alteration in cerebral regional ACh stores and that alternate mechanisms for the neurologic dysfunction will have to be sought.

Physostigmine reversal of diazepam-induced hypnosis. A study in human volunteers

Under randomized double-blind conditions, 1.00 to 1.67 mg of intravenous physostigmine (Antilirium) reversed sleep induced by administration of 0.102 to 0.238 mg/kg body weight of intravenous diazepam in eight healthy human volunteers. Awakening occurred 330 to 740s after initiation of the physostigmine infusion at a rate of 0.5 mg/min every 4 min. Diazepam plasma levels were not significantly different at the start of either the physostigmine or placebo infusion. Physostigmine did not effect plasma binding of diazepam. Six subjects experienced nausea, and one subject developed an arrhythmia. Physostigmine reverses diazepam-induced hypnosis but causes side-effects requiring cautious administration.

Impaired secretion of triglycerides by the liver; a cause of tetracycline-induced fatty liver.

Summary The increments in plasma triglyceride levels observed after administration of Triton were consistently and significantly lower in tetracycline-injected rats, when hepatic tetracycline concentration was high, than in Triton-injected controls. These data are interpreted as indicating impaired release of hepatic triglyceride in tetracycline-injected animals. Hepatic triglyceride increased in tetracycline-injected rats and most of this could be accounted for by impaired release of liver triglyceride. This mechanism, possibly due to impaired synthesis of hepatic lipid acceptor protein, appears to be the major cause of tetracycline-induced fatty liver.

Studies on the pathogenesis of tetracycline-induced fatty liver

SummaryThe present study assesses the roles of hepatic ATP and of pregnancy in the pathogenesis of tetracycline-induced fatty liver.Pregnant and nonpregnant female rats were infused with tetracycline (10 mg./100 gm.) daily for 3 days. At that time, mean total hepatic lipid and triglyceride concentrations for the tetracycline-injected nonpregnant and pregnant rats were significantly higher than control values. The total lipid and triglyceride levels, as well as plasma decay rates and hepatic concentrations of tetracycline, were comparable in the tetracycline-injected nonpregnant and pregnant rats. Hepatic ATP levels were normal in animals given tetracycline for 3 or 7 consecutive days as well as in those studied during maximal hepatic tetracycline concentration.It is concluded that in the rat: (1) tetracycline-induced fatty liver is not mediated via hepatic ATP depletion, and (2) large doses of tetracycline are metabolized comparably and result in a similar increase in hepatic lipid in pregnant and nonpregnant animals.

Cerebral Acetylcholine, Serotonin, and Norepinephrine in Acute Ammonia Intoxication

Summary The primary purpose of this study was to assess the hypothesis that a depletion of cerebral acetylcholine (ACh) may be responsible for the coma induced with ammonia. An ancillary aim was to determine the effect of ammonia on cerebral levels of two other likely neurotransmitters, serotonin and norepinephrine. Acetylcholine, serotonin, and norepinephrine were measured in the brain of rats with NH4Ac-induced stupor and in asympotomatic NaAc-injected and uninjected controls. Studies were carried out during and after the development of stupor; and both cortex and brainstem were assayed separately since these areas are believed to be primarily responsible for the maintenance of consciousness. Acetylcholine was measured by a specific and accurate fluorometric procedure. In rats with ammonia-induced precoma and coma, the ACh and norepinephrine levels in the cerebral cortex and brainstem were comparable to values seen in control animals. Cerebral serotonin likewise was normal during the development of stupor but fell modestly in both cortex and brainstem of animals with established coma. This study indicates that cerebral regional stores of ACh, serotonin, and norepinephrine are normal during the development of acute ammonia-induced coma and that other mechanisms for this neurologic dysfunction will have to be considered.

Hepatic metabolism and transport in thiamine deficiency

Thiamine deficiency often accompanies alcoholism which causes liver disease, but the role of thiamine depletion per se in modifying hepatic metabolism and function is uncertain. Thiamine is the coenzyme for transketolase and pyruvate decarboxylase in tissues. Decreased pyruvate decarboxylase activity theoretically may impair synthesis of acetyl CoA and then of ATP, the ultimate tissue energy source. In this study, hepatic metabolism, especially ATP stores, and the transport of Rose Bengal across the liver, were assessed in rats with encephalopathy due to dietary thiamine deprivation, and in asymptomatic pair-fed controls. Compared to controls, in the thiamine-deficient rats, (a) hepatic transketolase and pyruvate decarboxylase activity were 89 and 74% lower (P<0.01) respectively; however, (b) hepatic acetyl CoA and ATP concentrations decreased only 21 and 12% (P<0.01), hepatic morphology was normal, and transport of Rose Bengal-131l across the liver was unimpaired. Depressed hepatic pyruvate decarboxylase activity and ATP concentration in thiamine-deficient rats in vivo responded to exogenous thiamine much more slowly than it did in brain, heart or kidney. In vitro, however, hepatic pyruvate decarboxylase activity rose briskly when exogenous thiamine pyrophosphate was added, indicating that the apoenzyme was not impaired. In conclusion, in severe thiamine deficiency, hepatic acetyl CoA and ATP stores are only slightly decreased, and hepatic transport of Rose Bengal is normal.

Impaired Biliary Excretion of Phenol 3, 6-Dibromphthalein Disulfonate in Neonatal Guinea Pigs

Summary Hepatic disposition of DiBSP was studied in adult and newborn guinea pigs from days 2 through 16 of life after intravenous administration of DiBSP in doses sufficient to achieve maximal rates of dye excretion into bile. Neonatal guinea pigs showed a significant reduction in the maximal rate of dye excretion into bile when compared to adult animals. A minimal estimate of hepatic uptake of DiBSP showed that uptake was similar in neonatal and adult animals and was significantly greater than the maximal rates of excretion into bile. Hence hepatic uptake did not limit hepatic disposition of DiBSP. With aging, injected DiBSP was excreted at progressively more rapid rates reaching adult levels of excretion at the beginning of the second week of life. This study demonstrates the presence of a defect in the excretory process by which DiBSP is transported from liver cells into bile in the neonatal guinea pig.