H. P. T. Ammon

Inactivation of coenzyme a by ethanol—I: Acetaldehyde as mediator of the inactivation of coenzyme a following the administration of ethanol in vivo

Abstract Ethanol inactivates coenzyme A in liver and brain of white mice in vivo . In order to determine whether this effect is caused by ethanol itself or by acetaldehyde its metabolite the influence of ethanol and acetaldehyde on brain and liver was studied in vitro . Acetaldehyde lowered coenzyme A activity in homogenates of brain and liver. The concentrations required were 0.1–1.6 mM for brain and 1–32 mM for liver. On the other hand ethanol (20–360 mM) inactivated coenzyme A only in liver but not in brain homogenates. Since brain tissue is not able to oxidize ethanol in measurable quantities and, therefore, acetaldehyde is formed only in liver homogenates it is concluded that the action of ethanol on coenzyme A is mediated by acetaldehyde.

Modification by two beta-adrenergic blocking drugs of the effects of methamphetamine on behaviour and brain metabolism of mice

AN ANTAGONISTIC influence of propranolol on methamphetamine-induced excitation and the concomitant changes in brain metabolism has been reported (ESTLER and AMMON, 1967) but unfortunately propranolol has not only antiadrenergic j3-receptor blocking but also central depressant properties (ESTLER and AMMON, 1969; LESZKOVSKY and TARDOS, 1965; MURMANN, -ANTE and SACCANIGUELFI, 1966). Thus it could not be ruled out that the antagonism between propranolol and methamphetamine was a mere functional one. For this reason another adrenergic &receptor blocking drug, ~-(-)-(l-(4’-nitrophenyl)-2-isopropy~amino-ethano~ HCI) (INPEA) which is not only free of central depressant effects but has even central stimulant properties (MURMANN et nl., 1966; ESTLER unpublished) has been tested under the same experimental conditions. The combined effects of methamphetamine and the 8-adrenergic blocking drugs INPEA and propranolol on spontaneous motor activity and metabolites of the cerebral carbohydrate metabolism are described. Methamphetamine enhances motor activity and produces a decrease of the glycogen and an increase of the pyruvate content of the brain. INPEA and propranolol diminish the methamphetamine-induced motor excitation and prevent or reverse the changes in the cerebral glycogen and pyruvate contents produced by methamphetamine. It seems that glycogenolysis and-at least in part-central stimulation, too, have to be ascribed to the sympathomimetic properties of methamphetamine. The results are compared with those of our previous study with methamphetamine and propranolol (BTLER and AMMON, 1967).

Effect of tolbutamide on aminophylline-, 3,5-AMP-dibutyrate- or glucagon-induced insulin release from pancreatic islets after impairment of pyridine nucleotide metabolism caused by 6-aminonicotinamide (6-AN).

SummaryThe effect of tolbutamide on pyridine nucleotides and insulin secretion stimulated by aminophylline, 3,5-AMP-dibutyrate or glucagon was studied in pancreatic islets of rats previously treated with 6-aminonicotinamide (6-AN), an inhibitor of pyridine nucleotide synthesis.After being incubated for 60 min in a Krebs-Ringer-Bicarbonate-Buffer in the absence of glucose, pancreatic islets of rats i.p. injected with 35 mg/kg of 6-AN 6 hrs before pancreas removal contained about 30% less NADP and NADPH than did islets of control rats. No changes of NAD or NADH were observed in islets of 6-AN-treated animals. Addition of 16.5 mM glucose led to an increase of NADH, NADPH and a decrease of NADP in islets of both groups of animals; NAD levels remained unchanged. In vitro addition of tolbutamide to islets of control rats did not affect the levels of NADPH or NADP in the presence of 5.5 mM glucose. When 16.5 mM glucose were present, a decrease of NADPH and an increase of NADP was obvious. No effect of tolbutamide on insular NADPH or NADP was observed in islets of rats previously treated with 6-AN be it in the presence of 5.5 or 16.5 mM glucose.In islets of 6-AN-treated rats insulin release in response to aminophylline or 3,5-AMP-dibutyrate in the presence of 5.5 mM glucose was significantly depressed, when compared to islets of untreated controls. Addition of tolbutamide increased insulin release due to aminophylline, 3,5-AMP-dibutyrate or glucagon from islets of controls. Tolbutamide alone was without effect. In islets of 6-AN-treated rats aminophylline, 3,5-AMP-dibutyrate or glucagon stimulated insulin release only when tolbutamide was present.Our data suggest that there is no direct interference of tolbutamide with pyridine nucleotides of pancreatic islets, and that tolbutamide increases the secretory response of the β-cell to aminophylline, 3,5-AMP-dibutyrate or glucagon when insulin release due to these agents is inhibited during decrease of insular NADP and NADPH, caused by 6-AN.

Der einfluss von acetaldehyd auf coenzym a-aktivität und atmung von leber- und hirnmitochondrien

Abstract Two hr after the intravenous injection of 6 mg/g ethanol the tissues and mitochondria of the liver and brain contain only 13–22 per cent of their normal content of active CoA. Acetaldehyde decreased the content of active CoA in isolated mitochondria of the liver and of the brain. In the brain mitochondria only 7 per cent of the normal content of active CoA are found in the presence of 0.5 μmoles acetaldehyde/ml. In the liver mitochondria 9 per cent of the normal content of active CoA are found in the presence of 6.1 μmoles acetaldehyde/ml. It is suggested that acetaldehyde combines with the thiolgroup of the CoA forming a semimercaptale, which does not take part in the transacetylating reaction in the test of Kaplan and Lipmann. With increasing concentrations of acetaldehyde the total respiration of the mitochondria of the liver and brain decreases. In the mitochondria of the liver the amount of acetaldehyde oxydation increases, while total respiration tends to decrease. Brain mitochondria, which contain less than 7 per cent of active CoA are able to maintain 23–46 per cent of their total respiration.

Substrate supply and energy metabolism of skeletal muscle of mice treated with methamphetamine and propranolol

Abstract In order to examine, whether the inhibition by propranolol of methamphetamine-induced motor excitation has to be ascribed to lack of substrate supply and inadequate energy production in skeletal muscle, the influence of 3 μg/g methamphetamine subcutaneously (s.c.) alone or in combination with 5 μg/g propranolol intraperitonially (i.p.) on liver glycogen, blood glucose, non-esterified fatty acids in the blood and the glycogen, pyruvate, lactate, ATP and phosphocreatine contents of skeletal muscle has been investigated in mice. The following results have been obtained: (1) Methamphetamine stimulates lipolysis in adipose tissue and glycogenolysis in liver and muscle and thus provides the substrate required for an adequate energy production in skeletal muscle. (2) Propranolol inhibits methamphetamine-stimulated lipolysis and at the same time enhances the mobilization of hepatic glycogen and the utilization of carbohydrates in skeletal muscle. In this way enough substrate can be supplied to skeletal muscle to maintain constant ATP and phosphocreatine levels. It is concluded from the results, that the inhibition by propranolol of methamphetamine-induced excitation is not due to an inhibition of energy metabolism of skeletal muscle.

The influence of aliphatic alcohols and their halogen derivatives on the coenzyme A in the liver of mice

Abstract The effect was studied of i.v. administration of various aliphatic alcohols such as methanol, ethanol, propanol, monochloroethanol, trichloroethanol and tribromoethanol and their corresponding aldehydes on the activity ofcoenzyme A in the liver of white mice. All compounds except trichloroacetaldehyde hydrate, tribromoethanol and acetone blocked the CoA. The blocking effect reached a maximum 30–120 min after the administration of the alcohols and immediately after the administration of the aldehydes. The results support the view that CoA is not blocked by the alcohols themselves but by the aldehydes, derived from the alcohols.

Different effects of inhibition of lipolysis by nicotinic acid on the rate of clycolytic carbohydrate breakdown in brain and skeletal muscle

Abstract Nicotinic acid inhibits lipolysis in adipose tissue and leads to a reduced supply of FFA to the organs. Compensatorily the breakdown of carbohydrates is accelerated in liver and skeletal muscle. In the brain, however, which does not depend on the oxidation of FFA glycolysis is not affected by the administration of nicotinic acid.

Catecholamine-Independent Glycogenolysis in Brain During Carbon Monoxide Poisoning

In carbon monoxide poisoned mice enhanced glycogenolysis and lactate production in the brain are not prevented by pretreatment of the animals with reserpine or an adrenergic β- recep

Metaboliten des Kohlenhydratstoffwechsels und energiereiche Phosphate im Gehirn weißer Mäuse nach wiederholter Kohlenmonoxydvergiftung

The influence of single (4 hours) or repeated (35 times, 9 hours plus once for 4 hours within a period of 7 weeks) exposure to 0.1% (v/v) carbon monoxide in air on the glycogen, pyruvate, lactate, ATP and phosphocreatine content of the brain and on the blood glucose level was investigated in mice. By a carbon-monoxyhemoglobin concentration of 35% after a single exposure to carbonmonoxide, the pyruvate content of the brain was found to be increased and the blood glucose level decreased. After 7 weeks of repeated exposure, additional changes found by the same CO-Hgb content included an increase in the lactate and a decrease in the phosphocreatine content of the brain. The changes produced by repeated carbon monoxide poisoning were found to be only partly reversibel after the animals were subsequently allowed to breathe normal air for 15 hours.ZusammenfassungAn weißen Mäusen wurde der Einfluß einer einmaligen (4 Std) und einer 7wöchigen, intermittierenden (35mal 9+1 mal 4 Std) Vergiftung mit Kohlenmonoxyd (0,1 Vol.- % in Luft) auf den Gehalt des Gehirns an Glykogen, Pyruvat, Lactat, ATP und Kreatinphosphat sowie den Blutzucker untersucht. Im akuten Versuch war bei einem CO-Hämoglobingehalt des Blutes von 35% der Pyruvatgehalt des Gehirns erhöht und der Blutzuckerspiegel erniedrigt. Nach 7 Wochen fanden sich bei gleichem CO-Hämoglobingehalt zusätzlich noch ein Anstieg des Lactat- und ein Abfall des Kreatinphosphatgehaltes. Die Veränderungen waren innerhalb von 15 Std Aufenthalt in CO-freier Atmosphäre nur z. T. reversibel.

Potentiation of the anticalorigenic action of the adrenergic beta-receptor antagonist MJ 1999 by cyclic 3′,5′-AMP

Abstract Oxygen consumption, rectal temperature and survival rate of acutely cold exposed mice are reduced by the adrenergic β-receptor blocking drug MJ 1999. Since it was supposed that this effect was due to lack of cyclic 3′,5′-AMP, which is required for the stimulation of lipolysis and glycogenolysis, it was tried to overcome the anticalorigenic action of MJ 1999 by i.v. administration of N 6 -2′-0-dibutyryl-3′,5′-AMP. Dibutyryl-3′,5′-AMP did, however, not prevent but potentiate dose dependently the anticalorigenic action of MJ 1999 on oxygen consumption, rectal temperature and survival rate.