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D J Jenden

Publications and source records attributed to D J Jenden.

At least 91 records · Page 5Linked to original sources
PubMed1985

In vivo metabolism of a cholinergic false precursor after dietary administration to rats.

The false cholinergic precursor [2H4]N-amino-N,N-dimethylaminoethanol (N-aminodeanol, NADe) was fed ad libitum to weanling rats in a low choline (Ch), low methionine synthetic diet. The free [2H4]NADe plasma concentration achieved at 32 days was 51 microM. The free Ch plasma concentration was reduced to 6 microM, compared to 20 microM measured in control rats which were fed Ch in place of [2H4]NADe. After 33 days the rats were killed by rapid microwave fixation, and tissues were assayed for [2H4]NADe, [2H0]Ch and their acetate esters using combined gas chromatography mass spectrometry. Approximately 50% of the acetylcholine content of cortex, striatum, hippocampus, diaphragm and ileum had been replaced by the false transmitter [2H4]O-acetyl-N-aminodeanol. In all tissues measured except striatum the sum of the true + false transmitters was not significantly different from the acetylcholine content in control rats. In striatum the sum of the transmitters was significantly reduced to 79% of control. [2H4]NADe was incorporated into lipids. The ratio of lipid bound [2H4]NADe to lipid bound Ch in the plasma of experimental rats was 2.6. In cortex, the ratio of lipid bound [2H4]NADe to lipid bound Ch (1.3) was comparable to the ratio of false to true transmitter (1.0), although the ratio of free [2H4]NADe to free Ch was much higher (4.9). NADe caused no obvious toxicity, although both control and experimental groups gained weight more slowly than rats fed standard laboratory chow. These results demonstrate that NADe can enter the biochemical pathways for Ch in vivo, causing replacement of endogenous acetylcholine with the false transmitter acetyl-NADe.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1984

An alkylating derivative of oxotremorine interacts irreversibly with the muscarinic receptor.

A 2-chloroethylamine derivative of oxotremorine was studied in pharmacological experiments and muscarinic receptor binding assays. The compound, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123), forms an aziridinium ion in aqueous solution at neutral pH that stimulates contractions of the guinea pig ileum with a potency similar to that of oxotremorine. Following the initial stimulation, there is a long lasting period of lack of sensitivity of the guinea pig ileum to muscarinic agonists. BM 123 also produces muscarinic effects in vivo. When homogenates of the rat cerebral cortex were incubated with BM 123 and assayed subsequently in muscarinic receptor binding assays, a loss of binding capacity for the muscarinic antagonist, [3H]N-methylscopolamine ( [3H]NMS), was noted without a change in affinity. Similar observations were made in [3H]1-3-quinuclidinyl benzilate ( [3H]1-QNB) binding assays on the forebrains of mice that had been injected with BM 123 24 hr earlier. The loss in receptor capacity for both [3H]NMS and [3H]1-QNB was prevented by atropine treatment. Kinetic studies of the interaction of BM 123 with homogenates of the rat cerebral cortex in vitro showed that the half-time for the loss of [3H]1-QNB binding sites increased from 10 to 45 min as the concentration of BM 123 decreased from 10 to 1 microM. In contrast to the aziridinium ion, the parent 2-chloroethylamine compound and the alcoholic hydrolysis product were largely devoid of pharmacological and binding activity.

Animals↗
PubMed1984

Biochemical effects of phosphatidylcholine treatment in rats.

We measured several biochemical effects of 10 days of intragastric administration of phosphatidylcholine (10 mmoles/kg) to rats because of the expanding clinical use of chronic phosphatidylcholine treatment for disorders involving impaired cholinergic neurotransmission. The plasma and erythrocyte choline concentrations were increased 3.5-fold, which was the same percent increase as found after an acute treatment with phosphatidylcholine. The lipid and fatty acid compositions of the plasma were also altered; free and total cholesterol levels increased, triglycerides increased, the monoene fatty acids generally decreased, and the diene and tetraene fatty acids generally increased. We found no effect of this treatment on the hepatic microsomal cytochrome P-450 activity or on the N-demethylation of benzphetamine or methamphetamine. Ten days of phosphatidylcholine treatment increased the concentration of choline in the brain but had no effect on the concentration of acetylcholine, the activity of choline acetyltransferase, cholinesterase activity, the apparent KD or Bmax of muscarinic receptors, or the fatty acid composition of rat brain lipids. These findings indicate that the largest effect caused by this treatment was an increase in the choline levels. No indication of altered cholinergic metabolism was observed. Further studies of the effects of chronic phosphatidylcholine treatment are required to clarify its therapeutic mechanism of action.

Acetylcholinesterase↗
PubMed1984

The conversion of 2-chloroalkylamine analogues of oxotremorine to aziridinium ions and their interactions with muscarinic receptors in the guinea pig ileum.

Two mustard analogues of oxotremorine, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123) and N-[4-(2-chloromethylpyrrolidino)-2-butynyl]-2-pyrrolidone (BM 130), were synthesized. BM 123 and BM 130 cyclize in neutral aqueous solution to aziridinium ions. These aziridinium ions are potent stimulants of the guinea pig ileum. This agonist activity is unaffected by hexamethonium but is inhibited by methylatropine and by pretreatment of solutions of BM 123 and BM 130 with thiosulfate. The parent 2-chloroalkylamines and the alcohols formed by hydrolysis of the aziridinium ions have very weak pharmacological effects. Incubation of the isolated guinea pig ileum for 30 min with BM 123 at 20 microM and 2 microM caused 94% and 48% receptor alkylation, respectively, as calculated from the shift in the agonist dose-response curve. Similar incubations with BM 130 at 20 microM and 5 microM alkylated 85% and 63% of the receptors. No recovery from this apparent blockade was observed over a 4-hr time period. These calculated receptor occupancies by BM 123 and BM 130 agreed with those estimated from reduction of [3H] (-)-3-quinuclidinyl benzilate binding to homogenates of the ileum following exposure to BM 123 and BM 130. Methylatropine (20 nM) protected against the irreversible actions of BM 123 and BM 130. In homogenates of the guinea pig ileum, BM 123 and BM 130 also caused a selective reduction in the binding capacity of [3H]N-methylscopolamine without significantly affecting the apparent affinity. This inhibitory effect persisted after extensive washing. BM 130 was a weak agonist at nicotinic receptors of the frog rectus abdominis muscle, whereas BM 123 was almost inactive. In conclusion, BM 123 and BM 130 are potent and specific muscarinic agonists that bind irreversibly to muscarinic receptors.

Alkylation↗
PubMed1984

Electrophysiological and neurochemical investigations of the action of presynaptic neurotoxins.

Previous experiments have suggested that hemicholinium-3 might directly antagonize certain actions of beta-bungarotoxin at the neuromuscular junction. Data presented here show that, on the contrary, hemicholinium-3 neither inhibits the phospholipase activity of beta-bungarotoxin nor does it affect the characteristic pattern of transmitter release observed at end plates exposed to the toxin. Lanthanum ions were found to promote the release of acetylcholine from sartorius nerve-muscle preparations that had been paralyzed by botulinum toxin. However, the acceleration of transmitter release by lanthanum was not nearly as great as in control preparations as monitored either electrophysiologically or by chemical measurement of ACh.

Acetylcholine↗
PubMed1984

Comparison of the muscarinic receptor binding activity of some tertiary amines and their quaternary ammonium analogues.

A series of tertiary amines and their N-methyl quaternary salts were examined for their ability to inhibit specific [3H]3-quinuclidinyl benzilate binding to rat brain muscarinic receptors. The more flexible tertiary amines, like dimethylaminoethyl acetate, were less potent than their respective quaternary ammonium analogues, while rigid tertiary amines, like aceclidine, were more potent than their quaternary derivatives. The competition curves of most of the compounds were adequately described by a two-site binding equation. A good correlation between pharmacological activity and the high-affinity dissociation constant was observed. The influence of pH on the competitive inhibition of [3H]3-quinuclidinyl benzilate binding by arecoline and scopolamine was also examined. The potency of these amines declined relative to that of their N-methyl derivatives as the pH increased from 8.0 to 9.0, suggesting that it is primarily the protonated form of arecoline and scopolamine which interacts with the muscarinic receptor.

Amines↗
PubMed1983

Pharmacological properties of oxotremorine and its analogs.

The mechanism of action of oxotremorine is reviewed. A number of analogs of oxotremorine, including agonists, partial agonists and antagonists, are described. Many of these are potent and highly specific in their central actions. The possible basis for this specificity is outlined.

Acetylcholine↗
PubMed1983

Muscarinic activity of some secondary and tertiary amines and quaternary ammonium salts structurally related to oxotremorine.

A number of secondary and tertiary amines as well as quaternary ammonium compounds, obtained by structural modification of the amino group of oxotremorine (1) and its acetamide analogue (14), were investigated for muscarinic and antimuscarinic activity in vivo and in vitro. For the quaternary ammonium analogues, decrease of in vitro muscarinic potency is well correlated with increase of the size of the quaternary ammonium group, as estimated from increments in apparent molal volumes. A similar decrease of muscarinic potency with increasing substitution at the nitrogen atom is generally observed for the secondary and tertiary amines. For the latter the reduction in muscarinic activity appears to be due to loss of efficacy, since the higher homologues are partial agonists or antagonists. There is a highly significant correlation between muscarinic activity in vitro and central tremorogenic activity of the tertiary amines.

Amines↗
PubMed1983

Rapid decline in acetylcholine release and content of rat extensor digitorum longus muscle after denervation.

The amount of acetylcholine (ACh) and choline (Ch) in normal and denervated rat extensor digitorum longus (EDL) muscles, as well as that released spontaneously from these muscles, was determined by an extremely sensitive gas chromatographic-mass spectrometric assay method. We found decreases in ACh content and spontaneous, resting ACh release as early as 8 h after denervation. The ACh content decreased to a plateau of 30% of control by 11 h; ACh release attained a plateau of 50% of control several hours later. These results showed that in denervated EDL muscles ACh content and spontaneous release (measured biochemically) decreased before nerve-evoked and spontaneous quantal release (measured physiologically) ceased at most synapses. The rapid reduction in ACh, or possibly in other substances that may be released with ACh, may be an important factor in initiating postsynaptic degenerative changes after nerve transection. Choline content and choline resting release increased significantly at both 1 and 3 days after nerve transection. These increases may be related to onset of postsynaptic neuromuscular degenerative changes.

Acetylcholine↗
PubMed1983

The effect of beta-bungarotoxin on acetylcholine and choline content of vertebrate tissues.

We have investigated the effects of intraventricularly or i.p. administered beta-bungarotoxin on the tissue content of acetylcholine and choline in three vertebrate species. A gas chromatographic mass spectrometric assay was used to measure acetylcholine and choline. Intraventricular administration of beta-bungarotoxin (1 microgram, 105 min) in rats raised the acetylcholine content of hippocampus and striatum but not of cortex. Choline was significantly increased in all three brain regions. Injection of the toxin i.p. (5 micrograms, 90 min) in rats caused variable increases of the acetylcholine content of diaphragm, tongue, temporalis muscle and adrenal gland, but no significant change was seen in heart atrium, eye, ileum or superior cervical ganglion. Significant increases of choline content were seen in heart and adrenal. The toxin caused the same degree of increase of acetylcholine in mouse diaphragm as in the rat. No alteration of sartorius muscle or tongue acetylcholine was observed after i.p. injection of beta-bungarotoxin (5 micrograms) in frog. Results with 125I-labelled beta-bungarotoxin (rats, i.p.) suggest that the observed differences in response to beta-bungarotoxin cannot be accounted for by the distribution of toxin alone. From these data we make suggestions regarding the variable effects of beta-bungarotoxin on tissue acetylcholine and choline content and the implication of these findings for the mechanism of action of the toxin.

Acetylcholine↗
PubMed1983

Behavioral responses to amphetamines in identical twins.

Male, monozygotic twins (six pairs) were repeatedly tested before and after d-amphetamine, l-amphetamine, or placebo administration. Drug effects on cognitive, psychomotor, personality, mood, and pain variables were assessed. Members of a twin pair tended to respond similarly on several tests under placebo conditions, indicating genetic determination of the behavioral variables. In addition, cotwins tended to show similar responses to amphetamine as measured by one test of cognitive function, by several mood and personality variables (hostility, autonomic arousal, friendliness, feelings of tension and loss of control), and tended to have similar plasma levels of both amphetamine isomers. Although shared environmental effects cannot be ruled out, the results are consistent with genetic mediation of a variety of behavioral effects of amphetamines.

Adult↗
PubMed1983

Metabolic effects of nicotinamide administration in rats.

Male rats fed a 12% casein diet without choline were injected i.p. daily for 2 or 5 weeks with either saline or 6, 20 or 60 mg of nicotinamide (NAM) per 100 g body weight. Weight gain, food intake and gain/food were lower for the NAM-treated groups compared to the controls. Urinary excretion of the major metabolite, N1-methylnicotinamide (NMN) increased with increasing dose of NAM. NAM administration did not alter the activity of hepatic nicotinamide methyltransferase. Excretion of another metabolite, N1-methyl-2-pyridone-5-carboxamide (2-PYR) was low and showed minimal changes in response to NAM administration. NAM administration did not affect urinary creatinine excretion. Livers of the NAM-injected groups were hypertrophied, and the total lipid content was increased. Kidney hypertrophy was also noted. Plasma and liver choline levels were decreased in response to NAM administration. We conclude that chronic NAM administration resulted in a methyl-group deficiency state due to the greatly increased need for methylation of NAM.

Animals↗
PubMed1983

Choline and acetylcholine metabolism in rat neostriatal slices.

Choline (Ch) uptake and release and acetylcholine (ACh) synthesis and release have been studied by gas chromatography mass spectrometry (GCMS) in slices of rat neostriatum in vitro to assess the effects of depolarization by 25 mM K+ and the influence of elevated concentrations of Ch in the incubation medium. During the first 60 min after preparation, 25 mM K+ increased ACh release by 182% and reduced ACh levels by 40%. The rate of ACh synthesis was unchanged. After a 1-h equilibration period, the rate of ACh synthesis was considerably less (2.41 nmol mg-1 h-1, compared to 9.78 nmol mg-1 h-1). Exposure to 25 mM K+ during the second hour increased the rate to 6.47 nmol mg-1 h-1. During the first 10 min of exposure to 25 mM K+, ACh synthesis was reduced, regardless of incubation. Increasing concentrations of external [2H4]Ch apparently favored initial rates of net ACh synthesis, since the rank order of initial net ACh synthesis rates is the same as the rank order of external [2H4] Ch concentration under both normal and depolarized conditions. However, the only significant effect of external [2H4]Ch on ACh metabolism was that it increased ACh release during the initial 10 min, when the preparation was depolarized with K+. The efflux of endogenous [2H0]Ch was increased initially (10 min) and slowed over a 60-min period by 25 mM K+, and increased when [2H4]Ch in the medium was increased. Changes in ACh synthesis and release were dependent upon the time exposure of slices to high K+, and the results suggest that Ch favors initial rates of ACh synthesis, but that Ch influences ACh release primarily under conditions of stress (i.e., depolarization).

Acetylcholine↗