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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

At least 289 records · Page 16Linked to original sources
PubMed1982

Nicotine-induced antinociception in rats and mice: correlation with nicotine brain levels.

Nicotine was found to be potent in producing antinociception in mice and rats as measured by tail-flick latency but its action was of short duration. Nicotine's ED50 values (confidence limits) were 0.7 (0.4-1.1) and 2.0 (1.2-3.4) mg/kg in rats and mice, respectively, at the time of maximum effect. Brain levels of nicotine reached a maximum at 10 min, whereas antinociception was maximal within 2 min in rats. However, there was a good correlation between the time courses of antinociception and brain levels of nicotine in mice with both attaining maximal levels at 5 min. It was found that tachyphylaxis developed to the antinociception in rats within 10 min and lasted for up to 14 h, but tachyphylaxis did not develop to nicotine-induced antinociception in mice. The effect of nicotine appeared to be central in both rats and mice inasmuch as mecamylamine antagonized completely but hexamethonium (5 mg/kg) antagonized partially. Nicotine-induced antinociception was not blocked in either rats or mice by atropine in doses up to 10 mg/kg. Naloxone did not block nicotine in rats but did antagonize the antinociception in mice. In addition, yohimbine, a selective alpha-2 antagonist, blocked the antinociception in both species. These data implicate several different mechanisms in the antinociceptive action of nicotine.

Analgesics↗
PubMed1981

Characteristics of the calcium-mediated mechanism activating adenylate cyclase in Trypanosoma brucei.

1. The adenylate cyclase of bloodstream forms of Trypanosoma brucei is regulated by Ca2+. 2. The Ca2+-stimulated activity is not inhibited by trifluperazine, tentatively suggesting that the stimulation may not be mediated by calmodulin. 3. The Ca2+-binding site of the receptor regulating the adenylate cyclase is buried within the hydrophobic region of the plasma membrane and is not exposed to either the inner or the outer aqueous-phase bounding the membrane in unstimulated cells. 4. The response of the adenylate cyclase to stimulation by Ca2+ within the membrane is a transient increase in activity followed by a period of 'down regulation'. 5. The 'down regulation' of the adenylate cyclase also occurs by a Ca2+-dependent mechanism.

Adenylyl Cyclases↗
PubMed1981

The effect of insulin on plasma-membrane and mitochondrial-membrane potentials in isolated fat-cells.

1. A recently developed technique for the measurement of plasma-membrane and mitochondrial-membrane potentials in intact cells by using the distribution of 86Rb+ and [3H]methyltriphenylphosphonium+ has enabled us to characterize a novel insulin effect on fat-cell mitochondria. For control cells the plasma-membrane and mitochondrial-membrane potentials were 75 mV and 152 mV respectively. Insulin (10 mu units/ml) caused a 9 mV hyperpolarization of the plasma membrane and a 19 mV depolarization of the mitochondrial membrane. 2. The insulin-dependent mitochondrial depolarization was observed at physiological insulin concentrations (10 mu units/ml) and was apparent when the cells metabolized a wide variety of substrates. 3. Evidence from the uptake of the weak acid 5,5-dimethyloxazolidine-2,4-dione by fat-cells was interpreted as indicating that the mitochondrial pH gradient was increased by insulin. 4. Insulin alters the balance between the electrical and pH-gradient components that form the mitochondrial protonmotive force. A model is proposed.

Adipose Tissue↗
PubMed1981

Quantification of phencyclidine in mainstream smoke and identification of phenylcyclohex-1-ene as pyrolysis product.

Parsley cigarettes containing [3H]phencyclidine were machine smoked, and the mainstream smoke was trapped in glass wool filters. Radioactivity was extracted from these filters with chloroform. The average recoveries of radioactivity were 76, 85, 70, and 69% for cigarettes containing 3, 10, 30, and 50 mg of [3H]phencyclidine hydrochloride, respectively. TLC and GLC-mass spectrometry were employed to identify and quantify compounds in the filter extracts. Approximately one-half of the recovered radioactivity represented a pyrolysis product, phenylcyclohex-1-ene. Formation of this product involved loss of piperidine from phencyclidine. Piperidine, which was not radiolabeled, also may appear in smoke intact. The remainder of the radiolabeled material represented unchanged phencyclidine. Therefore, the percentage of [3H]phencyclidine delivered was approximately 40% of the amount smoked. This result was independent of puff frequency and quantity of phencyclidine hydrochloride smoked over the range tested. The [3H]phencyclidine delivery was compared to the quantities of [3H]-delta 9-tetrahydrocannabinol and [3H]nicotine delivered in mainstream smoke. The recovery of unchanged [3H]-delta 9-tetrahydrocannabinol from placebo marijuana cigarettes injected with a solution containing 3 mg of delta 9-tetrahydrocannabinol was 60%. Tobacco cigarettes injected with [3H]nicotine yielded 70% unchanged nicotine in mainstream smoke.

Cannabis↗
PubMed1981

Synthesis of 4,4-ditritio-(+)-nicotine: comparative binding and distribution studies with natural enantiomer.

The preparation of 4,4-ditritio-(+)-nicotine (Vb) (specific activity 10.3 Ci/mmole)from (+)-nicotine (Ib) via (-) 4,4-dibromocotinine (IIIb) is described. Although Ib is 10-30 times less potent than (-)-nicotine (Ia) in the CNS, its binding affinity for the crude mitochondrial or nuclear fraction of whole rat brain is only three times less than that of Ia. However, distribution studies showed that the maximum brain levels of (-)-[3H] nicotine are nearly twice those of (+)-[3H]-nicotine following administration of a 2-micrograms/kg dose. Binding affinity and disposition of the stereoisomers account for a portion of the pharmacological stereospecificity of nicotine.

Animals↗
PubMed1981

Nicotine binding sites and their localization in the central nervous system.

The resolution of racemic nicotine to provide optically pure (+)-nicotine and the synthesis of radiolabeled nicotine with high specific activity have facilitated the study of nicotine binding in brain. The actions of the stereoisomers of nicotine on the central nervous system are qualitatively similar in most tests but (-)-nicotine is more potent than the unnatural (+)-isomer by 10-fold or greater. Binding of radiolabeled nicotine to brain has both saturable and nonsaturable components. Only saturable binding is affected by incubation conditions such as time, temperature, pH and ion concentration. Excess concentrations of the stereoisomers are equally effective in displacing (-)-[3H]-nicotine from brain homogenates. Nevertheless, a direct comparison of (+)-[3H]-nicotine and (-)-[3H]-nicotine binding shows that the latter has a KD three times lower than the former. (-)-[3H]-Nicotine is bound to the greatest degree in hypothalamus and hippocampus, areas that also exhibited the most stereoselectivity for nicotine. However, differences in the binding affinities of the two isomers were far less than the pharmacological stereospecificity observed.

Animals↗
PubMed1981

Neurochemical and behavioral effects of polychlorinated biphenyls in mice.

The effects of polychlorinated biphenyls (PCBs) were assessed on some behavioral and neurochemical parameters in mice. Acute administration of a dose of 500 mg/kg (po) depressed spontaneous motor activity for a period of 15 min to 3 hr. Subchronic dosing of 30 or 100 mg/kg for 14 days was virtually without effect. PCBs given acutely had no effect on motor coordination nor on pentylenetetrazol-induced convulsions. Exposure of isolated mouse brain synaptosomes to PCBs produced a dose-dependent inhibition of neurotransmitter and precursor uptake (IC50 = 10(-5) to 10(-4) M) as well as stimulation of neurotransmitter release (EC50 = 10(-5) to 10(-4) M). Mitochondrial 45Ca2+ uptake was also enhanced (EC50 = 2.8 x 10(-4) M). Disposition of 14C-PCBs in mitochondria and synaptosomes following an oral dose of 500 mg/kg yielded levels comparable to those in isolated mitochondria and synaptosomes incubated with 14C-PCBs at concentrations that altered central neurotransmitter function in vitro.

Animals↗
PubMed1980

The effect of fluoride on the state of aggregation of adenylate cyclase in rat liver plasma membranes.

Irradiation inactivation was used to monitor changes in the state of adenylate cyclase in rat liver plasma membranes in the presence of F-.F- caused a decrease in the target size from 328000 to 237000 at 0 degrees C and from 329000 to 219000 at 30 degrees C. Adenylate cyclase was activated by F- at both 0 degrees C and 30 degrees C. The effect of F- was biphasic, activating up to a concentration of 10mM and inhibiting at higher concentrations. If adenylate cyclase weas maximally activated with glucagon and p[NH]ppG ([beta gamma-imido]GTP) all concentrations of F- were inhibitory. The implications of the results with respect to the mechanism of activation of adenylate cyclase are discussed.

Adenylyl Cyclases↗
PubMed1980

Requirement for guanosine triphosphate for cholera-toxin-catalysed incorporation of adenosine diphosphate ribose into rat liver plasma membranes and for activation of adenylate cyclase.

1. Cholera toxin was shown to require the presence of GTP to activate rat liver plasma-membrane adenylate cyclase. ATP did not affect the activation process. 2. Cholera toxin catalysed the incorporation of 32P from NAD labelled in the alpha-phosphate group of the ADP moiety into a rat liver plasma-membrane protein with a subunit mol.wt. of 42 500. This is taken to demonstrate ADP-ribosylation. The ADP-ribosylation of this protein also required GTP and was unaffected by ATP. 3. Nicotinamide inhibited both the activation of adenylate cyclase by cholera toxin and the ADP-ribosylation of the protein of 42 500 subunit mol wt. Neither the activation nor the ADP-ribosylation could be reversed by treatment with nicotinamide in the presence of cholera toxin.

Adenosine Diphosphate Ribose↗
PubMed1980

Modification of the behavioral effects of phencyclidine by repeated drug exposure and body weight changes.

In the first experiment, the effects of phencyclidine (PCP) on intake of sweetened condensed milk by rats were compared before and during a period of repeated daily injections of PCP or saline. A shift to the right in the PCP dose-effect function was found in rats receiving daily PCP injections indicating tolerance development to the effects of PCP on milk intake. The dose-effect function of PCP was shifted to the right in animals receiving daily saline as well. However, when body weight changes were controlled for in this groups of animals, the effects of PCP were the same as they had been initially, implicating body weight as a determinant of the behavioral effects of PCP. In the second experiment, a direct comparison of the behavioral effects of PCP in high- and low-weight animals revealed diminished effects of PCP in high-weight animals. When these animals were treated with 3H-PCP, brain total radioactivity as well as 3H-PCP in the high-weight animals were significantly lower than those in the low-weight animals.

Animals↗
PubMed1980

3H-delta 9-Tetrahydrocannabinol, 3H-cannabinol and 3H-cannabidiol: penetration and regional distribution in rat brain.

3H-delta 9-Tetrahydrocannabinol (3H-delta 9-THC), 3H-cannabidiol (3H-CBD) and 3H-cannabinol (3H-CBN) were administered (1 mg/kg) to male rats which were decapitated either 0.5, 1, 15, 30 or 90 min later. The plasma concentration was similar for all cannabinoids throughout the time course. After 5 min greater than 80% of the plasma radioactivity in each treatment was due to metabolites. Radioactivity rapidly entered brain after the administration of 3H-CBD, 3H-CBN, and 3H-delta 9-THC. The concentrations of unchanged 3H-CBD aand 3H-CBN in whole brain were higher than that of 3H-delta 9-THC 5 min after administration. Regional distribution of radioactivity in the brain after 5 min was similar for all three cannabinoids, the only significant difference being in hypothalamus. Coadministration of 3H-delta 9-THC with a five-fold excess of either CBD or delta 9-THC did not produce any significant alteration in the levels of radioactivity in brain or plasma 5 min after their injection. The difference in behavioral activity of delta 9-THC, CBD and CBN cannot be explained by penetrability or regional distribution in the brain.

Animals↗
PubMed1980

'Swell dialysis' demonstrates that adenylate cyclase in Trypanosoma brucei is regulated by calcium ions.

A new technique, 'swell dialysis', is described that allows the study of cellular enzymes in situ if they are located in the cytoplasm or on the cytoplasmic face of any membrane. The technique is potentially applicable to any population of individual eukaryotic cells that lack a cell wall. In this study swell dialysis has been applied to an examination of the regulation of adenylate cyclase in blood-stream forms of Trypanosoma brucei (427-12/ICI-060). Adenylate cyclase in this protozoon is shown to be controlled by Ca2+. There is a 16-fold stimulation of the cyclase at 100 microM Ca2+ over basal activity without added Ca2+. The ability of Ca2+ to stimulate adenylate cyclase is lost upon rupture of the cell, which is reminiscent of the loss of control of the adenylate cyclase in Escherichia coli by sugars of the phosphotransferase system when cell breakage occurs. The physiological function of the Ca2+ activation of adenylate cyclase in T. brucei has not been established but a possible role in the change of surface coat in bloodstream forms should be considered.

Adenylyl Cyclases↗
PubMed1980

Identification of in vivo liver metabolites of delta 1-tetra-hydrocannabinol, cannabidiol, and cannabinol produced by the guninea-pig.

The metabolites of delta 1-tetrahydroannabinol (delta 1-THC), cannabidiol (CBD), and cannabinol (CBN) produced in vivo by the guinea-pig have been studed by combined gas-liquid chromatography-mass spectrometry, 45 metabolites of delta 1-THC were identified of which 12 have not been reported before. Several other metabolites were detected but not identified. The major metabolic routes involved allylic and aliphatic hydroxylations, oxidations to ketones and acids, oxidative degradation of the side-chain presumably by the beta-oxidation pathway, and formation of glucuronide conjugates. Di- and tri-substituted metabolites were abundant. The metabolism differed considerably from that observed in mouse and rat in that 1''- and 6 beta-hydroxylation and oxidation degradation of the side-chain were major metabolic pathways. 1''-Hydroxy-delta 1-THC was found as a pair of diasteroisomers. Similar metabolic pathways were observed with CBD; twenty metabolites were identified of which two were new. Only 6 metabolites of CBN were identified. These mainly mono-substituted in the same positions as were observed with delta 1-THC and CBD.

Animals↗