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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 253 records · Page 14Linked to original sources
PubMed1986

Depletion of norepinephrine in mouse heart by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mimicked by 1-methyl-4-phenylpyridinium (MPP+) and not blocked by deprenyl.

A single dose of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in mice caused 75-87% depletion of heart norepinephrine (NE) concentration 24 hrs later. MPP+ (1-methyl-4-phenylpyridinium) caused similar depletion of heart NE. The effect of MPTP was not blocked by pretreatment with deprenyl, an inhibitor of type B monoamine oxidase (MAO-B). Also, deprenyl pretreatment did not prevent the depletion of heart NE after 4 daily doses of MPTP, even though in the same mice deprenyl pretreatment did prevent depletion of dopamine in the striatum and of NE in the frontal cortex. Apparently the depletion of heart NE by MPTP, unlike the depletion of brain catecholamines, does not require that MPTP be metabolized by MAO-B and can be mimicked by systemic injection of MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Brain anoxia releases striatal dopamine in rats.

Immediately following death resulting from discontinuance of artificial respiration in anesthetized rats, a large increase in electrochemically reactive materials in the extracellular fluid was detected by in vivo voltammetry with an electrode in the striatum. The use of in vivo brain dialysis permitted identification of the reactive material as dopamine. The release of dopamine occurred about 6 minutes after cessation of artificial respiration and death. A similar release of dopamine was found after intrastriatal ouabain administration. A large release of dopamine might result in irreversible tissue damage in certain pathological conditions such as stroke or anoxia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Antagonism of a peripheral vascular but not an apparently central serotonergic response by xylamidine and BW 501C67.

Xylamidine and BW501C67 (alpha-anilino-N-2-m-chlorophenoxypropylacetamidine), serotonin antagonists that have been reported not to cross the blood-brain barrier, were compared to other serotonin antagonists: mianserin, ketanserin, metergoline and LY 53857. All six compounds were potent inhibitors of the binding of tritiated spiperone to 5HT2 receptors in rat frontal cortex membranes in vitro and were less potent inhibitors of the binding of tritiated serotonin to 5HT1 receptors in rat brain membranes. All were potent antagonists of the 5HT2 receptor-mediated contractile response to serotonin in the rat jugular vein in vitro. At doses of 0.1 and 0.3 mg/kg i.p., xylamidine and BW501C67 antagonized the pressor response to intravenously injected serotonin in pithed rats. In contrast, neither xylamidine nor BW501C67 at doses of 1 or 3 mg/kg i.p. antagonized the elevation of serum corticosterone concentration by quipazine in rats, although the other compounds antagonized this effect with ED50 values between 0.03 and 0.9 mg/kg. These data corroborate the previously reported antiserotonin activity of xylamidine and BW501C67. Since xylamidine and BW501C67 were potent antagonists of a peripheral serotonergic response in vivo, their inability to antagonize the elevation of serum corticosterone concentration by quipazine suggests that this effect results from activation of central serotonin receptors.

Amidines↗
PubMed1986

MD 240928 and harmaline: opposite selectivity in antagonism of the inactivation of types A and B monoamine oxidase by pargyline in mice.

In mice treated 24 hrs earlier with pargyline (20 mg/kg i.p), both type A and type B monoamine oxidase (MAO-A and MAO-B) were partially inactivated in brain, heart and liver. The abilities of two short-acting, reversible inhibitors of MAO to antagonize that inactivation were compared. Pretreatment with MD 240928 at doses of 10, 20 or 30 mg/kg i.p. antagonized the inactivation of type B MAO but did not alter the inactivation of type A MAO in all three tissues. In contrast, pretreatment with harmaline at a dose of 10 mg/kg i.p. antagonized the inactivation of type A MAO but did not alter the inactivation of type B MAO. Antagonism of the pargyline-induced inactivation is interpreted as being due to the transient selective inhibition of MAO-A by harmaline and of MAO-B by MD 240928, preventing the mechanism-based inactivation of those enzymes by pargyline. The selective protection by harmaline is in agreement with earlier results with that compound in rats; the selective protection by MD 240928 is the first report of selective protection against MAO-B inactivation.

Alkaloids↗
PubMed1986

Fluoxetine enantiomers as antagonists of p-chloroamphetamine effects in rats.

The dextrorotatory enantiomer of fluoxetine was slightly more potent than the levorotatory enantiomer in antagonizing the depletion of brain serotonin by p-chloroamphetamine in rats. The time course of the depletion of brain serotonin at times out to 24 hr after the injection of p-chloroamphetamine was determined with or without simultaneous administration of one of the fluoxetine enantiomers. The dextrorotatory enantiomer prevented the depletion of brain serotonin at any time after p-chloroamphetamine. The levorotatory enantiomer prevented the initial depletion of brain serotonin at 2 and 4 hr, but by 8 hr brain serotonin concentration was decreased and by 24 hr the depletion of serotonin was almost as great as in rats treated with p-chloroamphetamine alone. The elevation of serum corticosterone that occurred acutely after injection of a low dose of p-chloroamphetamine was significantly antagonized by both enantiomers of fluoxetine, the dextrorotatory enantiomer being slightly more potent. In contrast, the lowering of DOPAC (3,4-dihydroxyphenylacetic acid) concentration in rat brain by p-chloroamphetamine was not antagonized by either enantiomer of fluoxetine, indicating this effect is not secondary to serotonin release by p-chloroamphetamine. The results are consistent with other evidence that both enantiomers of fluoxetine are potent inhibitors of serotonin uptake, the dextrorotatory enantiomer being longer-acting than the levorotatory enantiomer in rats.

Amphetamines↗
PubMed1986

Noradrenergic innervation of the cerebellar cortex in normal and in Purkinje cell degeneration mutant mice: evidence for long term survival following loss of the two major cerebellar cortical neuronal populations.

Purkinje cell degeneration mutant mice were examined during the course of Purkinje cell death (26 and 35 days old) and at 3, 5, 9 and 12 months of age. Glyoxylic acid fluorescence histochemistry for catecholamines was used to investigate possible alterations or reorganization of the noradrenergic fibers from the coeruleo-cerebellar system in response to the degeneration of two major cell types in the cerebellar cortex, of which one, the Purkinje cell, is reported to be the major target neuron. In control mice, noradrenergic fibers traveled in linear and tortuous profiles through the granule cell layer, formed pericellular arrays alongside Purkinje cell somata, and branched profusely into both radially oriented and longitudinally oriented chains. The density of noradrenergic varicosities diminished in the molecular layer, there was with age. In the mutants, concomitant with the progressive shrinkage of the molecular layer, there was a progressive increase in the density of noradrenergic varicosities. This was most conspicuous at 9 and 12 months of age, at which time the molecular layer has been depleted not only of Purkinje cell dendrites, but also of parallel fibers. Noradrenergic fibers in these zones formed dense parallel bundles of varicose profiles whose density reached 621.3 +/- 122.8% (mean +/- SD, n = 4) at 9-12 months of age, compared with age-matched controls. Neurochemical measurement of norepinephrine content in whole cerebellum of the Purkinje cell degeneration mutants revealed no change compared with age-matched controls. We conclude that noradrenergic innervation persists in the cerebellar cortex despite the death of Purkinje cells and most of the granule cells. Although we found an increased density of varicosities in the molecular layer of mutant mice, progressing with age, we believe that this can be explained on the basis of the resultant geometry of the altered cerebellar cortex. It appears that the health of the environment surrounding the noradrenergic fibers in cerebellar cortex has little influence on their anatomical integrity.

Adrenergic Fibers↗
PubMed1986

Characterization of the neurotoxic potential of m-methoxy-MPTP and the use of its N-ethyl analogue as a means of avoiding exposure to a possible Parkinsonism-causing agent.

1-Methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (2) produced persistent depletion of striatal dopamine in mice after four daily injections, although it was less potent than 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP has been implicated as a cause of Parkinsonism in drug abusers who inadvertently self-administered it and in industrial chemists who were exposed to it. Our results suggest that the m-methoxy compound has the same neurotoxic potential to cause destruction of nigrostriatal dopamine neurons that would lead to Parkinsonian symptoms in humans. In contrast, 1-ethyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (11) had no effects on striatal dopamine in mice, even at doses 8 times those of MPTP. A method of preparing 11 and using it as an intermediate in the synthesis of potential analgesic drugs, thus avoiding a potentially neurotoxic intermediate, is described.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogues stable to phosphodiesterase hydrolysis.

Thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-nucleoside tiazofurin (TR), is susceptible to phosphodiesteratic breakdown by a unique phosphodiesterase present at high levels in TR-resistant tumors. Since accumulation of TAD, as regulated by its synthetic and degradative enzymes, appears to be an important determinant for sensitivity to the drug, a series of hydrolytically resistant phosphonate analogues of TAD were synthesized with the intent of producing more stable compounds with an ability to inhibit IMP dehydrogenase equivalent to TAD itself. Isosteric phosphonic acid analogues of TR and adenosine nucleotides were coupled with activated forms of AMP and TR monophosphate to give dinucleotides 2 and 4. Coupling of protected adenosine 5'-(alpha, beta-methylene)diphosphate with isopropylidene-TR in the presence of DCC afforded compound 3 after deprotection. These compounds are more resistant than TAD toward hydrolysis and still retain potent activity against IMP dehydrogenase in vitro. beta-Methylene-TAD (3), the most stable of the TAD phosphonate analogues, produced a depletion of guanine nucleotide pools in an experimentally induced TR-resistant P388 tumor variant that was superior to that obtained with TR in the corresponding sensitive line.

Adenine Nucleotides↗
PubMed1986

Stimulation of IgE sensitized human alveolar macrophages by anti-IgE is unaffected by sodium cromoglycate.

Sodium cromoglycate is an effective prophylactic in the treatment of asthma. However, its mechanism of action is still uncertain. The release of thromboxane B2 and N-acetyl-beta-D-glucosaminidase activity was measured from human alveolar macrophages sensitized with human myeloma IgE. Cells were challenged with rabbit affinity purified anti-IgE (no activity against IgG) in the absence or presence of sodium cromoglycate (10(-4)-10(-8)M). There was no change in the release of either thromboxane B2 or N-acetyl-beta-D-glucosaminidase in the presence of sodium cromoglycate at these concentrations.

Acetylglucosaminidase↗
PubMed1986

Histamine is released from skin by substance P but does not act as the final vasodilator in the axon reflex.

We have explored in man the hypothesis that histamine released from dermal mast cells by neurotransmitters from afferent nerves contributes to vasodilatation of the axon reflex. The ability of substance P to release histamine from human skin in vivo, and the effects of a histamine H1-receptor antagonist on capsaicin-induced axon reflex flares were studied. Intradermal injections of substance P (50 pmol) produced a weal and flare response which was associated with increased histamine concentration in blood draining the site (mean plasma histamine concentration before injection 0.17 +/- 0.02 ng ml-1 (+/- s.e.mean), concentration one minute after injection 1.26 +/- 0.28 ng ml-1, n = 6). Terfenadine, an H1-receptor antagonist, had no effect on the flare response to intradermal injection of capsaicin at a dose which inhibited by more than 60% the flare response to exogenous histamine and to histamine released from dermal mast cells by substance P. Substance P releases histamine from human skin in vivo. However, whatever the nature of the neurotransmitter released from afferent nerves during the axon reflex, it does not produce vasodilatation through release of histamine from dermal mast cells. Histamine may still contribute to the flare by initiation of the reflex.

Axons↗
PubMed1986

Effect of fluoxetine pretreatment on the neurochemical changes induced by amfonelic acid combined with spiperone in rats.

Combined treatment with amfonelic acid plus spiperone caused large increases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and a decrease in dopamine in rat striatum. 5-Hydroxytryptamine (5-HT) was decreased in striatum (but not in hypothalamus), and 5-hydroxyindoleacetic acid (5-HIAA) was increased in the striatum. Pretreatment with fluoxetine, an inhibitor of uptake into 5-HT neurons, antagonized the decrease in 5-HT and the increase in 5-HIAA and in the ratio 5-HIAA/5-HT but did not antagonize the changes in dopamine or its metabolites. The amfonelic acid-spiperone combination apparently causes increased release of dopamine in striatum, and the released dopamine is accumulated by 5-HT nerve terminals via the membrane uptake carrier. Inhibition of that carrier by fluoxetine prevents the release of 5-HT caused by the dopamine influx.

Animals↗
PubMed1986

Effects of adenosine on ventilatory responses to hypoxia and hypercapnia in humans.

Adenosine infusion (100 micrograms X kg-1 X min-1) in humans stimulates ventilation but also causes abdominal and chest discomfort. To exclude the effects of symptoms and to differentiate between a central and peripheral site of action, we measured the effect of adenosine infused at a level (70-80 micrograms X kg-1 X min-1) below the threshold for symptoms. Resting ventilation (VE) and progressive ventilatory responses to isocapnic hypoxia and hyperoxic hypercapnia were measured in six normal men. Compared with a control saline infusion given single blind on the same day, adenosine stimulated VE [mean increase: 1.3 +/- 0.8 (SD) l/min; P less than 0.02], lowered resting end-tidal PCO2 (PETCO2) (mean fall: -3.9 +/- 0.9 Torr), and increased heart rate (mean increase: 16.1 +/- 8.1 beats/min) without changing systemic blood pressure. Adenosine increased the hypoxic ventilatory response (control: -0.68 +/- 0.4 l X min-1 X %SaO2-1, where %SaO2 is percent of arterial O2 saturation; adenosine: -2.40 +/- 1.2 l X min-1 X %SaO2-1; P less than 0.01) measured at a mean PETCO2 of 38.3 +/- 0.6 Torr but did not alter the hypercapnic response. This differential effect suggests that adenosine may stimulate ventilation by a peripheral rather than a central action and therefore may be involved in the mechanism of peripheral chemoreception.

Adenosine↗
PubMed1986

Prostaglandin D2 potentiates airway responsiveness to histamine and methacholine.

In the bronchi of asthmatic subjects many bronchoconstrictor mediators and neurotransmitters might be released together, and therefore, potential interactions might occur that could be important in airway hyperreactivity. We have studied the effect of inhaled methacholine, bradykinin, and prostaglandin D2 (PGD2) on bronchial reactivity to inhaled histamine in 6 mild asthmatic subjects, 22 to 36 yr of age. All of the test spasmogens were given at equivalent bronchoconstricting concentrations. Simultaneous dosing with PGD2 caused a significant increase in reactivity to histamine, mean dose of histamine causing a 35% fall in specific airway conductance being 0.72 mumol before, and 0.32 mumol with, PGD2; (p less than 0.01). This was not seen with histamine itself, methacholine, or bradykinin. Prostaglandin D2 caused a similar increase in bronchial reactivity to inhaled methacholine, suggesting a postreceptor potentiation of airway smooth muscle contractility. This positive interaction between inflammatory mediators known to be released in asthma has important implications for understanding bronchial hyperreactivity.

Adult↗
PubMed1986

1-(1-Naphthyl)piperazine, a central serotonin agonist.

1-(1-Naphthyl)piperazine (1-NP) had high affinity for tritiated serotonin, tritiated LSD (lysergic acid diethylamide) and tritiated spiperone binding sites in rat brain cortex in vitro. 1-NP at doses of 3-30 mg/kg i.p. decreased 5-hydroxyindoleacetic acid (5-HIAA) concentration in whole brain of rats in vivo. The 30 mg/kg dose caused a significant increase in serum corticosterone concentration. At doses of 3-30 mg/kg i.p., 1-NP reduced the accumulation of 5-hydroxytryptophan following decarboxylase inhibition by NSD 1015 in rat hypothalamus and striatum. Reduced serotonin turnover and elevated serum corticosterone concentrations are interpreted as evidence of central serotonin receptor activation by compounds of this structural class. 1-NP has previously been reported to antagonize vascular serotonin receptors, suggesting that it, like 1-(m-trifluoromethylphenyl)piperazine, behaves as an antagonist at peripheral (vascular) serotonin receptors despite being an agonist at central serotonin receptors.

Animals↗
PubMed1986

Central serotonin agonist actions of LY 165163, 1-(m-trifluoromethylphenyl)-4-(p-aminophenylethyl) piperazine, in rats.

1-(m-Trifluoromethylphenyl)-4-(p-aminophenylethyl)piperazine (LY 156163), reported previously to have selective affinity for the 5-HT1A subtype of serotonin receptor in vitro, was studied at doses of 1.25 to 20 mg/kg i.p. in rats to determine if it had properties characteristic of centrally acting serotonin agonists. LY 165163 decreased whole brain concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid, but not of serotonin itself, decreased the rate of accumulation of 5-hydroxyindoleacetic acid after probenecid administration to block its efflux from brain, decreased the rate of decline in serotonin concentration after inhibition of serotonin synthesis with alpha-propyldopacetamide and decreased the accumulation of 5-hydroxytryptophan after decarboxylase inhibition by m-hydroxybenzylhydrazine. LY 165163 also decreased 5-hydroxyindoleacetic acid concentrations in two specific brain regions, striatum and hypothalamus. Serum concentrations of corticosterone and prolactin were increased by doses of LY 165163 that reduced serotonin turnover. These effects are all consistent with evidence from other studies that LY 165163 is a centrally acting serotonin agonist. LY 165163 also increased the concentrations of two dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, measured in whole brain as well as in striatum and hypothalamus, but did not alter dopamine concentration. The accumulation of dopa after decarboxylase inhibition was accelerated by LY 165163. The increases in hormone concentrations in serum and of dopamine metabolite concentrations in brain were not antagonized by pretreatment with metergoline, a serotonin antagonist. The mechanisms of those effects require further study.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Flumezapine, an antagonist of central dopamine and serotonin receptors.

Flumezapine, 7-fluoro-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3- b] [1,5]benzodiazepine, antagonized the increases in serum corticosterone concentration caused by a serotonin agonist, quipazine, and by a dopamine agonist, pergolide, in rats. Flumezapine did not alter the elevation of serum corticosterone by a kappa opioid agonist, bremazocine. Flumezapine resembled but was more potent than clozapine and zotepine in blocking these effects of quipazine and pergolide, differing from spiperone and fluphenazine which were selective antagonists of pergolide and from metergoline and mianserin which were selective antagonists of quipazine. All of the antagonists had high affinity for 5HT2 receptors as measured by radioligand-binding in vitro. Spiperone, fluphenazine, zotepine and flumezapine had high affinity for dopamine D2 receptors as measured by radioligand-binding in vitro. The potency of the compounds in antagonizing the pergolide-induced elevation of serum corticosterone concentration matched their affinity for D2 receptors in vitro. There was poor correlation between the potency of the compounds in antagonizing the quipazine-induced elevation of serum corticosterone concentration and their affinity for 5HT2 receptors in vitro, possibly indicating that the receptor mediating the effect of quipazine is not identical to or exclusively the 5HT2 receptor. The results suggest that flumezapine is a potent blocker of dopamine D2 and of some serotonin receptors.

Animals↗
PubMed1986

Biochemical pharmacology of the serotonin system.

Although relatively few drugs that specifically influence serotonin neurons have been used in humans, a wide variety of drugs has been used to modify serotonergic function in experimental animals. Several classes of agents increase serotonergic function. These include serotonin precursors (L-5-hydroxytryptophan and L-tryptophan) and monoamine oxidase inhibitors, which elevate serotonin stores; uptake inhibitors and releasers, which increase the concentration of serotonin in the synaptic cleft; and direct serotonin agonists, which mimic the action of serotonin on synaptic receptors. In addition, several kinds of drugs decrease serotonergic function, including serotonin depletors and agents that destroy serotonin neurons, as well as direct serotonin-receptor antagonists. The array of drugs now available improves the opportunities for clarifying the physiological roles of serotonin and gives promise of several therapeutic applications, including treatment of myoclonus.

Alanine↗