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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 199 records · Page 11Linked to original sources
PubMed1989

Effects of buspirone and its metabolite, 1-(2-pyrimidinyl)piperazine, on brain monoamines and their metabolites in rats.

Buspirone, an anxiolytic drug with selective affinity for the 5-HT-1A subtype of serotonin receptors, caused a dose-related decrease in 5-hydroxyindole acetic acid (5-HIAA) concentration in rat hypothalamus after doses of 1 to 10 mg/kg s.c. The decrease in 5-HIAA concentration after a 3 mg/kg s.c. dose of buspirone persisted at 4 hr but not at 7 hr. The decrease was due apparently to a reduced turnover of serotonin; the accumulation of 5-hydroxytryptophan after decarboxylase inhibition was also suppressed by buspirone, not only in hypothalamus but also in brain stem, hippocampus and striatum. 1-(2-Pyrimidinyl)-piperazine (1-PP), a major metabolite of buspirone, did not affect hypothalamic 5-HIAA concentration at doses up to 10 mg/kg s.c. Both buspirone and 1-PP increased hypothalamic concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) sulfate, the norepinephrine metabolite, the effect being more pronounced with 1-PP but occurring after doses as low as 0.3 mg/kg s.c. with each compound. The increase in MHPG sulfate concentration persisted for at least 4 hr after a 3 mg/kg s.c. dose of each compound. The increase in MHPG sulfate produced by buspirone may have been due partly to 5-HT-1A receptor activation, inasmuch as other serotonin agonists have been found to cause a similar increase. 1-PP is reported to lack affinity for 5-HT-1A receptors so its elevation of MHPG sulfate concentration may have resulted from alpha-2 receptor blockade. The increase in MHPG sulfate concentration after buspirone injection may have been due at least partly to formation of the metabolite, 1-PP.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Preclinical studies on quinelorane, a potent and highly selective D2-dopaminergic agonist.

Quinelorane (LY163502) has the endocrine, neurochemical and behavioral profile of a potent and highly selective D2-dopaminergic agonist. The administration of quinelorane produced dose-related decreases in serum prolactin concentration of reserpinized, male rats and increases in serum corticosterone concentration of male rats. The minimum effective doses (MED) for these effects were 10 and 30 micrograms/kg i.p., respectively. Quinelorane induced increases in 3-methoxy-4-hydroxyphenylglycol-sulfate levels in the brain stem (MED, 30 micrograms/kg i.p.) and decreases in hypothalamic epinephrine levels (MED, 100 micrograms/kg i.p.) in male rats as determined by high-pressure liquid chromatography with electrochemical detection methods. Quinelorane induced increases in extracellular ascorbic acid as determined by in vivo voltammetry in the nucleus accumbens and striatum of male rats. Quinelorane produced concentration-dependent suppression of K+-evoked release of acetylcholine from superfused caudate slices, with an IC50 of approximately 10(-8)M. Quinelorane administration produced dose-related increases in compulsive, contralateral turning in male rats with unilateral nigrostriatal lesions and increases in locomotor activity and stereotypic behavior in male rats. In dogs, quinelorane administration produced dose-related increases in emetic response with an ED50 of 7 micrograms/kg i.v. Quinelorane administration also produced dose-related decreases in the striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic (MED, 1 microgram/kg i.p. for both metabolites) as determined by high-pressure liquid chromatography with electrochemical detection methods and decreases in extracellular concentrations of homovanillic acid in the nucleus accumbens and striatum as determined by in vivo voltammetry., Quinelorane produced concentration-dependent decreases in K+-evoked dopamine release from superfused striatal slices (IC50 = 3 X 10(-9) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

5-Hydroxytryptamine2 receptor antagonist activity of the acid metabolite (1-isopropyl dihydrolysergic acid) of the ergoline ester, sergolexole (LY281067).

The ergoline esters, LY53857 [6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid 2-hydroxy-1-methylpropylester (Z)-2-butenedioate] and sergolexole (LY281067) ([trans-(8 beta)]6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid, 4-methoxycyclohexyl ester (maleate salt] are potent 5-hydroxytryptamine2 (5-HT2) receptor antagonists in vivo and in vitro. Ester hydrolysis of either compound results in the formation of 1-isopropyl dihydrolysergic acid which in rats is a major metabolite of these ergoline esters. The present study details the pharmacological activity of 1-isopropyl dihydrolysergic acid and examines its relative contribution to the 5-HT2 receptor antagonism seen after sergolexole in rats. In vitro, 1-isopropyl dihydrolysergic acid was a competitive antagonist of 5-HT2 receptors in the rat jugular vein, with a dissociation constant approximating 10(-7) M. After i.v. administration to pithed rats, 1-isopropyl dihydrolysergic acid also antagonized the pressor response produced by serotonin, an in vivo estimate of vascular 5-HT2 receptor blockade. In fact, after i.v. administration, 1-isopropyl dihydrolysergic acid was nearly one-third as potent as sergolexole. After i.p. administration, 1-isopropyl dihydrolysergic acid was approximately one-tenth to one-thirtieth as potent as sergolexole. Likewise, 1-isopropyl dihydrolysergic acid antagonized central 5-HT receptors as measured by blockade of quipazine-induced increases in serum corticosterone concentration in rats and was approximately one-twentieth as potent as sergolexole.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Effect of fluoxetine pretreatment on plasma and tissue concentrations of desipramine in rats.

Because of clinical reports that fluoxetine co-administration has led to increased blood concentrations of desipramine and adverse clinical effects in depressed patients treated with desipramine, we investigated the effect of fluoxetine on desipramine metabolism by rat liver microsomes in vitro and on blood and brain concentrations of desipramine in rats treated with desipramine. Fluoxetine caused a concentration-dependent inhibition of the 2-hydroxylation and N-demethylation of desipramine in vitro. Fluoxetine increased blood and brain concentrations of desipramine and prolonged the half-life of desipramine in blood and brain in rats in vivo. The inhibition of desipramine metabolism by fluoxetine probably led to the increased blood levels of desipramine in the clinical cases and may have contributed to the acceleration of cortical beta adrenoreceptor downregulation reported in rats when desipramine and fluoxetine were co-administered.

Animals↗
PubMed1989

Cough associated with angiotensin-converting enzyme inhibitors.

Cough is reported by between 0.7% and 14% of patients taking angiotensin-converting enzyme (ACE) inhibitors. There are more reports from women and non-smokers. The development of cough during ACE inhibitor therapy is associated with a reversible increase in the response of the cough reflex. The response remains normal in those who do not develop cough while on ACE inhibitor therapy. Both hypersensitivity of the cough reflex and the symptom of cough are reversed by sulindac which suggests that the abnormal reflex is dependent on cyclo-oxygenase products.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

ACE inhibitors and strategies for managing hypertension.

Angiotensin converting enzyme inhibitors are effective hypotensive agents, lowering blood pressure in patients with mild to moderate hypertension either alone or in combination with a low dose loop diuretic. They are generally well tolerated and score well in quality of life studies. However, in some patients they do cause cough, which may lead to their withdrawal, and their association with renal failure and death in elderly patients may reduce their usefulness in this age group. Nevertheless they have established a role as first line therapy in patients with asthma and diabetes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Further characterization of tolerance to the corticosterone-elevating effect of pergolide in rats.

Four daily injections of pergolide, an ergoline dopamine agonist, made male rats tolerant to the corticosterone-elevating effects of an acute injection of pergolide on the fifth day. This tolerance occurred not only to acute treatment with pergolide, but also to other dopamine agonists differing in structure, potency and receptor subtype selectivity. Plasma corticosterone was elevated following administration of opioid or serotonin agonists in both vehicle- and pergolide-pretreated rats. The current findings strengthen the conclusion that tolerance to the acute elevation of corticosterone by pergolide is not due to impairment of pituitary-adrenocortical function but instead to changes in dopamine receptors that initiate the response.

Animals↗
PubMed1988

Comparison of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) effects on mouse heart norepinephrine.

MPP+ (1-methyl-4-phenylpyridinium) mimicked MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in producing marked, dose-related depletion of cardiac norepinephrine after a single oral or subcutaneous dose in mice. MPP+ was approximately 4-fold more potent than MPTP in depleting norepinephrine, but the onset of depletion was not faster for MPP+ than for MPTP. The time courses of the effects of both compounds were similar to that for 6-hydroxydopamine, with maximum depletion occurring at 1 day, partial recovery at 2 and 4 days, and full recovery of norepinephrine concentrations at 1 week. Desipramine, over a dose range that completely prevented the depletion of cardiac norepinephrine by 6-hydroxydopamine at 24 hr, did not prevent cardiac norepinephrine depletion by either MPP+ or MPTP. In a short duration experiment, one or two doses of desipramine also failed to prevent heart norepinephrine depletion by MPP+ or by MPTP, although a slight antagonism was found. EXP 561 (4-phenylbicyclo[2,2,2]octan-1-amine hydrochloride monohydrate), another uptake inhibitor with possibly longer duration of action, also did not protect against norepinephrine depletion by a single dose of MPP+ or MPTP at a dose that prevented norepinephrine depletion by 6-hydroxydopamine. In mice given four daily doses of MPTP, EXP 561 prevented the depletion of norepinephrine in the frontal cortex and of dopamine in the striatum but not the depletion of norepinephrine in heart or spleen. Thus, both MPTP and MPP+ deplete norepinephrine in mouse heart, and this effect of the two compounds is resistant to antagonism by uptake inhibitors that antagonize the effects of MPTP on brain catecholamines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Serotonin concentration and turnover in cerebellum and other brain regions of pcd mutant mice.

The Purkinje cell degeneration (pcd) mutant mouse is characterized by a loss of Purkinje cells in the cerebellum. Loss of granule cells occurs and is severe in pcd mutants after 9 months of age. Since Purkinje cells and granule cells represent two groups of target cells for serotonin neurons projecting from raphe nuclei and other brain areas, the content and turnover of serotonin in the cerebellum were determined in pcd mice aged 3-15 months. The content of serotonin was not decreased in pcd mouse cerebellum but tended to be slightly increased after 7 months. The ratio of 5-hydroxyindoleacetic acid (5-HIAA) to serotonin was significantly decreased in cerebellum at 7-15 months but not at 3 or 6 months. The decrease in this ratio is indicative of decreased serotonin turnover. Similar changes were not seen in brainstem or hypothalamus in mice up to 14 months old, but slight decreases were observed at 15 months. Another index of turnover, the accumulation of 5-HIAA after administration of probenecid to block its efflux from brain, was decreased by 46% in 7-month-old pcd mice in the cerebellum but not in the brainstem or hypothalamus. The decrease in serotonin turnover in pcd mouse cerebellum occurs subsequent to and perhaps due to the loss of the target Purkinje and granule cells.

Aging↗
PubMed1988

Different effects of monoamine oxidase inhibition on MPTP depletion of heart and brain catecholamines in mice.

Pargyline, an inhibitor of monoamine oxidase type B (MAO-B), did not prevent the depletion of heart norepinephrine 24 hr after a single dose of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in mice. In mice killed 24 hr after the last of 4 daily doses of MPTP, the depletion of dopamine in the striatum and of norepinephrine in the frontal cortex was completely prevented by pargyline, but the depletion of heart norepinephrine was not prevented. These results with pargyline are the same as results obtained earlier with deprenyl, another selective inhibitor of MAO-B. The doses of pargyline and of deprenyl that were used resulted in almost complete inhibition of MAO-B activity (phenylethylamine as substrate) in brain, heart and liver of mice. Deprenyl did not inhibit MAO-A activity (serotonin as substrate) in brain, but pargyline caused some inhibition of MAO-A in brain. In heart and liver, serotonin was oxidized only at about 1/10 the rate of phenylethylamine oxidation, suggesting that MAO-B predominates in these tissues. Both pargyline and deprenyl caused some inhibition of serotonin deamination in heart and liver, suggesting that the oxidation may have been due partly to MAO-B. Experiments with selective MAO inhibitors in vitro showed that only about 20% of the oxidation of serotonin was occurring via MAO-B in heart and liver. The in vitro oxidation of MPTP by MAO in mouse brain, heart and liver was almost completely inhibited by pretreatment with either pargyline or deprenyl. Neither pargyline nor deprenyl had any significant effect on the concentrations of MPTP in brain or heart one-half hr after injection of MPTP into mice. The concentrations of the metabolite, MPP+ (1-methyl-4-phenyl-pyridinium), were markedly reduced in brain and in heart by pretreatment with either pargyline or deprenyl. The data suggest that MPP+ formation, which is necessary for the depletion of brain catecholamines after MPTP injection, may not be necessary for depletion of norepinephrine in heart. Since the oxidation of MPTP in vitro was inhibited more by pargyline or deprenyl pretreatment than was the appearance of MPP+ in vivo, the possibility exists that some MPP+ formation might occur by an enzyme other than MAO.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release.

d-Fenfluramine is an anorectic drug believed to act by enhancement on serotonergic function in the brain. d-Fenfluramine (or the racemate) releases serotonin through a carrier-dependent mechanism, and serotonin release is the mechanism usually thought to produce its serotonergic effects. However, d-fenfluramine also inhibits serotonin uptake in vitro, and serotonin uptake inhibition is sometimes suggested to contribute to its mechanism of anorectic activity. Neurochemical experiments were done to examine serotonin release and serotonin uptake inhibition as mechanisms of action of d-fenfluramine in rats and to compare d-fenfluramine to fluoxetine, a serotonin uptake inhibitor. d-Fenfluramine decreased serotonin concentration in rat brain as early as 1 hr; at 1 hr 5-hydroxyindoleacetic acid (5HIAA) concentration was slightly increased, but at later times 5HIAA was also decreased. Fluoxetine, in contrast, did not change serotonin concentration in whole brain but decreased 5HIAA concentration at all time points. At all time intervals studied, the 5HIAA/serotonin ratio was increased by d-fenfluramine (and by Ro 4-1284, a nonspecific serotonin releaser) but was decreased by fluoxetine, a serotonin uptake inhibitor. No decrease in 5HIAA concentration or in the 5HIAA/serotonin ratio was apparent at any time or after any dose of d-fenfluramine studied. The possibility that doses of d-fenfluramine below those needed for serotonin release might inhibit serotonin uptake was tested by determining whether d-fenfluramine could block the acute depletion of brain serotonin by p-chloroamphetamine, or the long-term neurotoxic effect of p-chloroamphetamine on brain serotonin neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1988

Human alveolar macrophage activation: inhibition by forskolin but not beta-adrenoceptor stimulation or phosphodiesterase inhibition.

Alveolar macrophages are the most numerous cells within human airways. They release inflammatory mediators following immunological challenge and have been implicated in the pathogenesis of asthma. beta-agonists and phosphodiesterase inhibitors are frequently used in the treatment of asthma and are potent inhibitors of human mast cells. We have examined the role of the beta-agonist, isoprenaline, the phosphodiesterase inhibitor Ro-20 1724, and the adenylate cyclase stimulator forskolin on the activation of human alveolar macrophages. This was assessed by monitoring the release of thromboxane B2 (TXB2), leukotriene B4, N-acetyl-beta-D-glucosaminidase (NAG), and superoxide (SO) following stimulation of the cells by opsonised zymosan or IgE/anti IgE complexes. Neither isoprenaline (1nM-10 microM) nor Ro-20 1724 (0.5-50 microM) alone or in combination had any inhibitory effect on release of these mediators. However, forskolin (0.1-100 microM) significantly inhibited release of both TXB2 and SO but not NAG. This result shows that human alveolar macrophages do not possess functional beta-receptors, although stimulation of adenylate cyclase with forskolin, inhibits some of the elements of macrophage activation.

Adrenergic beta-Agonists↗
PubMed1988

6-substituted 1,3,4,5-tetrahydrobenz[cd]indol-4-amines: potent serotonin agonists.

A series of 6-substituted tricyclic ergoline partial structures has been synthesized and found to possess very strong serotonin agonist activity. A methoxy group at the 6-position greatly enhances activity, but at the expense of compound stability. Substituting the 6-position with protophyllic groups that are also electron-withdrawing in character enhances both activity and stability.

Animals↗
PubMed1988

Absolute configurations and pharmacological activities of the optical isomers of fluoxetine, a selective serotonin-uptake inhibitor.

Fluoxetine is a potent and selective inhibitor of the neuronal serotonin-uptake carrier and is a clinically effective antidepressant. Although fluoxetine is used therapeutically as the racemate, there appears to be a small but demonstrable stereospecificity associated with its interactions with the serotonin-uptake carrier. The goals of this study were to determine the absolute configurations of the enantiomers of fluoxetine and to examine whether the actions of fluoxetine in behavioral tests were enantiospecific. (S)-Fluoxetine was synthesized from (S)-(-)-3-chloro-1-phenylpropanol by sequential reaction with sodium iodide, methylamine, sodium hydride, and 4-fluorobenzotrifluoride. (S)-Fluoxetine is dextrorotatory (+1.60) in methanol, but is levorotatory (-10.85) in water. Fluoxetine enantiomers were derivatized with (R)-1-(1-naphthyl)ethyl isocyanate, and the resulting ureas were assayed by 1H NMR or HPLC to determine optical purities of the fluoxetine samples. Both enantiomers antagonized writhing in mice; following sc administration of (R)- and (S)-fluoxetine, ED50 values were 15.3 and 25.7 mg/kg, respectively. Moreover, both enantiomers potentiated a subthreshold analgesic dose (0.25 mg/kg) of morphine, and ED50 values were 3.6 and 5.7 mg/kg, respectively. Following ip administration to mice, the two stereoisomers antagonized p-chloroamphetamine-induced depletion of whole brain serotonin concentrations. ED50 values for (S)- and (R)-fluoxetine were 1.2 and 2.1 mg/kg, respectively. The two enantiomers decreased palatability-induced ingestion following ip administration to rats; (R)- and (S)-fluoxetine reduced saccharin-induced drinking with ED50 values of 6.1 and 4.9 mg/kg, respectively. Thus, in all biochemical and pharmacological studies to date, the eudismic ratio for the fluoxetine enantiomers is near unity.

Analgesia↗
PubMed1988

Ergolines as selective 5-HT1 agonists.

The synthesis and serotonin receptor subtype affinity of a series of ergolines are described. High selectivity for the 5-HT1 subtype was found with a number of 8-substituted (3 beta, 5 beta)-9,10-didehydro-6-methylergolines. The more potent and selective of these compounds increased the concentration of serotonin and decreased the concentration of 5-HIAA in rat brain and increased corticosterone concentration in rat serum. Oral administration of 13, (3 beta)-2,3-dihydrolysergine, produced long-lasting decreases in serotonin turnover. Compound 13 lacked substantial dopaminergic activity as measured by its effects on dopamine turnover in whole brain or striatum and its affinity for alpha-adrenergic binding sites was significantly less than for 5-HT1 binding sites. The increases in serum corticosterone concentrations produced by 13 were not blocked by the serotonin uptake inhibitor fluoxetine or by the serotonin synthesis inhibitor p-chlorophenylalanine, suggesting that 13 exerts its effects through direct stimulation of serotonin receptors.

Animals↗
PubMed1988

LTD4-induced bronchoconstriction in patients with asthma: lack of a vagal reflex.

The mechanism by which leukotriene D4 (LTD4) induces bronchoconstriction in man is unclear. We have investigated this mechanism by examining the effect of nedocromil sodium and ipratropium bromide on LTD4-induced bronchoconstriction in six mild asthmatic patients. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.08 to 100 nmol) was assessed by measuring changes in respiratory resistance (Rrs) at 6 Hz by the forced oscillation method. Results were expressed as the provocative dose causing 100% increase in Rrs (PD100). Neither nedocromil (4 mg) nor ipratropium (0.8 mg) showed significant effect on LTD4-induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatics LTD4-induced bronchoconstriction is unlikely to involve vagal reflexes.

Adult↗
PubMed1988

Bradykinin induced wheal and flare is not mediated by histamine release or cyclooxygenase products.

The wheal and flare response to intradermal bradykinin was studied in man. The possibility that histamine and cyclooxygenase products are involved in the response to bradykinin was examined. Terfenadine given by mouth significantly inhibited the cutaneous response to histamine but the effect of bradykinin was unaltered. Similarly the cutaneous response to bradykinin was unchanged by aspirin.

Adult↗