PubMed Health⌕ Search

Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 289 records · Page 16Linked to original sources
PubMed1985

Inhibition of types A and B monoamine oxidase by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied as an inhibitor of type A monoamine oxidase (MAO) acting on [14C]serotonin as substrate and of type B MAO acting on [14C]phenylethylamine as substrate. MPTP was a reasonably potent (Ki = 9 microM), competitive, reversible inhibitor of MAO-A from rat brain in vitro. MPTP given at a 30-mg/kg i.p. dose antagonized the irreversible inactivation of MAO-A in rat brain by pargyline, indicating that it inhibited MAO-A in vivo. At that same dose, MPTP prevented the conversion of dopamine released by Ro 4-1284 to 3,4-dihydroxyphenylacetic acid and attenuated its conversion to homovanillic acid. Because dopamine is mainly deaminated by MAO-A, at least in rodent brain, inhibition of MAO-A by MPTP might play some part in its production of persistent effects on striatal dopamine neurons such as protection of intraneuronal, extragranular dopamine from deamination. MPTP was less potent as an inhibitor of MAO-B from rat brain in vitro (Ki = 106 microM). In contrast to the inhibition of MAO-A, the inhibition of MAO-B by MPTP showed noncompetitive kinetics, was not fully reversible by dialysis and was time dependent. The characteristics of MAO-B inhibition are like those of a kcat inhibitor, which is acted upon by an enzyme to produce a reactive product that can covalently attach to the enzyme or other macromolecules.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Effects of amfonelic acid, alpha-methyltyrosine, Ro 4-1284 and haloperidol pretreatment on the depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in 4 daily s.c. injections to mice resulted in marked depletion of striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) 1 week after the last dose. Pretreatment of mice with alpha-methyltyrosine or Ro 4-1284 to deplete dopamine prior to MPTP injection did not prevent these effects of MPTP, nor did pretreatment with haloperidol, a dopamine receptor antagonist. The depletion of striatal dopamine by MPTP in mice therefore differs from the persistent depletion of striatal dopamine by amphetamine in iprindole-treated rats, which is prevented by pretreatment with either alpha-methyltyrosine or haloperidol. The depletion of dopamine, DOPAC and HVA in mouse striatum by MPTP was totally prevented by pretreatment with amfonelic acid, an inhibitor of dopamine uptake. This finding suggests that these effects of MPTP, like those of amphetamine in iprindole-treated rats, are dependent upon a functional transport system into the dopamine neuron.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Pharmacological activity of the isomers of LY53857, potent and selective 5-HT2 receptor antagonists.

LY53857 is an ergoline derivative that is a potent and selective antagonist at 5-HT2 receptors. The present study investigated the activities of the diastereomers of LY53857. The SS- and RR-isomers and the meso mixture of isomers of LY53857 all showed affinity for 5-HT2 receptors approximately 100-fold higher than for 5-HT1 receptors based on radiolabeled ligand binding studies in rat cortical membranes. Based on these binding data, the meso mixture of isomers was one-half as potent as the other two isomers. Consistent with the binding data, the SS- and RR-isomers and the meso mixture of isomers all showed high affinity as antagonists of 5-HT2 receptors in the rat jugular vein, with the meso mixture of isomers being slightly less potent than the other two isomers. Affinity of the isomers at alpha-1 and alpha-2 receptors was low. Approximately 100,000- and 2000-fold higher concentrations were required for antagonism of alpha-1 and alpha-2 receptors, respectively, relative to 5-HT2 receptors. A similar profile of selectivity was demonstrated for each of the isomers studied. These in vitro data were consistent with in vivo data showing the high i.v. and p.o. potency of all the isomers to antagonize the pressor response to i.v. administration of serotonin in pithed spontaneously hypertensive rats. As seen in vitro, the meso mixture of isomers was slightly less potent than the SS- and RR-isomers after p.o. administration in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Depletion of cardiac norepinephrine in rats and mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a commercially available chemical reagent. Although little has been known about its biological effects, recently MPTP has been reported to cause irreversible Parkinson's disease-like symptoms in humans and in monkeys. We describe here another pharmacologic effect of MPTP, the ability to deplete cardiac norepinephrine in rats and mice. In mice, cardiac norepinephrine concentration decreased within 1 hr, was maximally depleted at 24 hr, and recovered by 4-7 days after i.p. injection of a 32 mg/kg dose of MPTP. The depletion was antagonized by desipramine pretreatment, as was norepinephrine depletion by tyramine. In rats, cardiac norepinephrine depletion by 10-30 mg/kg, i.p., doses of MPTP was accompanied by depletion of cardiac dopamine and of norepinephrine in the mesenteric artery. In rats and in mice, norepinephrine in brain was affected to a smaller degree than was norepinephrine in heart, and dopamine in brain was depleted very little if at all. In spontaneously hypertensive rats, the depletion of cardiac norepinephrine was associated with a marked antihypertensive effect. The p-hydroxy analog of MPTP did not deplete cardiac norepinephrine in rats, indicating that its possible formation as a metabolite of MPTP was not involved in the depletion of cardiac norepinephrine. These findings extend the spectrum of known pharmacologic effects of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Stimulation of presynaptic dopamine autoreceptors by 4-(2-di-n-propylaminoethyl) indole (DPAI).

The dopaminergic activity of 4-(2-di-n-propylaminoethyl)indole (DPAI) was investigated. In animal models for postsynaptic dopaminergic activity DPAI showed only very weak or no effects. In rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal tract, very weak contralateral turning behavior was induced in 4/6 rats. DPAI did not induce stereotyped behavior but caused a pronounced reduction in locomotor activity. In male rats pretreated with reserpine, DPAI lowered serum prolactin levels. Levels of homovanillic acid (HVA) were monitored in the striatum of the chloral hydrate anesthetized rat by means of in vivo voltammetry. DPAI administration reduced the faradaic peak corresponding to HVA. In rats pretreated with the decarboxylase inhibitor, NSD-1015, DPAI blocked the accumulation of dopa in response to gamma-butyrolactone. The results of this study indicate that DPAI possesses a high degree of selectivity for presynaptic dopamine autoreceptors, and little or no effect on postsynaptic dopamine receptors.

Animals↗
PubMed1984

Interactions of trazodone with serotonin neurons and receptors.

Trazodone, 2-[3-[4-(m-chlorophenyl)-1-piperazinyl]propyl]-s- triazolo[4,3-a]pyridin-3(2H)one, was evaluated as an inhibitor of uptake into serotonin neurons in vivo in the brains of mice and rats by determining its ability to antagonize the depletion of brain serotonin by p-chloroamphetamine. In mice, trazodone was inactive under conditions in which many antidepressant drugs and other inhibitors of uptake are potent antagonists of the depletion of serotonin in brain induced by p-chloroamphetamine. Weak inhibition of uptake into serotonin-containing neurons in brain in vivo was demonstrated early after the injection of trazodone in rats, especially when the dose of p-chloroamphetamine was reduced to facilitate competitive inhibition of its effects. However, the effects of trazodone were short-lasting. Trazodone did not potentiate the elevation of serum corticosterone by L-5-hydroxytryptophan, in contrast to the effect of fluoxetine, a potent and selective inhibitor of the uptake of serotonin. Instead, trazodone antagonized a response mediated by a serotonin receptor, i.e. elevation of serum corticosterone by a serotonin agonist, quipazine, in rats. Trazodone also antagonized the serotonin-induced contraction of the rat jugular vein in vitro (a response mediated by 5-HT2 receptors), the pA2 being 8.79. These findings agree with previous reports that trazodone is a potent antagonist of serotonergic function. These data, together with earlier evidence, suggest it is unlikely that the inhibition of uptake of serotonin contributes to the clinical antidepressant effects of trazodone.

5-Hydroxytryptophan↗
PubMed1984

Central dopamine receptors mediating pergolide-induced elevation of serum corticosterone in rats. Characterization by the use of antagonists.

Fourteen dopamine antagonists were compared for their ability to antagonize the elevation of the concentration of serum corticosterone in rats by pergolide, a dopamine agonist. Clozapine did not antagonize the effect of pergolide at the largest dose (10 mg/kg) that could be tested without alteration of basal levels of corticosterone. For the other antagonists, calculation of ED50 values [dose antagonizing by 50% the elevation of corticosterone caused by a 0.3 mg/kg (i.p.) dose of pergolide mesylate] revealed the following order of potency: spiperone greater than loxapine greater than fluphenazine greater than perphenazine greater than flupentixol greater than haloperidol greater than cyclophenazine greater than zotepine greater than flumezapine greater than molindone greater than metoclopramide greater than chlorpromazine greater than sulpiride. All of these compounds caused increases in the concentration of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the brains of rats. The dose that increased the concentration of DOPAC to 200% of the control value (ED200) was calculated for each compound. The ratio of the ED50 value for antagonism of the elevation of corticosterone induced by pergolide to the ED200 value for the elevation of DOPAC in brain varied, probably related to differing selectivity for pre- versus postsynaptic dopamine receptors between the compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Dexamethasone inhibits the production of thromboxane B2 and leukotriene B4 by human alveolar and peritoneal macrophages in culture.

Cultured human alveolar and peritoneal macrophages have been shown to release thromboxane B2 and leukotriene B4. The release was facilitated by stimulation of the macrophages with opsonized zymosan A (1.2 mg/ml). The release was inhibited in a concentration-dependent manner by incubation of the cells with dexamethasone (1 nmol/l to 1 mumol/l).

Acetylglucosaminidase↗
PubMed1984

Capsaicin inhalation in man and the effects of sodium cromoglycate.

The inhalation of capsaicin for 1 min, delivered as an aerosol by nebulising solutions of capsaicin at concentrations of 2-65 mumol 1(-1), caused dose-dependent coughing in normal volunteers and subjects with mild asthma. Capsaicin did not cause a feeling of breathlessness, and had no effect on forced expiratory volume in 1 s (FEV1) measured at the 1st, 5th and 9th min after the challenge was completed. Coughing started within seconds of applying the face mask, continued throughout the minute of capsaicin inhalation, and stopped within seconds of the mask being removed. In any one subject the number of coughs was reproducible when repeated on the same day or after an interval of several days. Experiments using local anaesthesia applied to the buccal mucosa or larynx indicated that the cough was caused by the stimulation of capsaicin-sensitive nerve terminals situated in the larynx. Cough response was not altered by the prior inhalation of sodium cromoglycate.

Aerosols↗
PubMed1984

Elevation of serum corticosterone in rats by bremazocine, a kappa-opioid agonist.

Bremazocine at doses of 0.01 mg kg-1 s.c., and higher, increased serum corticosterone concentration several-fold in rats. The increase occurred within 20 min, was maximum at 40-60 min and subsided after 120 min. Pretreatment with naloxone (1-10 mg kg-1 s.c.) antagonized the corticosterone increase. These data support the view that kappa-opioid agonist activity of bremazocine mediated the corticosterone increase.

Animals↗
PubMed1984

Tropolone antagonism of the L-dopa-induced elevation of S-adenosylhomocysteine: S-adenosylmethionine ratio but not depletion of adrenaline in rat hypothalamus.

Tropolone, an inhibitor of catechol O-methyl transferase, largely prevented the increase in SAH : SAMe ratio in rat hypothalamus following L-dopa injection. Tropolone did not prevent but instead enhanced the decrease produced by L-dopa of adrenaline concentration in rat hypothalamus. The results imply that the decrease in hypothalamic adrenaline concentration following L-dopa injection was not caused by the increase in SAH : SAMe ratio.

Animals↗
PubMed1984

Sodium cromoglycate and atropine block the fall in FEV1 but not the cough induced by hypotonic mist.

In a group of patients with mild asthma the inhalation of mist derived from ultrasonically nebulised distilled water caused an increase in cough and a fall in FEV1. Double blind administration for five minutes of sodium cromoglycate (from an original solution containing 30 mg/ml) or atropine (2 mg/ml) by inhalation from a Minineb nebuliser, 30 minutes before the mist challenge, caused a significant reduction in the fall in FEV1 (p less than 0.05), but not in cough, by comparison with the protection afforded by placebo (saline). In a second study the fall in FEV1 caused by the inhalation of distilled water was not significantly different from that seen in response to hypotonic sodium chloride (1.7 g/l, 58 mmol/l), but both produced a significantly greater fall than did a similar mist containing sodium cromoglycate at an original concentration of 10 mg/ml (58 mmol/l). The results show that both atropine and sodium cromoglycate can block the fall in FEV1 due to mist and that protection by sodium cromoglycate is immediate. These results suggest that sodium cromoglycate blocks the nervous reflexes concerned in the response to mist, probably in the afferent limb of the reflex.

Aerosols↗
PubMed1984

Serotonin receptors.

Explore the source record for details and available documents.

Adaptation, Physiological↗
PubMed1984

In vivo cardiovascular responses to isoproterenol, dopamine and tyramine after prolonged infusion of isoproterenol.

Effects of prolonged in vivo infusion of isoproterenol on acute cardiovascular responses to isoproterenol, dopamine and tyramine were studied in pithed rats. Isoproterenol infusion resulted in a significant decrease in control values for maximum left ventricular dP/dt; heart rate and left ventricular systolic blood pressure were not altered. This treatment also depleted both atrial and ventricular stores of norepinephrine and caused cardiac hypertrophy. Isoproterenol infusion resulted in a desensitization of drug-induced cardiovascular responses. The acute in vivo effects of isoproterenol on maximum left ventricular dP/dt, heart rate and left ventricular systolic blood pressure responses to isoproterenol were severely attenuated. The ED50 for maximum left ventricular dP/dt was increased 36-fold and maximal responses were reduced by half; changes in heart rate occurred in a parallel fashion. By contrast, ED50 values for inotropic responses to tyramine and dopamine were increased 14- and 4-fold, respectively, whereas increases in heart rate were blunted. Tyramine and dopamine-mediated increases in heart rate were completely attenuated by desensitization; chronotropic effects were again evident after pretreatment with the selective alpha-1 blocker prazosin. In addition, prazosin blocked the inotropic responses to tyramine and dopamine after desensitization and this antagonism was only slightly enhanced by addition of propranolol (prazosin + propranolol); propranolol alone was ineffective. These results are consistent with the down-regulation of beta adrenoceptors after prolonged exposure to catecholamines and indicate that under such conditions the alpha-mediated cardiovascular responses may be unmasked. Compared to pure beta agonists, agents with a degree of alpha-1 activity might be superior inotropes in heart failure patients who characteristically present with depleted stores of myocardial norepinephrine and minimal beta adrenoceptor reserve.

Animals↗