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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 235 records · Page 13Linked to original sources
PubMed1987

Effect of enalapril on the skin response to bradykinin in man.

We tested the effect of oral enalapril on intradermal bradykinin to determine if kininase II inhibition occurs with therapeutic doses in vivo. Six normal male volunteers took either 5 mg enalapril orally or placebo on 2 days. Three hours later bradykinin was injected into the skin of the back in doses increasing from 10(-11) to 10(-9) M. Enalapril increased the bradykinin-induced wheal. Inhibition of kininase II may cause accumulation of endogenous bradykinin. This could be an important mechanism in the occasionally reported side effect of angioedema with the angiotensin converting enzyme (ACE) inhibiting group of drugs.

Administration, Oral↗
PubMed1987

The effect of an angiotensin converting enzyme inhibitor, ramipril, on bronchial responses to inhaled histamine and bradykinin in asthmatic subjects.

The effect of a potent inhibitor of angiotensin-converting enzyme, ramipril, was studied on both inhaled histamine and bradykinin-induced bronchoconstriction in six male, normotensive, mild asthmatic subjects. Oral administration of 10 mg ramipril caused no change in lung function or airway reactivity to inhaled histamine or bradykinin despite achieving adequate reduction in angiotensin-converting enzyme activity.

Adult↗
PubMed1987

Oral nafazatrom in man: effect on inhaled antigen challenge.

The effect of oral nafazatrom (Bay g6575, 2 X 3 g) or placebo on inhaled antigen challenge was assessed in a double-blind study. In four subjects antigen challenge resulted in an immediate fall of 93.2 +/- 3.36% in airflow at 40% of vital capacity (Vp40) and a 45.85 +/- 4.95% reduction in forced partial expiratory volume at one second (FEV1). Neither nafazatrom nor placebo had any effect on baseline lung function or that after challenge. Leukotriene B4 was generated by ex vivo stimulus of blood with ionophore A23187, and quantified by high performance liquid chromatography (h.p.l.c.)-radioimmunoassay. No inhibition of LTB4 formation occurred ex vivo following oral nafazatrom, although addition of 10(-5) M nafazatrom to blood in vitro significantly inhibited LTB4 release. Peak plasma nafazatrom levels during the study ranged from 3.3 X 10(-7) M to 1.47 X 10(-6) M which are below the concentration (10(-5) M) at which significant 5-lipoxygenase inhibition occurs in vitro. Oral nafazatrom is ineffective as a 5-lipoxygenase inhibitor in man, probably because of poor bioavailability after administration.

Adult↗
PubMed1987

Circulatory and respiratory effects of infused adenosine in conscious man.

1. The nucleoside, adenosine, was infused into six conscious healthy male subjects at rates up to 100 micrograms kg-1 min-1. 2. Compared with a control 0.9% saline infusion, adenosine in all subjects caused dose dependent increases in heart rate, skin temperature and minute ventilation with corresponding falls in PaCO2, estimated transcutaneously. 3. There were no changes in systemic blood pressure, airways resistance (measured by forced partial expiratory manoeuvres), or plasma catecholamines. At the top infusion rates subjects experienced tolerable chest and abdominal discomfort. 4. These findings conflict with some previous studies in anaesthetised man and animals, in which higher doses of adenosine and its long acting analogues have caused hypotension and central respiratory depression. 5. Although some of these changes may have been due to symptoms, the cardiovascular changes may have been due to a vasodilator action and the respiratory stimulation may have been due to an action on peripheral chemoreceptors.

Adenosine↗
PubMed1987

Sensory neuropeptide effects in human skin.

1 Neuropeptides released from sensory nerves may account for cutaneous flare and wheal following local trauma. In 28 normal subjects we have studied the effects of four sensory neuropeptides given by intradermal injection on the forearm or back. 2 All peptides caused a flare distant from the site of injection, presumably due to an axon reflex. Substance P (SP) was the most potent (geometric mean dose causing 50% of maximum flare, 4.2 pmol). Neurokinin A (NKA) was the next most potent with neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) the least. The distant flare response to SP, NKA and NKB was maximal at 5 min and disappeared within 2 h. 3 CGRP caused a local erythema over the site of injection at doses above 0.5 pmol which at higher doses lasted for up to 12 h. 4 SP, NKA and NKB caused wheals at doses above 5 pmol with SP and NKB being the most potent. CGRP (up to 250 pmol) did not consistently cause wheal formation. There was no significant effect of coinjection of CGRP upon the response to SP although there was a tendency for an enhancement of the wheal response. 5 The H1-histamine antagonist terfenadine (60 mg orally) significantly inhibited the wheal and distant flare response to histamine (5 nmol) and NKA, but not that caused by NKB. The distant flare of CGRP was also reduced but the local erythema was unaltered. 6. Aspirin (600 mg orally) significantly inhibited the distant flare response to SP, NKA and CGRP, but not that caused by NKB or histamine; the local erythema induced by CGRP was unaffected by aspirin. Aspirin also inhibited the wheal formed by NKA but not the wheal induced by the other substances. 7. These results suggest that tachykinins cause a distant flare response partially via the release of histamine and cyclo-oxygenase products, but cause a wheal by a direct effect on the skin microvasculature. The order of potency SP > NKB > NKA suggests that an SPp or NK, receptor is involved in the wheal response. CGRP by contrast has a direct vasodilator effect which is very prolonged.

Adult↗
PubMed1987

Contrasting effects of two xanthines, theophylline and enprofylline, on the cardio-respiratory stimulation of infused adenosine in man.

Six normal male subjects, ages 28-40 years, were studied on separate days during increasing infusions with adenosine, 40-120 micrograms kg-1 min-1, before and during infusions of two xanthine derivatives, theophylline (mean plasma concentration 9 mg l-1) and enprofylline (mean plasma concentration 3 mg l-1). The study was double-blind, randomized, placebo controlled. Cardio-respiratory variables were measured non-invasively. Adenosine by itself increased heart rate (P less than 0.05), skin temperature (P less than 0.05), resting minute ventilation (P less than 0.01) and decreased estimated Pa, CO2 (P less than 0.01). Compared with placebo enprofylline increased heart rate (P less than 0.05) and shifted the heart rate and ventilation dose-response curves of adenosine upwards (P less than 0.05 and P less than 0.02, respectively). Theophylline did not by itself affect heart rate but significantly (P less than 0.05) reduced the heart rate response to adenosine. Compared with placebo theophylline caused a small increase in minute ventilation (P less than 0.05) and flattened the dose-response curves of the effects of adenosine on ventilation (P less than 0.01) and Pa, CO2 (P less than 0.01). Theophylline also reduced abdominal and chest discomfort caused by adenosine permitting significantly (P less than 0.05) higher infusion rates of adenosine. These findings suggest that, with equipotent bronchodilating plasma concentrations, theophylline can inhibit while enprofylline augments some cardio-respiratory stimulant effects of infused adenosine in man.

Adenosine↗
PubMed1987

Persistent depletion of striatal dopamine and its metabolites in mice by TMMP, an analogue of MPTP.

TMMP (1-methyl-4-[methylpyrrol-2-yl]-1,2,3,6-tetrahydropyridine) mimicked MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in causing persistent depletion of striatal dopamine and its metabolites one week after the last of four daily subcutaneous injections in mice. MMPP (1-methyl-4-[1-methylpyrrol-2-yl]-4-piperidinol) produced no depletion of dopamine or its metabolites under these conditions. None of the three compounds affected dopamine or its metabolites when administered orally. TMMP was even more rapidly oxidized by type B monoamine oxidase in-vitro than was MPTP, but MMPP was a very poor substrate for the enzyme. The lack of neurotoxicity of MMPP toward nigrostriatal dopamine neurons when it was given orally or subcutaneously to mice contrasts with previously reported results in monkeys, in which case MMPP was reported to be neurotoxic.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Effect of nedocromil sodium on sulphur dioxide induced bronchoconstriction.

Nedocromil sodium is a pyranoquinoline derivative that has been developed for the treatment of asthma. We report the results of a double blind randomised study of the effect of two doses of nedocromil sodium (2 and 4 mg) and matched placebo, delivered by metered dose pressurised aerosol, on bronchoconstriction induced by sulphur dioxide in six asthmatic subjects. Nedocromil sodium had no effect on baseline lung function. The magnitude of sulphur dioxide induced bronchoconstriction monitored by partial forced expiratory flow at 30% of reference vital capacity was significantly inhibited by nedocromil sodium 4 mg (p less than 0.05) but not by 2 mg. The maximum changes after placebo and after nedocromil 2 mg and 4 mg were -44.7, -32.7, and -11.8 l min-1. The area under the curve monitoring the effect over 6 minutes was significantly inhibited by both doses to the same extent, the mean changes after placebo and after nedocromil 2 mg and 4 mg being -349.3, -31.2, and 44.6 l. Dyspnoea was monitored by visual analogue scale and showed a significant reduction over 6 minutes with both doses of nedocromil. After placebo and after nedocromil 2 mg and 4 mg the mean maximum changes were 31.5, 13.7, and 15.7 mm, and the mean changes in area under the visual analogue scale-time curve were 289, 194, and 151 mm.min respectively.

Adult↗
PubMed1987

Effect of substance P on cardiovascular and respiratory function in subjects.

The effect of substance P (SP), administered both intravenously and by inhalation, has been studied in normal and asthmatic humans. Intravenous infusion of SP (0.2-3.3 pmol X kg-1 X min-1) achieving a plasma concentration of SP between 5 and 25 pM produced vasodilatation (mean +/- SD), maximal increase in skin temperature (0.9 +/- 0.3 degree C) (P less than 0.05), and fall in diastolic blood pressure (8.5 +/- 2.9 mmHg) (P less than 0.05) associated with an increase in heart rate (15 +/- 10 beats/min) (P less than 0.05). All subjects had a fall in Vp30 (airflow at 70% of forced vital capacity measured from total lung capacity after a forced partial expiratory flow maneuver) at low infusion rate (P less than 0.05) and a significant rise at the highest infusion rate (P less than 0.05). Ventilation at rest and when stimulated by transient hypoxia increased (mean increase in resting ventilation 0.73 +/- 0.4 l/min and mean percent increase in transient ventilatory hypoxic response 41 +/- 27%). There was a small nonsignificant increase in plasma norepinephrine but no change in epinephrine or histamine. Inhaled SP, up to 0.7 mumol, caused a small nonsignificant fall in airway function in asthmatic subjects. SP has demonstrable effects on vascular smooth muscle and control of ventilation but at the doses studied had little effect on airway function.

Adult↗
PubMed1987

Bradykinin-induced bronchoconstriction in humans. Mode of action.

The effect of bradykinin was studied by inhalation in normal and asthmatic human subjects, as well as on human bronchial smooth muscle in vitro. Bradykinin caused cough and retrosternal discomfort in all subjects and bronchoconstriction in asthmatic subjects. Bradykinin was approximately 10 times more potent than histamine and methacholine, and there was a significant correlation between the subjects' sensitivity to histamine and bradykinin. Bradykinin-induced bronchoconstriction was prolonged when compared with that of histamine and the C-fiber stimulant capsaicin. This bronchoconstriction was subject to tachyphylaxis, which was also associated with desensitization of the subjects to inhaled histamine. The provocative dose causing a 35% fall in specific airway conductance (PD35) was unaffected by aspirin (1 g orally). However, ipratropium bromide (0.25 mg by nebulizer) significantly inhibited the effect of bradykinin, the PD35 being 0.8 mumol (range, 0.16 to 3.4) and 0.15 mumol (range, 0.047 to 1.15) after active dose and placebo, respectively (p less than 0.05). Likewise, cromolyn sodium (40 mg dry powder) also significantly reduced response to bradykinin, with a PD35 of 0.04 mumol (range, 0.13 to 0.31) after placebo and 0.39 mumol (range, 0.05 to 4.45) after SCG (p less than 0.05). Bradykinin only weakly constricted human bronchial smooth muscle in vitro. Bradykinin at 10(-4) caused only 21.5 +/- 5.5% of the maximal carbamylcholine contraction in 11 of 18 airways. Captopril did not enhance the effect of bradykinin. Bradykinin is a potent bronchoconstrictor of human airways in vivo, acting in part through cholinergic mechanisms but not because of the formation of prostaglandins.

Administration, Inhalation↗
PubMed1987

Effect of meta-chlorophenylpiperazine (mCPP), a central serotonin agonist and vascular serotonin receptor antagonist, on blood pressure in SHR.

mCPP (meta-chlorophenylpiperazine) has agonist activity at some central serotonin receptors and antagonist activity at peripheral vascular 5HT2 receptors, both effects that have been postulated to lower blood pressure. mCPP (10 and 30 mg/kg, i.p. 1 hr after administration) increased serotonin and decreased 5-hydroxy-indolacetic acid (5-HIAA) brain concentrations and elevated serum corticosterone and prolactin, indications of central serotonergic agonist activities. The same doses of mCPP also antagonized vascular 5HT2 receptors as measured by blockade of pressor responses to serotonin in pithed rats. Although mCPP could be demonstrated to activate central serotonergic receptors and block peripheral vascular 5HT2 receptors, mCPP (10 and 30 mg/kg, i.p.) produced little effect on blood pressure in either the anesthetized or conscious spontaneously hypertensive rat (SHR) up to 1 hr after intraperitoneal administration. The findings are consistent with initial studies in normotensive humans that have not demonstrated a reduction in blood pressure clinically after mCPP in doses that produce elevations in serum cortisol and prolactin levels.

Animals↗
PubMed1987

Influence of route of administration on potency of the selective 5HT-1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, in rats.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased the concentration of 5-hydroxyindoleacetic acid (5HIAA), the deaminated metabolite of serotonin, in rat brain. 8-OH-DPAT was much more potent when injected subcutaneously than when injected intraperitoneally, the potency difference being approximately 17-fold. The important influence of route of administration on the potency of 8-OH-DPAT must be considered in interpreting the various functional effects that have been reported with it.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Serotonin reuptake blockers in vitro and in vivo.

Agents that inhibit selectively the neuronal reuptake of serotonin but not catecholamines, and that do not interact directly with neurotransmitter receptors, can have antidepressant activity clinically. Their antidepressant action presumably is initiated by enhanced serotonergic input to other neuronal systems in brain, which leads to primary and secondary (adaptive) changes in neurotransmission and results in remission of depressive symptoms.

Animals↗
PubMed1987

Comparison of the effects of two 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs, 1-methyl-4-(2-thienyl)-1,2,3,6-tetrahydropyridine and 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine, on monoamine oxidase in vitro and on dopamine in mouse brain.

1-Methyl-4-(2-thienyl)-1,2,3,6-tetrahydropyridine (2-MTTP) and 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine were compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with respect to their interactions with MAO (monoamine oxidase) in vitro and their ability to produce persistent depletion of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in mice. Both 2-MTTP and 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine were like MPTP in being potent, competitive inhibitors of MAO-A (MAO type A) and weak, noncompetitive inhibitors of MAO-B (MAO type B) in vitro. 2-MTTP resulted in persistent depletion of striatal dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid 1 week after the last of four daily injections to mice although 2-MTTP was less than one-fourth as potent as MPTP. The other isomer, 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine, failed to deplete dopamine or its metabolites in mouse striatum. Dopamine and its metabolites were also depleted in mouse nucleus accumbens by 2-MTTP and by MPTP; however, norepinephrine in frontal cortex was depleted by MPTP but not by 2-MTTP. The depletion of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid by 2-MTTP was prevented by pretreatment with deprenyl, a selective inhibitor of MAO-B, or with EXP 561, a dopamine uptake inhibitor, just as the depletion by MPTP was prevented. Mouse brain MAO oxidized 2-MTTP in vitro less rapidly than it oxidized MPTP; deprenyl was a potent inhibitor of the oxidation of both substrates, suggesting that MAO-B oxidizes both 2-MTTP and MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Pharmacologic properties of serotonergic agents and antidepressant drugs.

The ways in which pharmacologic intervention is possible in the synthesis, storage, release, inactivation, and actions of serotonin as a brain neurotransmitter are outlined, and the effects on serotonergic neuron function of the drugs used in the treatment of depression are discussed. Antidepressant drugs that inhibit monoamine oxidase increase brain concentrations of serotonin as well as other monoamines. Some tricyclic antidepressant drugs inhibit serotonin uptake along with norepinephrine uptake. There is some evidence that serotonin precursors and serotonin-releasing drugs can have antidepressant efficacy. Recently, selective inhibitors of serotonin uptake have been shown to be effective in the treatment of depression. Selective drugs for modulating serotonergic function will facilitate understanding of the role of serotonin and of specific subtypes of serotonin receptors in depression.

5-Hydroxytryptophan↗
PubMed1987

Depletion of heart norepinephrine in mice by some analogs of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

The effects of ten analogs of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on heart norepinephrine concentration in mice were compared to those of MPTP itself. A single dose of MPTP (10 mg/kg s.c.) caused 73% depletion of heart norepinephrine 24 hrs after its injection. m-Hydroxy-MPTP caused an identical degree of depletion, and six other analogs caused statistically significant but lesser depletion. Three analogs caused no significant change in heart norepinephrine concentration. Since MPTP is oxidized by type B monoamine oxidase (MAO-B), the analogs were compared for their ability to be oxidized by mitochondrial MAO preparations from mouse brain and liver. MPTP and seven analogs were oxidized by MAO-B (oxidation was inhibited by deprenyl); three analogs were not oxidized or were oxidized only slowly and not by MAO-B. The ability of the compounds to deplete heart norepinephrine paralleled their ability to deplete striatal dopamine in the case of MPTP and seven analogs. Three analogs--the same three that were not substrates for MAO-B--depleted heart norepinephrine but not striatal dopamine. One conclusion is that the ability of an MPTP analog to be a substrate for MAO-B is a necessary but not sufficient requirement for depletion of striatal dopamine, but is not necessary for depletion of heart norepinephrine.

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