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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 181 records · Page 10Linked to original sources
PubMed1989

Endocrine and neurochemical effects of (+)-PHNO, a dopamine D2 agonist.

The naphthoxazine compound, (+)-PHNO, is a dopamine D2 receptor agonist which acts within the central nervous system. The effects of this drug on serum concentrations of corticosterone and prolactin and on brain concentrations of catecholamines and some of their metabolites were determined in male rats. Administration of (+)-PHNO in doses ranging from 3-300 micrograms/kg i.p. resulted in increased serum corticosterone, decreased serum prolactin and decreased concentrations of the dopamine metabolites, DOPAC and HVA, in the brain. At the higher doses of (+)-PHNO, concentrations of MHPG sulfate in the brain stem were increased and hypothalamic epinephrine concentrations were decreased. Pretreatment with centrally acting dopamine antagonists (spiperone or haloperidol) prevented the (+)-PHNO-induced changes in serum corticosterone, prolactin and brain catecholamines. In contrast, pretreatment with halopemide, a dopamine antagonist which penetrates poorly into the brain, was unable to block the effects of (+)-PHNO on serum corticosterone and brain catecholamines. These data show that (+)-PHNO, a dopamine agonist structurally unrelated to other dopamine agonists, acts centrally to affect serum corticosterone and brain catecholamines.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Tissue concentrations of MPTP and MPP+ in relation to catecholamine depletion after the oral or subcutaneous administration of MPTP to mice.

One hour after MPTP was given to mice at a dose of 30 mg/kg s.c., its concentration in tissues varied in the order kidney greater than liver greater than lung greater than brain greater than heart. When the same dose of MPTP was given orally, concentrations in most tissues were much lower at 1 hr than after s.c. administration, although the MPTP concentration in liver was only slightly lower. The concentrations of MPP+ (a metabolite of MPTP) at 1 hr were as high or higher than those of MPTP in all tissues except kidney, and MPP+ disappeared from the various tissues with half-lives from 3-20 hrs. The highest concentrations of MPP+, both absolute and relative to MPTP, were in heart. After oral administration of MPTP, no MPP+ was found in brain, and MPP+ concentrations in other tissues were lower than those after s.c. dosing. The depletion of heart norepinephrine was similar after MPTP administration by either route of administration even though MPTP and MPP+ concentrations in heart were lower after oral administration, suggesting that other metabolites of MPTP might also contribute to heart norepinephrine depletion.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Lack of a difference between ketanserin and ritanserin in central vs. peripheral serotonin receptor antagonism.

Ketanserin and ritanserin antagonized with similar potency the pressor response to serotonin in pithed rats, a measure of antagonism of vascular 5HT2 receptors. Both compounds also antagonized the elevation of serum corticosterone concentration by quipazine, a centrally acting serotonin agonist; higher doses of both antagonists were needed, but ketanserin was not less potent than ritanserin. Earlier suggestions that ketanserin mainly blocks peripheral serotonin receptors and that ritanserin mainly blocks central serotonin receptors seem unfounded.

Animals↗
PubMed1989

Effect of the oral leukotriene D4 antagonist LY171883 on inhaled and intradermal challenge with antigen and leukotriene D4 in atopic subjects.

Sulfidopeptide leukotrienes have been suggested as potential mediators of the bronchoconstriction of asthma. The effect of the orally active leukotriene D4 (LTD4) antagonist LY171883 (LY) (400 mg) on antigen or LTD4-induced bronchoconstriction and wheal-and-flare responses was studied in atopic subjects on six occasions (three groups of 2 consecutive days). On the first 2 study days, subjects were screened for their response to inhaled LTD4 and antigen. On the second and third groups of 2 study days, subjects received LY, 400 mg, or placebo 2 hours before inhaled leukotriene LTD4 or antigen challenge. After antigen challenge, the lung function was measured for 6 hours. After the inhaled challenge, intradermal LTD4 and antigen challenges were performed. LY had no effect on baseline lung function. Geometric mean (95% confidence intervals) for the provocative dose of LTD4 causing a 40% fall in forced expiratory flow at 40% vital capacity from a forced expiratory flow maneuver was 1.8 (0.5 to 5.6) nmol after placebo and 5.6 (2.0 to 15.7) nmol after LY. This difference was not significant. The mean maximum change during the early phase of antigen-induced bronchoconstriction was reduced, being 54.7 (26.9% to 82.4%) after placebo and 35.8 (2.3% to 69.3%) after LY (p less than 0.05). There was, however, no difference in the maximum response observed during the late phase. There was also a significant reduction in the area under the curve of the early but not late-phase response to antigen. LY significantly shifted the intradermal LTD4 dose-response curve for both wheal and flare to the right (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1989

Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities.

The neplanocin A analogue 3-deazaneplanocin A (2b) has been synthesized. A direct SN2 displacement on the cyclopentenyl mesylate 3 by the sodium salt of 6-chloro-3-deazapurine afforded the desired regioisomer 4 as the major product. After deprotection, this material was converted to 3-deazaneplanocin A in two steps. X-ray crystallographic analysis confirmed the assigned structure. Consistent with its potent inhibition of S-adenosylhomocysteine hydrolase, 3-deazaneplanocin A displayed excellent antiviral activity in cell culture against vesicular stomatitis, parainfluenza type 3, yellow fever, and vaccinia viruses. Antiviral activity was also displayed in vivo against vaccinia virus by using a mouse tailpox assay. The significantly lower cytotoxicity of 3-deazaneplanocin A, relative to its parent compound neplanocin A, may be due to its lack of conversion to 5'-triphosphate and S-adenosylmethionine metabolites.

Adenosine↗
PubMed1989

Substituted 5-amino-4,5,6,7-tetrahydroindazoles as partial ergoline structures with dopaminergic activity.

Two series of tetrahydroindazoles were synthesized and evaluated for dopaminergic activity. A number of these partial ergoline analogues possess substituents that could mimic the C-8 substituent of the dopaminergic ergolines. Of the unsymmetrically substituted amine series 7a-k, the (monopropylamino)tetrahydroindazole 7b was most interesting as it was found to selectively activate the dopamine (DA) autoreceptor at a dose of 5 mg/kg in rats. The disubstituted amines 7g-k had significant DA postsynaptic activity as measured by increases of serum corticosterone levels in rats. The 6-substituted-5-aminotetrahydroindazoles 10a-d were found to possess only marginal dopaminergic activity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Assessment of MK-912, an alpha 2-adrenoceptor antagonist, with use of intravenous clonidine.

MK-912, a new alpha 2-adrenoceptor antagonist, was assessed in six volunteers by use of antagonism of the effects of intravenous clonidine as the main index of response. Subjects received single doses of either 0.2 or 2 mg of orally administered MK-912 or placebo in a randomized, double-blind, balanced, crossover design. Clonidine was infused intravenously over 10 minutes, 1 hour after dosing, and observations were made for 8 hours. The 2 mg dose of MK-912 significantly inhibited the clonidine-induced hypotension, bradycardia, xerostomia, and increase in plasma glucose concentrations that were observed during the placebo treatment period (p less than 0.05). The peak elevation in plasma growth hormone that was produced by clonidine on the day the placebo was given was inhibited an average of 87% by the 2 mg dose of MK-912 (p less than 0.01). Although there was a trend toward antagonism of clonidine by the 0.2 mg dose of MK-912, statistically significant differences from placebo were not consistently demonstrated for most parameters. However, a mean 59% inhibition of the clonidine-induced peak elevation of plasma growth hormone was observed (p less than 0.05). Oral MK-912 almost completely inhibits the effect of 200 micrograms of intravenous clonidine in human subjects, which is consistent with its role as a potent alpha 2-antagonist over the dose range of 0.2 to 2.0 mg.

Adrenergic alpha-Antagonists↗
PubMed1989

Angiotensin converting enzyme inhibitors and cough.

Angiotensin converting enzyme (ACE) inhibitors produce a dry, nonproductive cough in some patients. Retrospective surveys have suggested an incidence of cough of between 0.7 and 14%. Those patients who develop cough show a marked increase in the sensitivity of the cough reflex to inhalation of the extract of red pepper, capsaicin. They have a normal response before treatment, and the sensitivity of the cough reflex returns to normal when therapy is discontinued. The mechanism of this important side effect is not known. Further studies are required to clarify the mechanism of cough, both as a side effect of therapy and as a common symptom of respiratory disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Leukotriene E4 release in cold urticaria.

Cold urticaria is a rare condition characterized by abnormal wealing following exposure to cold. It has been suggested that lipid-derived mediators may be involved in the pathogenesis of this condition. We have investigated whether the inflammatory reaction in cold urticaria is associated with the release of cysteinyl-leukotrienes. Leukotriene E4 (LTE4; a stable metabolic product of LTC4 and LTD4) and histamine were measured in the blood draining the site of a cold-challenge in five patients with clinical histories of cold urticaria. Three of the patients showed a typical clinical response to the challenge, and this was associated with an increase in the concentration of LTE4 and histamine. No increase in LTE4 or histamine levels were observed following cold challenge in the non-responding individuals.

Adolescent↗
PubMed1989

Decreased 5-hydroxytryptamine turnover in striatum and other brain regions after administration of 5-methoxy-3-(di-n-propylamino)chroman to rats.

5-Methoxy-3-(di-n-propylamino)chroman (5-MeO-DPAC) caused a dose-dependent decrease in the accumulation of 5-hydroxytryptophan after decarboxylase inhibition in rat striatum, hippocampus and frontal cortex. The decreased 5-hydroxytryptamine (5-HT) turnover may have resulted from activation of 5-HT receptors on cell bodies of 5-HT neurons that project to the striatum and other brain regions, since 5-MeO-DPAC had earlier been reported to lack affinity for striatal binding sites.

5-Hydroxytryptophan↗
PubMed1989

A high dose of MPTP overcomes the protective effect of selegiline against dopaminergic neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 90 mg kg-1 s.c., a dose lethal in non-pretreated mice, was well tolerated in selegiline [-)-deprenyl)-pretreated mice and produced persistent depletion of striatal dopamine and its metabolites one week after the last of four daily injections. The protective effect of selegiline against dopaminergic neurotoxicity of MPTP can thus be overridden by a high dose of MPTP that would be lethal without selegiline pretreatment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Effect of inhaled leukotriene B4 alone and in combination with prostaglandin D2 on bronchial responsiveness to histamine in normal subjects.

The effect of intradermal injection of leukotriene B4 alone and in combination with prostaglandin D2 and E2 and the effect of inhaled leukotriene B4 in combination with prostaglandin D2 were studied in six non-asthmatic men. The intradermal injection of leukotriene B4 (1 microgram) alone caused no immediate or late response in five of the six subjects but greatly potentiated the flare response to intradermal prostaglandin D2 (0.5 microgram) and E2 (0.5 microgram) in all subjects. In contrast, inhaled prostaglandin D2 (6 micrograms) alone and in combination with inhaled leukotriene B4 (12 micrograms) caused no change in the response to inhaled histamine, measured 30 minutes and three and six hours after the inhalation. These findings provide no support for the suggestion that leukotriene B4 has an important role in causing bronchial hyperresponsiveness. The possibility that higher doses of inhaled leukotriene B4 may alter bronchial responsiveness cannot, however, be ruled out.

Administration, Inhalation↗
PubMed1989

Substance P dilates epicardial coronary arteries and increases coronary blood flow in humans.

The effects of intracoronary infusions of substance P in conscious humans on epicardial vessel diameter and coronary sinus oxygen saturation were investigated in 13 patients who had angiographically normal coronary arteries. The dose of substance P ranged from 2.8 to 89.6 pmol/min, starting at 2.8 pmol/min and rising by doubling increments. All infusions were performed for 2-minute periods. Epicardial vessel diameter was measured by a computerized analysis system (CAAS) of the angiogram performed at the end of each infusion period. Coronary sinus oxygen saturation (CSO2) was measured continuously by a fiber-optic oximeter catheter in the coronary sinus. A reduction of arterial pressure, indicative of a systemic effect of substance P, occurred only when infusions were 44.8 pmol/min or more. At considerably smaller dosages, a dose-dependent increase in the left anterior descending artery diameter was seen with substance P; maximal dilation occurred at a dosage of 11.2 pmol/min. The percent increase in vessel diameter for this dosage was 29.4 +/- 19.8% (mean +/- SD) at the distal site of analysis and 16.7 +/- 10% at the proximal site of analysis. CSO2 rose in a dose-dependent manner and was maximal at a dosage of 11.2 pmol/min, which caused a 14.6 +/- 7.2% O2 rise above the preinfusion saturation of 43.5 +/- 11.1% O2. As the heart rate-blood pressure double product showed no change, it is argued that these changes in CSO2 probably reflect rises in coronary flow that were seen with dosages of substance P without systemic effect. In three patients, preconstriction induced by ergonovine was reversed by substance P infusions, which produced a degree of dilation equivalent to that of isosorbide dinitrate. We conclude that substance P at very small dosages, which are without peripheral effects, causes in vivo epicardial coronary artery dilatation as well as resistive vessel dilatation in humans.

Adult↗
PubMed1989

Anticholinergic blockade of beta-blocker-induced bronchoconstriction.

The mechanism of propranolol-induced bronchoconstriction (PIB) remains unclear. Previous uncontrolled studies have suggested that atropine antagonizes PIB in asthma. We conducted a randomized, double-blind, placebo-controlled study of the effect of a new anticholinergic agent, oxitropium bromide, on bronchoconstriction induced by inhaled propranolol in seven subjects with mild asthma 24 to 39 yr of age. Inhaled propranolol induced long-lasting reduction in specific airway conductance (SGaw) in all subjects. This was associated with airway beta-adrenoceptor blockade as demonstrated by a shift in the isoproterenol dose-response curve. Propranolol was less potent than methacholine, with a geometric mean dose causing a 35% fall in SGaw of 4.7 mumol for propranolol compared with 0.48 mumol for methacholine. Pretreatment with oxitropium 200 micrograms completely inhibited the fall in SGaw in response to inhaled propranolol in all subjects. Oxitropium also revealed PIB. Cholinergic receptor blockade by oxitropium inhibits bronchoconstriction induced by inhaled propranolol, supporting involvement of cholinergic mechanisms in PIB.

Adult↗
PubMed1989

Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine.

Prostaglandins may cause hyperresponsiveness to bronchoconstrictor agents in the lung and hyperalgesia in the skin. Increased airway concentration of both prostaglandins and bradykinin has been suggested as the possible cause of the increased cough sensitivity sometimes found in patients with cough associated with taking drugs that inhibit angiotensin-converting enzyme. We have therefore investigated the effect of prostaglandin E2 (PGE2), bradykinin (BK), histamine (H), and citric acid (C) on capsaicin-induced cough and increase in respiratory resistance (Rrs). Capsaicin-induced changes in Rrs and dose-cough response were measured before and after inhaling 0.76 mumol of PGE2, BK, H, and C. All the test substances caused cough, which was subject to tachyphylaxis, but no significant change in Rrs. Neither BK, H, nor C altered the capsaicin cough or Rrs response. However, PGE2 significantly increased both responses to capsaicin, the geometric mean (95% Cl) for the dose of capsaicin causing 5 or more coughs being 16.2 (14.3 to 18.3) nmol before and 4.4 (2.4 to 7.9) nmol after PGE2 (p less than 0.05). The percent increase (95% Cl) in Rrs after capsaicin was 20 (16.5 to 23.5)% before and 37.2 (32.2 to 43.2)% after PGE2 (p less than 0.05). The results suggest that the cough reflex will be increased in the presence of PGE2 in the airway.

Adult↗
PubMed1989

5'-thioadenosine derivatives as potent and selective inhibitors of histamine N-methyltransferase.

Several new analogues of adenosine bearing a lipophilic side chain at the 5'-position have been synthesized and investigated for their ability to inhibit histamine N-methyltransferase (HNMT). The 5'-deoxy-5'-[4-(3-indolyl)but-1-yl]thio]adenosine (2e), exhibited a pI50 of 5.00 against guinea pig brain HNMT. Interestingly, the polar methyl sulphonium analogue (1c) was a more potent inhibitor of this enzyme (pI50 = 5.26). Both compounds were relatively ineffective inhibitors of rabbit adrenal phenylethanolamine N-methyltransferase (PNMT), rabbit lung indoleamine N-methyltransferase (INMT), and rat brain catechol O-methyltransferase (COMT). 5'-[N(4-phenylbutyl)]-amino-5'deoxyadenosine (2a) and 5'-[N-methyl,N-(4-phenylbutyl]-amino-5'deoxyadenosine (2b) also exhibited potent and selective inhibition against guinea pig brain HNMT. Results from kinetic studies indicate that the above compounds are inhibitors that compete for both the histamine and the S-adenosylmethionine (SAM) binding sites of HNMT. Compound 1c is one of the most potent adenosine analogue inhibitors of HNMT known.

Adenosine↗