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PubMed1982

Reduction of ventricular fibrillation threshold by histamine: resolution into separate H1- and H2-mediated components.

The effects of histamine and the selective agonists impromidine (H2-agonist) and 2-(2-thiazolyl ethylamine)(H1-agonist) on ventricular fibrillation threshold were tested in the isolated guinea-pig heart. All three compounds produced reversible concentration-dependent decreases in ventricular fibrillation threshold. Ventricular fibrillation threshold reduction was not secondary to the positive chronotropic effect of the three compounds. Computer analysis of the data using appropriate theoretical models suggests that the net effect of histamine on ventricular fibrillation threshold is the resultant of two components: H1 and H2. Pyrilamine inhibited the H1-mediated effects of histamine on ventricular fibrillation threshold with a Kb value of 0.449 nM. H1- and H2-receptors mediating ventricular fibrillation threshold reduction differ in their relative sensitivity to histamine (H1 greater than H2; EC50 for histamine, 53.9 nM at H1- and 311 nM at H2-receptors) and in the maximum response which they are capable of producing (H1 congruent to 1/2 that of H2). The finding that extremely low concentrations of histamine (less than 1 pg/ml) can effectively reduce ventricular fibrillation threshold reinforces the concept that histamine is highly arrhythmogenic.

Animals↗
PubMed1983

Evaluation of presynaptic histamine receptors in the canine renal vascular bed.

Histamine has been shown to increase renal blood flow via H1- and H2-receptors. Furthermore, H2-receptors have been demonstrated to attenuate stimulation-induced release of norepinephrine. The present studies examined whether histamine has a presynaptic effect on sympathetic nerves in the canine renal vascular bed. Renal blood flow was measured in anesthetized dogs, and vasoconstrictor responses to renal nerve stimulation and i.a. injections of norepinephrine were compared before and during i.a. infusions of histamine. Histamine increased renal blood flow and decreased stimulation-induced vasoconstriction to a greater degree than norepinephrine responses. 2-(2-pyridyl)ethylamine, an H1-agonist, did not produce consistent effects. Dimaprit, an H2-agonist, produced responses similar to histamine but to a lesser extent. The H1-antagonist tripelennamine and the H2-antagonist cimetidine each minimally antagonized the effect of histamine on nerve stimulation. When both blocking agents were infused together, maximum antagonism of histamine occurred. Thus, it appears that histamine will produce a neuroinhibitory effect in the canine renal vascular bed and this effect appears to be mediated by both H1- and H2-receptors because both receptor antagonists are necessary to block this effect.

Animals↗
PubMedDate not supplied

Metabolism of 4-nitroaniline by rat liver microsomes.

The principal rat liver microsomal metabolite of 4-nitroaniline was isolated by high pressure liquid chromatography and was characterized as 2-amino-5-nitrophenol (2-hydroxy-4-nitroaniline) by comparison of its mass, nuclear magnetic resonance, and ultraviolet spectra and HPLC retention time to the synthetic compound. A metabolite with the chromatographic retention time of authentic N-hydroxy-4-nitroaniline was not detected. Pretreatment of rats with phenobarbital and 3-methylcholanthrene increased the rate of conversion of 4-nitroaniline to 2-hydroxy-4-nitroaniline by 2-fold and 4-fold, respectively; the reaction required NADPH and was inhibited by heat treatment of microsomes, by argon and carbon monoxide:oxygen atmospheres and by the cytochrome P-450 inhibitor, 2-[(2,4-dichloro-6-phenyl)phenoxy]ethylamine. In the presence of a molecular oxygen (18O2) atmosphere, 18O was quantitatively incorporated into the metabolite. Microsomes did not catalyze the isomerization of N-hydroxy-4-nitroaniline to 2-hydroxy-4-nitroaniline. A primary isotope effect was not observed upon comparison of the rate of conversion of 2,6-dideutero-4-nitroaniline to 2-hydroxy-4-nitroaniline with that of the nondeuterated compound. The 2-hydroxy-4-nitroaniline derived from microsomal incubation mixtures of 2,6-dideutero-4-nitroaniline contained about 20%, 3,6-dideutero-2-hydroxy-4-nitroaniline.

Aniline Compounds↗
PubMed1982

Identification and characterization of surface receptors for histamine in the human promyelocytic leukemia cell line HL-60. Comparison with human peripheral neutrophils.

The magnitude, the potency, the duration, and the specificity of histamine-induced cyclic AMP formation has been compared in human promyelocytic leukemic HL-60 cells and in human peripheral neutrophils. In HL-60 cells incubated at 37 degrees in the absence of phosphodiesterase inhibitor, histamine caused a 20-fold stimulation of basal cyclic AMP levels, with an EC50 of 5 X 10(-6) M. Typical H2 receptors were involved as shown by the relative potencies of the H1-selective agonists, 2-(2-pyridyl)ethylamine (PEA) and 2-(2-amino-ethyl)thiazole (AET), and the H2-selective agonists, impromidine and 4-methyl)histamine(4-MH): impromidine greater than histamine greater than 4-MH greater than AET greater than PEA. In this system, impromidine had mixed agonist-antagonist properties as shown by the rightward shift of the concentration-response curve of histamine (EC50 = 2 X 10(-3) M histamine in the presence of 10(-4) M impromidine). Histamine stimulation was competitively inhibited by the furane derivative ranitidine (Ki = 0.16 X 10(-6) M) as well as by the imidazole analogues oxmetidine (Ki = 0.48 X 10(-6) M) and cimetidine (Ki = 0.65 X 10(-6) M), whereas the H1 antagonist diphenhydramine inhibited histamine action at about 100-300 times higher concentrations (Ki = 51 X 10(-6) M). Prostaglandin E1 (PGE1) also stimulated cyclic AMP levels (50-fold increase) in HL-60 cells; half-maximal activation by PGE1 occurred at 3.2 X 10(-6) M. Our results indicate, first, that prostaglandin and histamine H2 receptors are present and functional at an early stage during myeloid differentiation; second, that there is no substantial difference between the pharmacological properties of the histamine H2 receptors in HL-60 cells and in mature human peripheral neutrophils; third, that the remarkable capacity for cyclic AMP formation noted in HL-60 leukemic cells after cell surface interaction by histamine or prostaglandin suggests that cyclic AMP and agents which increase its formation may have a role in the regulation of proliferation and/or differentiation of human myeloid progenitor cells.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Pharmacological modification of immunoregulatory T lymphocytes. I. Effect of adenosine, H1 and H2 histamine agonists upon T lymphocyte regulation of B lymphocyte differentiation in vitro.

Human peripheral blood T lymphocytes were fractionated according to the lability of their sheep red blood cell (E) receptors to theophylline. Theophylline sensitive (Ts) cells function as suppressors of pokeweed mitogen induced B cell differentiation into plasma cells, while theophylline resistant (Tr) cells function as helper/inducer cells in this reaction. The Ts fraction is enriched for cells bearing receptors for the Fc portion of IgG (RFc gamma) while the Tr fraction is depleted of RFc gamma bearing cells. Brief exposure of Tr cells to adenosine or impromidine, an H2 histamine agonist, cause a rapid increase in the number of Tr cells bearing RFc gamma and the development of radioresistant suppressor cell activity. The RFc gamma induced on Tr cells by adenosine or impromidine are more stable in culture than the spontaneously occurring RFc gamma on Ts cells. Ts suppressor activity is radiosensitive and exposure of Ts cells to 2(2-pyridyl)ethylamine, an H1 histamine agonist, results in a marked decrease in RFc gamma on Ts cells as well as loss of Ts suppressor activity. These data indicate that RFc gamma expression and the immunoregulatory function of T lymphocyte subsets may be modified by drugs acting upon adenosine, H1 and H2 histamine receptors.

Adenosine↗
PubMed1981

Cyclic AMP increase by histamine and its analogues in guinea-pig submandibular gland.

The effect of histamine and its analogues on the cyclic AMP level in chopped guinea-pig submandibular glands was investigated. These agonists increased the cyclic AMP level dose-dependently. The ED50 values for histamine and 4-methylhistamine were approximately 1.3 x 10(-5) M and 2.2 x 10(-5) M, respectively. The efficacy of 4-methylhistamine was higher than that of histamine. 2-(2-Pyridyl)-ethylamine was far less effective compared with histamine or 4-methylhistamine. Metiamide markedly antagonized the cyclic AMP response to histamine and 4-methylhistamine, but mepyramine was ineffective. A combination of aminoguanidine and quinacrine had no influence on the effect of histamine on the cyclic AMP level. These results indicate the H2-type histamine receptors which mediate the cyclic AMP increase are present in the guinea-pig submandibular gland.

Animals↗
PubMed1984

Effects of fluorination on in-vitro metabolism and biological activity of N-nitrosodialkylamines.

Substitution of N-nitrosodialkylamines with fluorine at specific sites inhibits oxidative metabolism at the respective carbon atoms. The results of in-vitro metabolism studies with N-nitrosodiethylamine (NDEA), N-nitrosodibutylamine (NDBA) and their fluorinated analogues, N-nitroso-2,2,2-trifluoroethyl-ethylamine (NDEA-F3), N-nitroso-bis(2,2,2-trifluoroethyl)amine (NDEA-F6), N-nitroso-4,4,4-trifluorobutyl-butylamine (NDBA-F3), N-nitroso-bis(4,4,4-trifluo-robutyl)amine (NDBA-F6) and N-nitroso-bis(2,2,3,3,4,4,4-heptafluorobutyl)amine (NDBA-F14), showed effects of fluorination on biotransformation which can explain results of carcinogenicity and mutagenicity experiments; NDEA-F6 and NDBA-F14 were practically not metabolized by microsomal fractions, even though no decrease in binding affinity to cytochrome P450 was observed. Both compounds were not biologically active and were exhaled unchanged in high proportions after oral administration to the rat. Biologically active analogues, NDEA, NDBA, NDBA-F3 and NDBA-F6, were found to be dealkylated at the unfluorinated alkyl chains and, to a lesser extent, at the omega-fluorinated alkyl chains. Detection of corresponding alcohols as hydrolysis products confirmed the generation of electrophilic intermediates by alpha-C-hydroxylation. However, trifluorethanol was detected only in very small proportions from dealkylation of NDEA-F3, although dealkylation occurred almost exclusively at the unfluorinated site.

Animals↗
PubMed1984

Effects of histamine-receptor agonists on transvascular fluid and macromolecular efflux in the canine forelimb.

Histamine increases transvascular fluid and protein efflux in the canine forelimb resulting in edema formation. To clarify the receptor mechanisms of histamine edema, we infused H1 and H2-receptor agonists into the forelimb perfused at constant flow while measuring skin lymph parameters or forelimb weight. The H1-receptor agonist 2(2-pyridyl) ethylamine [PEA] or the H2-receptor agonist 4-methyl histamine (8-40 micrograms/min) singly or in combination fails to increase lymph flow, protein concentration or protein transport. PEA in a dose of 80-400 micrograms/min increases lymph flow, protein concentration and protein transport. 4-Methyl histamine in a dose of 40-200 micrograms/min produces a small but significant decrease in lymph flow and protein transport subsequent to a fall in systemic pressure. 4-Methyl histamine at 40 and 80 micrograms/min produces a progressive and sustained increase in forelimb weight PEA at 40 micrograms/min produces a small increase in forelimb weight which quickly plateaus much like the response seen with acetylcholine (10 micrograms base/min). However, infusion of PEA at 80 micrograms/min progressively increases forelimb weight, similar to that seen with 4-methyl histamine or histamine (1.4 microgram base/min). These data indicate that either H1 or H2-receptor agonists can cause edema formation in the canine forelimb, and imply that histamine edema involves both H1 and H2-receptor interaction.

Animals↗
PubMed1983

A fluorescent probe for the active site of bovine trypsin.

The compound 2-p-toluidinylnaphthalene-6-(N-beta-ethylamine hydrochloride) sulfonamide (compound III) has a structure that is appropriate for binding to the active site of trypsin. It also has the property of fluorescence when in a nonpolar environment such as when bound to trypsin. Kinetic studies show that compound III competitively inhibits the trypsin-catalyzed hydrolysis of L-alpha-N-Benzoylarginine-p-nitroanilide (L-BAPNA) with a KI' of 3.6 X 10(-4)M at pH 8.1. The fluorescence enhancement of III when bound to bovine trypsin further confirms the existence of a hydrophobic specificity region within the active site of trypsin. The pH dependence of the fluorescence of compound III with trypsin was also determined.

Animals↗
PubMed1983

Serum levels of dimenhydrinate. Determination by HPLC with UV detection after intake of dimenhydrinate in a coated chewing gum dragee.

HPLC with UV detection allowed to separate dimenhydrinate and three major metabolites (diphenyl-methoxy-ethylamine, diphenyl-methoxy-acetic acid, diphenyl-methoxy-N-methyl-amine) in human serum without extraction procedure. Detection limit was 25 ng per 500 microliter injected sample, the recovery ranged from 70 to 95%. Serum levels of dimenhydrinate were measured in healthy volunteers 15, 30, 60 and 120 min after intake of two commercially available preparations, one of them a dimenhydrinate tablet, the other one a dimenhydrinate containing coated chewing gum dragee (Travel-Gum dragee). The rise of the serum concentration of dimenhydrinate up to 30 min was smaller after intake of the coated chewing gum preparation than after swallowing the tablet. The serum concentrations at 1 or 2 h after the intake of either a tablet or the chewing gum were comparable. The variability of the serum concentrations was considerable with both preparations and seemed to be influenced more by individual factors than by previous food intake.

Administration, Oral↗
PubMedDate not supplied

[Peroxidation of lipids in mitochondrial membranes, induced by enzymatic deamination of biogenic amines].

In presence of ferrous cations and ascorbate lipid peroxidation in mitochondrial membranes has been induced by incubation of fragments of the membrane devoid of catalase activity with amines which are substrates of monoamine oxidases of the B type (2-phenyl ethylamine, benzylamine) or transformed monoamine oxidases of type A (cadaverine). In the samples containing both cadaverine and benzylamine the highest stimulation of lipid peroxidation was noted. To the contrary, a substrate of the monoamine oxidases of the type A (serotonin) caused under the same conditions an antioxidative effect. The following conditions are obligatory to induce lipid peroxidation in mitochondria by incubation with amines: I. absence of catalase activity in the biomembranes; 2. presence of physiological concentrations of Fe2+. Physiological concentrations of ascorbate or alterations of pH in the samples caused additional stimulation of the lipid peroxidation.

Animals↗
PubMed1980

Antibodies against sialyloligosaccharides coupled to protein.

The beta-(p-aminophenyl)ethylamine derivatives of sialyloligosaccharides can be coupled to proteins via their phenylisothiocyanate intermediates under conditions that preserve labile sugar linkages. Bovine serum albumin containing 10 to 40 mol of oligosaccharides/mol of protein and keyhole limpet hemocyanin containing 1,100 mol of oligosaccharide/mol of protein have been prepared with the following oligosaccharides: Neu-NAc alpha 2-3Gal beta 1-4Glc, NeuNAc alpha 2-6Gal beta 1-4Glc, Neu-NAc alpha 2-6Gal beta 1-4GlcNAc beta 1-4Glc, Gal beta 1-3[Neu-NAc alpha 2-6]GlcNAc beta 1-4Glc, and NeuNAc alpha 2-3Gal- beta 1-3[NeuNAc alpha 2-6]GlcNAc beta 1-4Glc. Rabbits immunized with these synthetic glycoproteins produce antibodies directed against the oligosaccharides. The specificities of these antibodies are determined by comparing inhibitory activities of structurally related oligosaccharides in radioimmunoassay and by double diffusion analysis in agarose gels using oligosaccharide-protein conjugates as precipitating antigens. The antibodies distinguish positional isomers of sialic acid.

Animals↗
PubMed1981

Serotonin autoreceptors on dorsal raphe neurons: structure-activity relationships of tryptamine analogs.

A series of indole-ethylamines were tested for their ability to suppress the spontaneous firing of single dorsal raphe serotonergic neurons in the rat. The compounds were all derivatives of either tryptamine or N,N-dimethyltryptamine possessing hydroxy or methoxy substituents on the benzene ring portion of the indole nucleus. Their activity was assessed using quantitative microiontophoresis or following systemic (intravenous) administration. The serotonin autoreceptor or so-called "S2 receptor" mediating the inhibition of raphe serotonergic neurons was found to exhibit a high degree of structural specificity among the closely related tryptamine analogs. The following structure-activity rules were demonstrated: (1) for either hydroxy or methoxy derivatives, the relative favorability of the ring positions conforms to the series 5 much greater than 4 greater than 6; (2) methoxy derivatives are more sensitive to a shift of the ring substituent from the 5- to the 4- or 6-positions than are hydroxy compounds; and (3) activity is enhanced by N,N-dimethylation. Furthermore, addition of a methyl group at the 7-position of 5-methoxy-N,N-dimethyltryptamine markedly reduces the activity of this potent agonist. Of the radioligands which label brain serotonin receptors, the pharmacological characteristics of D-[3H]lysergic acid diethylamide binding best correspond to those displayed by the S2 receptor as determined in the present physiological analysis, although sufficient data are not yet available to make a complete comparison.

Animals↗
PubMed1978

[Inhibition of the process of sugar transport stimulation in the frog sartorius muscles by amines and amides].

In the experiments on isolated frog sartorius muscles, amines and amides were found to inhibit the process of stimulation of D-xylose transport induced by insulin, 2,4-dinitrophenol or potassium contracture. The inhibitory action was produced by urea, acetamide, guanidine, NH4Cl, mono-, di- and trimethyl- or ethylamines, some diamines (all the substances being, applied in the concentration range equal to 100 mM). The similar effect was obtained when cystamine (20 mM), tryptamine, 5-methoxytryptamine (2 mM) and adenine, adenosine, guanosine (1-10 mM) were used. There was no inhibitory effect of acetone, glycerol, tetraethylammonium, propilamine, butylamine, aminoacids, spermine, spermidine, ATP, AMP or cAMP. It has been suggested that the inhibitory substances may interact by producing hydrogen bonds from NH-groups with the neutrally or negatively charged groups at the external surface of the muscle membrane in the region with a slow hydrophobicity. As a result, no structural changes required for activation of the sugar transport system occur in the membrane.

Amides↗
PubMed1982

[Derivatives of 4-phenylcyclohexylethylamine with antidepressive activity].

Several new derivatives of trans-1-(4-phenylcyclohexyl)-ethylamine (M.G. 6669) have been synthesized with various substituents at the alpha-carbon and/or at the amine nitrogen atom. All compounds were evaluated for a potential antidepressant activity taking M.G. 6669 as reference. They turned out to be less active than the reference substance. Pharmacological evaluation of M.G. 6669 itself was broadened during this work. The good antidepressant properties of this compound were confirmed, accompanied however by some toxic phenomena.

Aggression↗
PubMedDate not supplied

[Kinetic properties of monoamine oxidase isoenzymes from the bovine brain].

Multiple forms of monoamine oxidase (MAO I, IIa, IIb, III) from bovine brain, separated by means of affinity chromatography on AH-Sepharose 4B, were dissimilar in kinetics of deamination of serotonin and beta-phenylethylamine used as substrates of the MAO of A and B types. MAO-I catalyzed the deamination of beta-phenyl ethylamine and serotonin. Km and Vmax values could not be calculated for MAO-IIa since the rate of enzymatic reactions was characterized by a complicated dependence on concentration of serotonin in a sample. MAO-IIb catalyzed also the deamination of both AMO substrates.

2-Hydroxyphenethylamine↗
PubMed1981

Relationship of rat urinary metabolites of N-nitrosomethyl-N-alkylamine to bladder carcinogenesis.

Nitrosomethylalkylamines with chain lengths from C4 (n-butyl-) to C14 (n-tetradecyl-) were each administered in three rats at doses equimolar with 12 mg of the butyl compound. All of the compounds administered to rats at this dose, twice a week for 30 weeks, induced tumors in 100% of the animals. Some of the compounds with even-numbered alkyl chains induced bladder tumors, and a connection was sought with the metabolites of these excreted in urine. The pooled 24-hr urine was extracted with ethyl acetate before and after acidification to provide a neutral fraction and a fraction containing nitrosoamino acids. The fraction containing the acids was analyzed by capillary gas chromatography and by gas chromatography-mass spectrometry after esterification with diazomethane; the neutral fraction was analyzed similarly. The principal metabolite of the nitrosoamines with odd-numbered chains was found in the acidic fraction and was identified as nitrosomethyl-2-carboxy-ethylamine. There were several acids in the mixtures derived from the nitrosamines with even-numbered chains, nitrososarcosine and nitrosomethyl-3-carboxypropylamine being the major components. There was no trend in the yields of the nitrosamino acids that could be correlated with the differences in carcinogenic potency between the nitrosamines; the maximum yield of acids was more than 30% (from the tetradecyl compound). The principal component of the neutral fraction (less than or equal to 1% of the nitrosomethylalkylamine administered) was nitrosomethyl-2-oxopropylamine. The yield of this compound increased with length of the even-numbered chain nitrosamines.

Animals↗
PubMed1980

Carcinogenicity in rats of nitrosomethylethylamines labeled with deuterium in several positions.

Nitrosomethylethylamine and four of its derivatives labeled with deuterium at various positions were administered to male Fischer 344 rats in drinking water at equimolar doses for 30 weeks. The doses were 30 and 6 mg/liter at the rate of 3 and 0.6 mg/week, approximately. The rats receiving the higher doses died earlier and had more tumors than those given the lower doses. At both dose levels, nitrosomethylethyl-1-d2-amine and nitrosomethylethyl-d5-amine were more effective carcinogens than was unsubstituted nitrosomethylethylamine. Rats died earlier and more of them had tumors after receiving the deuterium-labeled compounds. Nitrosomethyl-d3-ethylamine and nitrosomethyl-d3-ethyl-d5-amine did not greatly differ in carcinogenic effectiveness from the unsubstituted compound. Both nitrosamines having deuterium in the methyl portion of the ethyl group, nitrosomethylethul-d5-amine and nitrosomethyl-d3-ethyl-d5-amine, induced esophageal tumors as well as liver tumors in the rats.

Animals↗