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PubMed1987

[Blood phenolsulfotransferase and monoamine oxidase-B activity in essential arterial hypertension].

Circulating phenolsulfotransferase M and P and monoamine oxidase activities were determined in 18 untreated essential hypertensive patients and in 35 normotensive healthy controls. Phenolsulfotransferase M is involved in the sulfoconjugation of catecholamines and their metabolites while PST P preferentially sulfates phenolic substrates. After lysis of whole blood, enzymatic activities were determined by radioenzymatic techniques using as substrates 3-methoxy-4-phenoxyphenylglycol for PST M, phenol for PST P and [14C] beta-phenylethylamine for MAO. Blood MAO activity measured by this method is fully accounted for by platelet MAO-B activity. Concerning blood PST activities, no significant difference was found in hypertensive patients compared to normotensive controls (PST M: 1.69 +/- 0.17 versus 1.66 +/- 0.08 nmoles of MHPG-sulfate/ml of blood/hour; PST P: 0.36 +/- 0.05 versus 0.27 +/- 0.04 nmoles of phenol-sulfate/ml of blood/hour). MAO activity was higher in women than in men. Significantly lower MAO B activities were observed in hypertensive patients both in men (19.25 +/- 2.20, n = 8 versus 24.35 +/- 2.22, n = 14, desaminated beta-phenyl-ethylamine/10(9) platelets/hour, x +/- SEM, p less than 0.05) and in women (23.92 +/- 2.74, n = 10 versus 35.76 +/- 2.35, n = 21, p less than 0.01) when compared to normotensive controls of the same sex. Recent in vitro studies have suggested that a reduction in platelet MAO B activity may be induced by an alteration in the phospholipidic and/or calcium environment of the enzyme. Low MAO activity in other tissues such as liver or vascular endothelium could contribute to the high sympathetic tone observed in these patients.

Arylsulfotransferase↗
PubMedDate not supplied

[Interaction of plasminogen activator of urokinase type with human serum].

Effects of blood serum on u-PA (EC 3.4.21.31) fibrinolytic activity were studied. After incubation for one hour at 37 degrees of the enzyme with human blood serum (55-145 IU/ml of blood serum) the enzymatic activity was completely inhibited. At the same time, amido-lytic activity of u-PA, estimated with low molecular substance S2444 as a substrate, was maintained in presence of blood serum. Blood serum inhibitors did not exhibit the specific affinity to u-PA. Serine proteases (trypsin, chymotrypsin and plasmin) competed with u-PA at equimolar concentrations. These inhibitors were inactivated after blood serum preincubation with primary amines methylamine, ethylamine, putrescine, spermidine and spermine (0.1-10 mM). The u-PA-inhibitor complexes were not dissociated in presence of 2.5 mM sodium dodecylsulfate. Trypsin-albumin copolymer bound specifically the blood serum u-PA inhibitors and the fraction adsorbed was electrophoretically characterized as a protein with molecular mass of 185 kDa.

Benzamidines↗
PubMed1977

[Pharmacological pecularities of natural and synthetic alpha-adrenomimetic substances II].

The comparative examination of noradrenaline, octopamine, Privin and 2-phenylethylamine on the isolated rat vas deferens made under controlled conditions (1) has been extended by introducing more complex experimental conditions. Pretreatment of the animal with reserpine does not change the response to Privin, while the response to the maximal doses of noradrenaline is reduced; the response to octopamine remains unchanged while that of 2-phenyl-ethylamine is abolished.

Animals↗
PubMed1987

In-vivo activation of N-nitrosodiethanolamine and other n-nitroso-2-hydroxyalkylamines by alcohol dehydrogenase and sulfotransferase.

Alcohol dehydrogenase (ADH) activates N-nitrosodiethanolamine (NDELA) to a potent mutagen in the Ames mammalian microsome mutagenicity assay. In vivo, NDELA, its metabolite N-nitroso-2-hydroxymorpholine (NHMOR) and other 2-hydroxylated N-nitrosoalkylamines induce single-strand breaks in rat liver after a single oral application. After competitive inhibition of ADH by pretreatment with ethanol, induction of single-strand breaks by NDELA and N-nitroso(2-hydroxyethyl)ethylamine (NHEEA) was completely suppressed, whereas breaks induced by NHMOR were only partially reduced. Ethanol also influences cytochrome P450-dependent monooxygenases. To investigate whether the observed effect depends on inhibition of ADH and/or of monooxygenases, rats were pretreated with the ADH inhibitor 3-butylthiolane-1-oxide; a considerable reduction in the single-strand-break-inducing potential of NDELA was seen. Moreover, DNA damage induced by NDELA, NHMOR and other hydroxylated N-nitroso compounds is strongly reduced by pretreatment with the sulfotransferase inhibitor, 2,6-dichloro-4-nitrophenol (DCNP). DCNP pretreatment completely suppressed the induction of single-strand breaks by NDELA, whereas the number induced by NHEEA was only partially reduced. Our data suggest that ADH and sulfotransferase are enzymes responsible for the in-vivo activation of N-nitroso-2-hydroxyalkylamines.

Alcohol Dehydrogenase↗
PubMed1986

Investigations on calmodulin antagonistic effects of bepridil in intact and skinned fibres of smooth muscle.

Potassium-induced contractions of rat aortic strips are completely inhibited by N-benzyl-beta-(isobutoxymethyl)-N-phenyl-1-pyrrolidine-ethylamine (bepridil, Cordium) 10(-5) mol/l. In contrast, contractions induced by norepinephrine are only partially inhibited (by 40%) by identical doses of bepridil. Since the latter effect could be due to an inhibition of calcium release from intracellular compartments it was investigated how bepridil influences the effect of calcium on functionally isolated contractile structures. Smooth muscle preparations (guinea pig taenia coli and pig coronary artery) were skinned with octoxinol and suspended in adenosine triphosphate salt solution. During long-term incubation (greater than 40 min) of skinned fibres in low-calcium solution (pCa greater than 8) the calmodulin (CaM) is extracted. A calcium-induced contraction occurs only by adding CaM, showing the necessity of CaM for contraction. In the presence of bepridil 10(-4) mol/l the following effects were observed: submaximal contractions induced by calcium (1.1-1.6 mumol/l) were inhibited completely, the effects of calcium (4 mumol/l and 30 mumol/l) were inhibited by 83 +/- 4.5% and 53 +/- 10.5% respectively (mean +/- S.E.M.; n = 5). These effects could be completely antagonized by addition of calmodulin, final concentration 5 mumol/l. Verapamil did not show any inhibitory effects even in high concentrations (up to 10(-3) mol/l). Thus the effects of bepridil on the contractile mechanism in vascular smooth muscle are at least partly mediated through an intracellular mechanism - most probably inhibition of calmodulin.

Animals↗
PubMedDate not supplied

Analgesic and anti-inflammatory activity of 10-amino-11H-indeno [1,2-b] quinolin-11-one derivatives.

Ten novel derivatives of 11H-indeno [1,2-b] quinolin-11-one (1-10) were synthesized and pharmacologically screened. All compounds showed analgesic activity. Anti-inflammatory activity was found only for alkylamine derivatives 1-6. The most active 10-ethylamine derivative 2 showed also ulcerogenic properties. The LD50/UD50 and UD50/ED50 values for compound 2 were less satisfactory than those for ibuprofen.

Animals↗
PubMed1986

Vasodepressor mechanisms in experimental hypertension: studies using chemical medullectomy.

There is evidence that neither activation of the renin-angiotensin system nor changes in sodium balance can fully explain the maintenance of blood pressure in Goldblatt hypertension. Thus, in Goldblatt two-kidney, one clip hypertension in the rat sodium balance is negative and in hypertension of a few months' duration plasma renin initially elevated has returned to normal. When hypertension is reversed by removal of the constricting clip from the renal artery, blood pressure falls within a matter of hours even when hypertension has been present for many months, suggesting that the effect of structural changes in vascular resistance vessels has been overcome. In addition, blockade of the renin-angiotensin system during renal artery declipping does not influence the pattern of the blood pressure fall. We investigated the role of the renomedullary vasodepressor system by inducing medullary necrosis with 2-bromo-ethylamine hydrobromide. This causes a moderate blood pressure increase in normal rats, and partly inhibits the fall of blood pressure in Goldblatt two-kidney, one clip hypertension when the renal clip is removed. Chemical medullectomy is associated with a slightly negative sodium balance, plasma volume contraction, a reduction in plasma renin activity and urinary PGE2, and a minimal elevation in plasma vasopressin. Blood pressure elevation appears to be attributable to inhibition of a vasodepressor system based on the renal medulla. Chemical medullectomy offers a valuable tool for investigating the role of this medullary vasodepressor system.

Animals↗
PubMed1987

Could N-nitrosamino phosphates be transport forms of activated N-nitrosamines?

The stability of N-nitroso-N-methylamine-N-ethyl phosphate (NMEP) and N-nitroso-N-ethylamine-N-ethyl phosphate (NEEP) was studied in rat serum and in rat liver homogenate and found to be sufficiently high for the phosphates to be transported in vivo. In liver homogenates, the cleavage was more efficient, and a higher phosphatase activity was found in liver microsomal and cytosolic fractions than in serum. The substances exert a distinct activity in the Salmonella typhimurium mutagenicity test.

Alkaline Phosphatase↗
PubMed1986

Effects of age on the pharmacokinetics of mexiletine.

Mexiletine (1-methyl-2-(2, 6-xylyloxy)ethylamine hydrochloride) is an antiarrhythmic drug eliminated primarily by hepatic metabolism. The influence of age on the plasma pharmacokinetics of mexiletine was assessed in seven young and ten elderly healthy subjects. Mexiletine (50 mg) was administered orally three times daily for 10 days. The use of low doses of mexiletine was possible owing to the development of a new fluorescence high performance liquid chromatography method with a limit of sensitivity lower than 20 ng/ml. No differences in the pharmacokinetic parameters of mexiletine related to age were observed. At steady-state plasma concentrations were 0.121 +/- 0.033 microgram-ml in the young volunteers, and 0.135 +/- 0.150 microgram/ml in the older subjects. The elimination t 1/2 was 11.4 +/- 1.78 h in the young subjects and 10.48 +/- 3.06 h in the elderly. The data provide no justification for lowering the recommended dose of mexiletine for older patients.

Administration, Oral↗
PubMed1987

An investigation of the relationship between the hepatotoxicity and the metabolism of N-alkylformamides.

The hepatotoxicity and metabolism of the following close analogs of the hepatotoxic antitumor agent N-methylformamide (NMF) were investigated in CBA/CA mice: N-ethylformamide (NEF), dimethylformamide (DMF), formamide and N-methylacetamide (NMA). Apart from NMF only NEF was potently hepatotoxic as measured by the elevation of plasma activities of the enzymes sorbitol dehydrogenase and alanine and aspartate aminotransferases 24 hr after drug administration. In freeze-dried urine samples of mice which had received NEF or NMF, but not in the case of DMF, formamide or NMA, thioesters were detected by thin-layer chromatography. Evidence based on high-pressure liquid chromatography analysis and 400 MHz 1H-NMR and mass spectrometry suggests that the thioester metabolite of NEF is S-(N-ethylcarbamoyl)-N-acetylcysteine. It has been shown previously that NMF is metabolized to S-(N-methylcarbamoyl)-N-acetylcysteine. NEF also underwent extensive metabolism to ethylamine; similarly NMF was biotransformed to methylamine. In contrast, the urine of mice which had received DMF contained only very small amounts of dimethylamine and methylamine could not be detected as a metabolite of NMA. Instead, the major metabolite of NMA was identified by 400 MHz 1H-NMR spectrometry as N-(hydroxymethyl)acetamide. DMF is known to undergo extensive metabolism to its N-hydroxymethyl derivative. The results suggest that two metabolic pathways of N-alkylformamides can be distinguished: Hydroxylation at the alpha-carbon of the N-alkyl group and oxidation of the formyl moiety. The former pathway presumably constitutes a detoxification route, and the latter may well be associated with hepatotoxicity, and affords a glutathione conjugate, excreted in the urine as a mercapturate.

Acetamides↗
PubMed1985

Agarose-polyacrolein microsphere beads: a new microcarrier culturing system.

A new microcarrier (MC) culturing system for anchorage-dependent cells is described. The system is based on polyacrylein microspheres encapsulated in agarose and derivatized by various amino ligands. In practice, any protein or ligand with primary amino groups may be covalently bound to the microspheres through their aldehyde groups. The ease with which the beads may be derivatized enables the preparation of MC with desired surface properties for growing a variety of cells. In this model system the beads were derivatized by 2-(diethylamino)ethylamine (DEAE), diaminohexane (DAH), poly-L-lysine (PL), gelatin and collagen. The derivatized beads supported the growth of primary cells, diploid cell strains and established cell lines for biological studies as well as for production of various cell products.

Acrolein↗
PubMed1985

In vitro metabolism of N-nitrodialkylamines.

The in vitro metabolism of N-nitramines was investigated in order to compare it with that of N-nitrosamines and to elucidate the mode of mutagenic action. N-Nitrodibutylamine (NO2DBA) and N-nitrodiethylamine (NO2DEA) were incubated with liver microsomes and hepatocytes prepared from rats treated with phenobarbital, and the products were analyzed by high-performance liquid chromatography and gas-liquid chromatography. The in vitro metabolic pattern of these nitramines was similar to that of the corresponding nitrosamines, except that N-nitro-N-alkylamines (produced via alpha-hydroxylation) were identified after incubation of the nitrodialkylamines. In the case of NO2DBA, besides N-nitro-N-butylamine, several nitramines produced by omega, omega-1, and omega-2 oxidations were identified as metabolites. NO2DBA and NO2DEA were mutagenic to Escherichia coli WP2 hcr- but not to Salmonella typhimurium TA1535. They were mutagenic only in the presence of hepatic microsomes, whereas their metabolites, N-nitro-N-butylamine and N-nitro-N-ethylamine, were direct mutagens. Thus, N-nitrodialkylamines are also metabolically activated to mutagens through alpha-hydroxylation.

Aniline Compounds↗
PubMedDate not supplied

[Disorders of oxidative deamination of biogenic amines in the myocardium in experimental atherosclerosis].

Statistically significant inhibition of oxidative deamination of several biogenic amines was found in mitochondrial fraction of heart muscle from rabbits and rats with experimental atherosclerosis and hypercholesterolemia, caused by various methods. Sensitivity of oxidative deamination of tryptamine to inhibitory effect of clorgyline (selective inhibitor of mitochondrial monoamine oxidases) was unaltered in rats with experimental hypercholesterolemia. The rate of oxidative deamination of beta-phenyl ethylamine, tryptamine, benzylamine as well as histamine and putrescine was inhibited after treatment of the mitochondrial fragments from healthy rabbit and rat heart muscles with preparations of oxidized linoleic and linolenic acids, concentration of which was increased in tissues under conditions of atherosclerosis.

Animals↗
PubMed1979

Potentiation by D-penicillamine and other sulfhydryl agents of the vascular response to histamine in the anaesthetized dog.

D-penicillamine (80 mg/kg) potentiates the fall in blood pressure produced by an i.v. injection of histamine in the anaesthetized dog but is inactive on the effects of acetylcholine and prostaglandin E1. Other sulfhydryl agents (alpha-thioglycerol, 2-mercaptoethanol, 2,3-dimercapto-l-propanol, DL-cysteine, glutathione, diethyldithiocarbamate) can similarly modify the effects of histamine on blood pressure but two metal complexing agents (CaNa2 EDTA and orthophenantroline) are inactive. After pretreatment with indomethacin (10 mg/kg) or cimetidine (0.5 mg/kg/min) D-penicillamine still increases the effect of histamine but not after pretreatment with pyrilamine maleate (1 mg/kg). Moreover D-penicillamine does not modify the blood pressure drop due to dimaprit but increases that to 2-(2-pyridyl) ethylamine. It is concluded that D-penicillamine and some other sulfhydryl agents can increase the blood pressure lowering effects of histamine at the level of vascular H1-receptors by a sensitizing mechanism which might involve the rupture of a disulfide bridge.

Anesthesia↗
PubMedDate not supplied

Inotropic effects of histamine in human myocardium: differentiation between positive and negative components.

Histamine is known to enhance the contractility of the human myocardium in vitro. We have observed that when the H2-receptor antagonist cimetidine (or ranitidine) blocks the positive inotropic effect of histamine in spontaneously beating pectinate muscles isolated from human right atrial appendage, a negative inotropic effect is unmasked. This decrease in contractility is independent of changes in rate, as it occurs in preparations paced at constant rate, is mimicked by the H1-receptor agonist 2-(2-thiazolyl)-ethylamine (ThEA) and is abolished by the H1-antagonist pyrilamine. Thus, the negative inotropic effect of histamine appears to be mediated by H1-receptors. Our data indicate that the inotropic response of the human myocardium to histamine consists of two opposing components: an increase in contraction, mediated by H2-receptors, and a decrease in contraction, mediated by H1-receptors. Given the widespread use of H2-blockers and the multitude of clinical conditions in which histamine is released, there may well be circumstances in which an H1-response predominates. This could result in a decrease in myocardial contractility.

Cimetidine↗
PubMed1980

Central effects of histamine and H1 and H2 receptors agonists and antagonists after intraventricular infusion in fowls.

In adult fowls (Gallus deomesticus) the effects of histamine H2 and H2 histamine receptors angonists and antagonists infused into the III cerebral ventricle were studied on behaviour, electrocortical activity and body temperature. Histamine produced biphasic effects, i.e. an initial period of electrocortical synchronization was followed by a longer-lasting behavioural stimulation, electrocortical desynchronization and shivering. Body temperature was increased in a dose-dependent manner. Dimaprit, an agonist at H2 receptors, produced behavioural and electrocortical sleep and decreased body temperature whereas, 2-(2-thiazolyl-)-ethyl-amine, an agonist at H1 receptors, behavioural stimulation, electrocortical desynchronization, vocalization and hyperthermia. Cimetidine, an antagonist at H2 receptors, produced intense behavioural stimulation and electrocortical desynchronization accompanied by vocalization, tachypnoea, occasional escape responses and stereotypies. Body temperature was increased. Mepyramine, an antagonist at H1 receptors, produced behavioural and electrocortical sleep and prevented behavioural excitation elicited by subsequent infusion of histamine and hyperthermia evoked by 2-(2-thiazolyl -ethylamine. Haloperidol, a neuroleptic drug, sharing with mepyramine membrane stabilizing properties, was unable to antagonize histamine-induced behavioural excitation. In conclusion, present experiments provide pharmacological evidence for the existence of H1 and H2 histamine receptors in avian brain and suggest an involvement of histamine H1 and H2 receptors in the control of arousal-sleep and thermoregulatory mechanisms.

Animals↗
PubMed1980

[Isolation and identification of some metabolites of bromazine from human urine (author's transl)].

In addition to the unchanged drug nine metabolites have been found in human urine after the administration of bromazine (2-(p-bromophenyl-phenylmethoxy)-1-N,N-dimethyl-ethylamine). Three compounds were extractable under alkaline conditions; they were identified as bromazine-N-oxide (II), N-monodesmethylbromazine (III) and N-didesmethylbromazine (IV). Two other substances were extractable under alkaline and acidic conditions, p-bromobenzhydrol (VI) and p-bromobenzophenone (VIII). Another metabolite--extractable at pH 7--was p-hydroxybenzophenone (IX). Treatment of precipitated conjugated compounds with beta-glucuronidase or hydrochloric acid resulted in the liberation of IV, VI and IX, all of which were also found as unconjugated compounds.

Biotransformation↗
PubMed1982

Histamine receptors in the myenteric plexus-longitudinal muscle of the guinea-pig ileum: H1- and H2-receptor-mediated potentiation of the contractile response to electrical stimulation.

The effect of histamine on the contractile response to low frequency-electrical field stimulation in the myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum was investigated. By blocking the direct increase in smooth muscle tone caused by histamine with low concentrations of pyrilamine (10(-9)--5 x 10(-8) M) a dose-dependent, histamine-induced potentiation of the twitch response to electrical stimulation was observed. Blocking the direct actions of histamine with concentrations of pyrilamine greater than 10(-7) M resulted in a biphasic histamine dose-response curve: lower histamine concentrations produced a dose-dependent decrease of the twitch response; higher concentrations produced a potentiation. The potentiating effect of histamine was inhibited by high concentrations of H2-receptor antagonists. Tiotidine (ICI 125, 211) had a pA2 of 5.25, 100 times greater than its pA2 in isolated guinea-pig atria. Blockade of the actions of the H2-receptor agonists dimaprit and tetrahydrozoline also required greater antagonist concentrations. The selective H1-receptor agonist, 2-(2-thiazolyl)-ethylamine, also enhanced the response to electrical stimulation. The potentiating effect of histamine could be blocked by hexamethonium (10(-7)--10(-5) M) but not by atropine. Atropine (10(-9)--10(-8) M) did prevent the decrease in the contraction amplitude induced by histamine in the presence of 10(-7) M pyrilamine. The purinergic antagonist theophylline, adrenergic antagonists or depletion of endogenous catecholamines were without effect. Tetrodotoxin (10(-6) M) inhibited the augmentation induced by histamine. Our results demonstrate that histamine potentiates the acetylcholine-mediated contractile response to electrical field stimulation of guniea-pig ileum via H1- and what may be an H2-receptor subtype.

Animals↗