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PubMed1978

Enhancement of 5-hydroxytryptamine-induced contraction of the guinea pig ileum by a new sulfur compound, tripropylsulfonium bromide.

In the presence of tripropylsulfonium bromide (TPS) (1 X 10(-4) g/ml), a new compound, the phasic contraction of the isolated guinea pig ileum to 5-hydroxytryptamine (5-HT) (5 X 10(-7) g/ml) was consistently enhanced ("TPS effect"). TPS alone increased moderatley the spontaneous movement of the ileum. When the contraction height was calculated as the percentage of that to 5-HT alone, such was observed in the "TPS effect" to be 167.1 +/- 3.6% (mean +/- S.E., n = 80). TPS did not enhance the contraction due to acetylcholine or histamine. The "TPS effect" remained unaffected in the presence of dibenzyline (1 X 10(-7) g/ml), was abolished by morphine(1 X 10(-6) g/ml), tetrodotoxin (2 X 10(-8) g/ml) adenosine (3 X 10(-6) g/ml) and atropine (1 X 10(-7) g/ml) and was not observed under anoxic conditions. Eserine (1 X 10(-8) g/ml) strengthened the "TPS effect" markedly. It is concluded that this effect may be the result of the potentiating effect of TPS on the action of 5-HT through the M receptors, possibly by the facilitation of the acetylcholine-liberation from the nervous tissue.

Acetylcholine↗
PubMed1963

The action of tyramine on the dog isolated atrium.

It has been confirmed that tyramine has positive inotropic and chronotropic actions on the dog isolated atrium. These responses were incompletely and reversibly inhibited by cocaine, but completely and irreversibly blocked by phenoxybenzamine. Blockade of the atrial beta-receptors by dichloroisoprenaline could be overcome by noradrenaline and by larger doses of tyramine. With the aortic strip of the reserpinized rabbit for assay, tyramine was shown to release a vasoactive material from the dog atrium whose receptors were blocked by dichloroisoprenaline. The use of an antihistamine and an anti-5-hydroxytryptamine agent (cyproheptadine) appeared to exclude the possibility that the effect was due to the release of histamine or 5-hydroxytryptamine from the atrium by tyramine. Further observations of the action of the vasoactive material on the guinea-pig ileum and on the rat fundal strip strongly suggested that the material was a catechol amine. It was concluded that under these conditions tyramine acts by liberating catechol amines from storage sites so that the amines are free to act at receptor sites. The behaviour of the atrium to tyramine in the presence of cocaine or of phenoxybenzamine suggests that the liberation of catechol amines by tyramine differs from the release due to adrenergic nerve stimulation. It is suggested that, after an infusion of tyramine, there is a much slower release of catechol amines than after stimulation of adrenergic nerves.

Amines↗
PubMed1990

Inhibition by adenosine 3':5'-monophosphate of eicosanoid and platelet-activating factor biosynthesis in the mouse PT-18 mast cell.

A mouse spleen-derived mast cell line (PT-18) was employed to examine the mechanisms of adenosine 3':5'-monophosphate (cAMP)-mediated inhibition of antigen-induced lipid mediator biosynthesis. Specifically, we tested the hypothesis that increasing cAMP in mast cells inhibits lipid mediator biosynthesis by a mechanism independent of effects on histamine release (degranulation) or changes in cytosolic calcium concentration. Forskolin inhibited antigen-induced prostaglandin D2 (PGD2), leukotriene C4 (LTC4), and leukotriene B4 (LTB4) production by 30-50%. In contrast, forskolin had no inhibitory effect on antigen-induced increases in cytosolic calcium concentration, as monitored by the calcium indicator fura-2, or histamine release from the cells. The combination of the phosphodiesterase inhibitor isobutylmethylxanthine with forskolin inhibited the antigen-induced production of PGD2 and LTC4 by 90-100% and histamine release by about 60%. These responses were accompanied by a virtual abolition of the antigen-induced increase in cytosolic calcium. To test further the hypothesis that increasing cAMP can lead to inhibition of lipid mediator biosynthesis in the absence of effects on cytosolic calcium, we employed the calcium ionophores A23187 and ionomycin. Forskolin alone or in combination with isobutylmethylxanthine had no effect on ionophore-induced increases in cytosolic calcium but effectively inhibited leukotriene biosynthesis. In addition, increasing cyclic AMP led to an inhibition of ionophore-induced production of platelet-activating factor and liberation of arachidonic acid. These data suggest that a relatively modest increase in cAMP-dependent protein kinase activity in mast cells leads to inhibition of the lipase-catalyzed cleavage of arachidonic acid from membrane phospholipids in the absence of measurable effects on either histamine release or changes in cytosolic calcium concentration. This effect results in a selective inhibition of the biosynthesis of lipid mediators including LTC4, LTB4, PGD2, and platelet-activating factor.

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Changes in nasal resistance and nasal geometry using pressure and acoustic rhinometry in a feline model of nasal congestion.

This is the first report describing the use and pharmacological characterization of nasal patency by both pressure rhinometry and acoustic rhinometry (AcR) in an experimental cat model of nasal congestion. In pressure rhinometry studies, aerosolized compound 48/80 (0.1-3.0%), a mast cell liberator, increased nasal airway resistance (NAR) 1.2 +/- 0.6, 5.8 +/- 0.5, 8.6 +/- 1.1 and 7.9 +/- 1.5 cmH2O.L/minute, respectively. Increases in NAR produced by compound 48/80 were associated with a 395% increase in histamine concentration found in the nasal lavage fluid. Pretreatment with the alpha-adrenoreceptor agonist, phenylpropanolamine (PPA; 0.1-3.0 mg/kg, i.v.), and the NO synthetase inhibitor, NG-nitro-L-arginine (L-NAME; 10 mg/kg, i.v.) attenuated the increases in NAR produced by compound 48/80. The histamine H1 antagonist chlorpheniramine (1.0 mg/kg, i.v.) and the H2 antagonist, ranitidine (1.0 mg/kg, i.v.) had no decongestant activity. Also without decongestant activity were the muscarinic antagonist atropine, the cyclooxygenase inhibitor indomethacin, and the 5-HT blocker methysergide. Aerosolized histamine (0.1-1.0%) also produced a dose dependent increase in NAR. In studies using acoustic rhinometry (AcR), intranasal application of compound 48/80 (0.1-1.0%) elicited pronounced decreases in nasal cavity volumes and minimum cross-sectional area (Amin). Pretreatment with PPA (3 mg/kg, i.v. or 10 mg/kg, p.o.) attenuated the decreases in nasal volume and Amin. The effects of topical intranasal histamine (0.1-1.0%) on nasal geometry were similar to compound 48/80. We conclude that the cat is a useful model for evaluating the pharmacological actions of potential nasal decongestants. Furthermore, we also conclude that AcR is a useful method for noninvasive assessment of nasal patency in a preclinical setting.

Acoustics↗
PubMed1994

Codeine-induced bronchoconstriction and putative bronchial opiate receptors in asthmatic subjects.

To determine whether a mu opiate agonist can constrict the human airways, the dose of codeine (C) or histamine (H) producing a 40% decrease (PD40) in specific airway conductance (SGAW) was measured in 17 asthmatic and 14 normal subjects. Then, the subjects were skin tested with C and H, and the effect of naloxone (N) and chlorpheniramine (CP) on PD40-C was assessed. In five asthmatic subjects responding to less than 5 mg (16.6 mumol) inhaled C, SGAW was also recorded after oral administration (30 mg) and pharyngeal spraying (5 mg) of C. PD40-C could be determined in 11 of the 17 asthmatics but in none of the normal subjects. This constrictor effect lasted less than 15 min, was unrelated to resting airway caliber, and required a relatively high bronchial sensitivity to H (PD40-H usually less than 0.2 mumol) and high doses of C (11.93 +/- 12.0 mumol). However, in C responders, PD40-C and PD40-H were unrelated. C-induced bronchoconstriction was blunted by N in a dose-dependent fashion and to a mild and inconsistent degree, by CP. Pharyngeal spraying or oral challenge with C failed to change SGAW. Skin sensitivity to H and C was similar in C-responders and non-responders. In conclusion, large doses of inhaled C constrict the airways of asthmatic subjects highly sensitive to H. This effect seems mediated through (mu?) opiate receptors located bronchially rather than centrally, pharyngeally or in the skin. In C-induced bronchoconstriction H liberation plays a contributory but minor role. Skin and bronchial sensitivity to C are unrelated.

Adolescent↗
PubMed1985

Studies on the causation of adverse reactions in microfilaraemic host following diethylcarbamazine therapy (Dipetalonema viteae in Mastomys natalensis).

The mechanism of the adverse reaction in microfilaraemic subjects following diethylcarbamazine (DEC) therapy has remained an enigma. To study the mechanisms involved Mastomys natalensis infected with Dipetalonema viteae have been used. Animals showing up to 50 mf/5 cmm of blood did not show any perceptible reactions when treated with the minimum effective dose of 350 mg/kg of DEC citrate, while those having more than 80 mf/5 cmm died, suggesting an intensity dependent severity of reactions. Infective larvae contained maximum amounts of biogenic amines followed by mf and adults in that order. 16 mg of histamine or 24 mg of 5-hydroxytryptamine caused death when injected into healthy animals, whereas sonicated mf (5 million) and adult somatic products (4 mg protein) did not, signifying that the biogenic amine contents of the parasites were less than the critical level to cause death. Adult somatic products did not produce any visible reactions when injected into animals with microfilariaemia, but sonicated mf (5 million) caused death. It is concluded that the adverse reactions seen after DEC treatment are due to the release of biogenic amines in an anaphylactic type of reaction subsequent to massive release of parasite antigen in a sensitised host, which is directly proportional to the intensity of microfilaraemia and that the adverse reactions are not due to liberation of endogenous biogenic amines from dead mf.

Animals↗
PubMed1990

Occurrence of phospholipase A2 and lysophospholipase in a gastric H,K-ATPase-containing membrane fraction, and the formation of lysophosphatidylcholine in stimulated pig parietal cells.

A membrane fraction containing H,K-ATPase (EC 3.6.1.36) was prepared from pig gastric mucosa and found to contain phospholipase A2 (EC 3.1.1.4) and lysophospholipase (EC 3.1.1.5) activities. Washing the membranes decreased their protein content by 25%. Recovery profiles of H,K-ATPase, phospholipase A2 and lysophospholipase were similar for membranes washed either with water or with 0.15 or 1.5 M KCl. Nearly identical distribution profiles were obtained for the three enzyme activities after centrifugation of washed vesicle membranes on a linear sucrose gradient. The phospholipase A2 activity was stimulated by calcium and increased further in the presence of calmodulin. The amount of cellular radioactively labelled lysophosphatidylcholine was doubled upon cholinergic stimulation of isolated parietal cells prelabelled with [3H]glycerol or 32Pi. The liberated lyso[32P]phosphatidylcholine had its acyl chain in the sn-1 position, which implies an activation of a phospholipase A2. These findings indicate that secretagogues which increase the cytosolic Ca2+ concentration, i.e. acetylcholine, histamine and gastrin, may activate a phospholipase A2 in the parietal cell.

Adenosine Triphosphatases↗
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↗
PubMed1996

Platelet activating factor: release from colonic mucosa in patients with ulcerative colitis and its effect on colonic secretion.

Inflammatory mediators have been implicated in the pathophysiology of ulcerative colitis. They may stimulate intestinal secretion and contribute to the production of diarrhoea. Platelet activating factor (PAF) may be responsible for a high proportion of this secretory response. Biopsy specimens from inflamed and quiescent mucosa of patients with ulcerative colitis and normal human colonic mucosa were cultured or co-cultured. The release of PAF, prostaglandin E2, and leukotriene D4 into the culture medium was measured and the ability of this culture medium, from inflamed and normal tissues, to influence secretion in rat colonic mucosa was assessed. PAF was liberated by inflamed tissue. Its release from quiescent but not normal tissue was stimulated by medium in which inflamed mucosal biopsy tissues had been cultured and by exogenous bradykinin and 5-hydroxytryptamine, but not by histamine. PAF stimulated eicosanoid production. The rise in short circuit current produced in vitro by inflamed tissue culture medium was inhibited by the PAF receptor antagonist (CV 6209) (46%) (32.4 (2.9) v 17.5 (1.19) muA.cm-2, p < 0.005) and further by combined cyclooxygenase and lipoxygenase inhibition (indomethacin plus ICI 207968) (58%) (32.4 (2.9) v 13.6 (1.9) muA.cm-2, p < 0.005). Mepacrine and hydrocortisone attenuated considerably the electrical response evoked by medium from inflamed mucosa to a similar extent (32.4 (2.9) v 6.3 (1.2) v 5.1 (0.9) muA.cm-2, p < 0.001). These data suggest that PAF accounted for 46% of the culture medium secretory effect. Thus, any attempt to block its release in patients with ulcerative colitis may have only a partial effect on their symptoms.

Adult↗
PubMed1994

Effect of compound 48/80 on the thalamic mast cells, serotonin level and corticosterone secretion in rats.

The effect of thalamic mast cells (MCs) degranulation and serotonin liberation by compound 48/80 on the hypothalamic-pituitary-adrenocortical (HPA) activity, measured indirectly through corticosterone secretion, was investigated in conscious rats. All drugs were given intracerebroventricularly (icv), the serotonin antagonists 15 min prior to compound 48/80. One hour after administration, compound 48/80 (1 and 5 micrograms) caused a significant increase in degranulated MC number in the thalamus, from control value of 20% up to 58%, and a considerable rise in the serum corticosterone level, but only minor diminution of the thalamic serotonin content. Pretreatment with methysergide, a serotonin receptor antagonist, only slightly dimished the compound 48/80-induced corticosterone response, while pretreatment with cyproheptadine, an antagonist of serotonin-histamine and cholinergic-receptors, significantly decreased the compound 48/80-elicited corticosterone response. These results show for the first time that thalamic mast cells contain a very small amount of serotonin, which may play only a minor role in increasing the HPA activity by compound 48/80. These findings also suggest that other mediators liberated from mast cells by compound 48/80 are responsible for the considerable increase in the HPA activity.

Animals↗
PubMed1999

Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic norepinephrine release?

We had shown that bradykinin (BK) generated by cardiac sympathetic nerve endings (i.e., synaptosomes) promotes exocytotic norepinephrine (NE) release in an autocrine mode. Because the synaptosomal preparation may include sensory C-fiber endings, which BK is known to stimulate, sensory nerves could contribute to the proadrenergic effects of BK in the heart. We report that BK is a potent releaser of NE from guinea pig heart synaptosomes (EC(50) approximately 20 nM), an effect mediated by B(2) receptors, and almost completely abolished by prior C-fiber destruction or blockade of calcitonin gene-related peptide and neurokinin-1 receptors. C-fiber destruction also greatly decreased BK-induced NE release from the intact heart, whereas tyramine-induced NE release was unaffected. Furthermore, C-fiber stimulation with capsaicin and activation of calcitonin gene-related peptide and neurokinin-1 receptors initiated NE release from cardiac synaptosomes, indicating that stimulation of sensory neurons in turn activates sympathetic nerve terminals. Thus, BK is likely to release NE in the heart in part by first liberating calcitonin gene-related peptide and Substance P from sensory nerve endings; these neuropeptides then stimulate specific receptors on sympathetic terminals. This action of BK is positively modulated by cyclooxygenase products, attenuated by activation of histamine H(3) receptors, and potentiated at a lower pH. The NE-releasing action of BK is likely to be enhanced in myocardial ischemia, when protons accumulate, C fibers become activated, and the production of prostaglandins and BK increases. Because NE is a major arrhythmogenic agent, the activation of this interneuronal signaling system between sensory and adrenergic neurons may contribute to ischemic dysrhythmias and sudden cardiac death.

Animals↗
PubMed1975

[Posterior hypothalamus action on gastric secretion (author's transl)].

Three groups of cats with surgically created total gastric pouches were employed in this experiment. They were divided as follows: in one group the innervation of the pouch was left intact; in another group the symphathetic innervation of the pouch was removed; and in the third group the pouch was completely denervated. It was seen that an infusion of histamine induced gastric secretion in all three groups. And when the secretion became constant it proved to be less acidic and more abundant in the sympathectomized group and also in the group that had suffered complete denervation. It was observed now that stimulating the posterior hypothalamus of the innervated group produced, in all of the cats, a decrease in the amount of acid secreted per unit of time. Consequently, it was seen that a symphathectomy did not eliminate the gastric effects produced when the posterior hypothalamus was stimulated. Specifically, stimulation of the posterior hypothalamus produced an increase in the amount of secretion rather than a decrease. The increase produced in these animals can be shown not to be due to irradiation of the anterior hypothalamus as the same response is obtained when a symphathectomy is combined with a vagotomy. It is, therefore, believed that it may be concluded that the Posterior hypothalamus does not produce its effect exclusively through its nervous pathways. It is believed its effect may possibly be mediated by an unknown substance liberated upon stimulation which then reaches the stomach by way of its blood supply.

Animals↗
PubMed1999

Human skin mast cells: in vitro and in vivo studies.

OBJECTIVE: This short review surveys our current knowledge on the development and heterogeneity of human mast cells, the distribution of mast cells within human skin and the properties of human skin mast cells both in vitro and in vivo. It also examines the effects of antihistamines in the wheal-and-flare response in the skin provoked by bradykinin. RESULTS: Mast cells derive from mononuclear precursor cells which undergo their final phase of their differentiation in the tissues. In normal skin, mast cells, which are primarily of the MC(TC) subtype, occur in the greatest density in the superficial dermal zone. Like all other mast cells, human skin mast cells bind IgE with high affinity to specific FcepsilonRI receptors, but unlike those from lung, tonsils, adenoids or intestine, they also express the C5a receptor (CD88) and activation sites for substance P, VIP, somatostatin, and compound 48/80. Both IgE-dependent stimulation by activating tyrosine kinases, and non-immunologic stimulation by activating G-proteins induce a characteristic compound exocytosis resulting in the liberation of the preformed mediators. Production of prostaglandin D2 and leukotriene C4, however, occurs only with IgE-dependent stimulation. In vivo, dermal microdialysis and scanning laser Doppler imaging have been used to assess the role of histamine in the wheal-and-flare response. These techniques were also used to show that low concentrations of intradermal bradykinin release negligible quantities of histamine. The results showed that although the resultant flare was inhibitable by antihistamines, low concentrations of bradykinin released negligible quantities of histamine. This suggests a potentially novel mechanism of action of antihistamines that requires further detailed investigation.

Humans↗
PubMed1991

Activation of phospholipase D in a rat mast (RBL 2H3) cell line. A possible unifying mechanism for IgE-dependent degranulation and arachidonic acid metabolite release.

RBL 2H3 cells (a model of mast cell function) were sensitized with anti-TNP IgE (0.5 micrograms/ml) and triggered to secrete both histamine and arachidonic acid (AA) metabolites by the addition of TNP-OVA (0 to 100 ng/ml). After a 3-min delay, the release of both groups of mediators proceeded in a parallel manner. In cells labeled with [14C]-AA, TNP-OVA produced a rapid increase in phosphatidic acid (PA), and subsequently, 1,2-diacylglycerol (DAG) and intracellular AA levels. Concurrently, there was a decrease in [14C]-AA labeled phosphatidylcholine. The release of labeled AA from phosphatidylcholine in response to TNP-OVA was paralleled by a liberation of free choline but no evidence of liberation of phosphorylcholine. When ethanol (0.05 to 2% v/v) was included in the culture medium, phosphatidylethanol was synthesized at the expense of PA and DAG, with a resulting inhibition of secretion. D,1 propranolol, an inhibitor of PA phosphohydrolase, inhibited the IgE-dependent production of [14C]-DAG, and [14C]-free fatty acid but not [14C]-PA. The IgE-dependent release of both histamine and AA metabolites was completely inhibited by pretreatment with propranolol. Taken together, the above results suggest that phospholipase D is activated upon cross-bridging of IgE receptors on the surface of RBL 2H3 cells and that this may be a pivotal step in the signal transduction cascade leading to the release of both presynthesized and de novo synthesized mediators.

Animals↗
PubMed2001

Enzyme-catalyzed prodrug approaches for the histamine H3-receptor agonist (R)-alpha-methylhistamine.

Five novel prodrug types of the potent and selective histamine H3-receptor agonist (R)-alpha-methylhistamine (1) were prepared and pharmacologically tested in vitro as well as in vivo. In particular, an amide of fatty acid, mono- and dicarbamates, an (acyloxy)alkylcarbamate, and a diphthalidyl derivative were synthesized, all of which require initial prodrug activation through an enzyme-catalyzed reaction in contrast to formerly developed azomethine prodrugs which are cleaved by chemical hydrolysis only. Further drug liberation may ensue spontaneously in a cascade to give 1. Since they have diverse stabilities the prodrugs were investigated for drug liberation in vitro under neutral, acidic, and basic conditions at different temperatures as well as with liver homogenates. In vivo investigation of prodrugs after oral administration to mice proved that the fatty amide 2, the Nalpha-methylcarbamate 4a, and the Nalpha-(1-(acetyloxy)ethylcarbamate) 5 showed moderate to high plasma levels of 1. Compound 5 displayed even more than 2.5 times the AUC for 1 than that of the reference azomethine prodrug BP2.94 in the periphery and also displayed a detectable drug level in the central nervous system. It was shown that prodrug approaches based on an initial enzyme-catalyzed liberation step are successfully applicable to different pro-moieties for improved bioavailability and prolonged half-live. These approaches may also be used for other aminergic compounds of this class to optimize pharmacokinetic behavior.

Animals↗
PubMed2004

Low-density lipoprotein inhibits receptor-mediated prostaglandin synthesis without affecting calcium and arachidonic acid mobilization in human endothelial cells.

Vascular serotonin 5-HT1 receptors have quiescent constrictor activity that is activated by other vasoactive agents such as histamine. Previously, we observed that the 5-HT1-selective agonist 5-carboxamidotryptamine (5-CT) potentiated histamine-stimulated arachidonic acid (AA) mobilization and prostaglandin production in human aortic endothelial cells (HAEC). In the present study, 5-CT was found to potentiate histamine-stimulated calcium mobilization but had no effect on intracellular calcium when added alone. Treatment of HAEC with human low-density lipoprotein (LDL) for 20 hours inhibited the histamine- plus 5-CT-stimulated production of prostaglandin F2alpha (PGF2alpha) and the prostacyclin metabolite 6-keto-PGF1alpha. However, the effects of histamine and histamine potentiation by 5-CT on intracellular Ca mobilization and AA release were resistant to LDL treatment. Conversely, the subsequent receptor-independent conversion of AA to prostaglandins was inhibited by LDL. These results demonstrate that histamine and serotonin receptor activity, measured as the stimulation of Ca and AA mobilization, is resistant to LDL exposure under mild oxidizing conditions, whereas the receptor-independent synthesis of prostaglandins is inhibited by LDL. The results also suggest that the LDL-stimulated mobilization of cellular AA is responsible for the LDL-mediated inhibition of prostaglandin synthesis. These findings suggest a mechanism by which LDL and/or atherosclerosis could promote the vascular liberation of AA that is not converted to endothelium-derived prostaglandins and is therefore available as substrate for the production of other eicosanoids.

6-Ketoprostaglandin F1 alpha↗