Antiarrhythmic properties of 3-(2-hydroxy-3 isopropylamino-propoxy)-3 phenyl-2 isoindolinone-1, (RS, SR) in the dog]

In the Dog, 3-(2-hydroxy-3 isopropylamino-proxy)-2-phenyl-1-isoindolinone (RS, SR) possesses an anti-arrhythmic activity similar to that of quinidine but at dose levels 2 to 6 times lower than in the case of the latter compound. Furthermore, in contrast to quinidine, at the dose levels where the antiarrhythmic activity is well observed, the compound is devoid of hypotensive activity and of depressive action on cardiac contractility. The first clinical studies of this compound have shown its usefulness in the treatment of ventricular and supraventricular arrhythmias.     

Behavior and catecholamine levels: comparative study of gregarious insects, solitary insects, and those treated with carbon dioxide in Locusta migratoria (Insecta, Orthoptera)]

The dopamine (DA) and noradrenaline (NA) was measured in Locusta migratoria for 3 groups of individuals showing differences in their motility: gregarious are very active, solitary and animals in chronic treatment by CO2 (1 mn/day) show a very low motility. NA is present in small amounts (0,120-0,250 microng/g) in the 3 groups without significant differences. On the contrary, the quantity of DA is 5 times greater in gregarious than in the 2 other groups (1,78 and 0,31-0,39 microng/g). Thus it is suggested that DA is related to motility and must play its own role of a neurochormone, distinct from that of a metabolic intermediary between DOPA and NA. The question of a relationship between the metabolism of catecholamine and melanization is open.     

Nervous control of smooth muscle by transmitters,cotransmitters and modulators

Conclusion The part played by peripheral neuroeffector control mechanisms has been underestimated. These are additional to central and ganglionic control mechanisms and are much more elaborate than originally thought. While the classical view is that the autonomic nervous system consists largely of antagonistic cholinergic and adrenergic nerves, about sixteen putative neurotransmitters have been proposed in autonomic nerves in the past few years, including various monoamines, polypeptides, purines and amino acids. Modulatory transmitter mechanisms have also been recognized, including prejunctional inhibition or enhancement of transmitter release, postjunctional modulation of transmitter action, and the secondary involvement of locally synthesized hormones and prostaglandins. The existence of more than one transmitter substance in some nerves is now widely recognized, and suggestions have been made about the ways that this can lead to differential peripheral control mechanisms at nerve terminals themselves. The cotransmitters always have synergistic actions on postjunctional effector cells, but two different operating mechanisms are postulated. 1) If both substances are stored in the same vesicles (for example, ACh or NA with ATP), release is closely parallel at all impulse frequencies. Upon release, the cotransmitter, in addition to having a direct action on postjunctional cells, may facilitate the action of the other transmitter and/or act as an inhibitor of its release. Differential actions at different impulse frequencies are achieved post-junctionally by ATP and NA acting via EJP-spike and spike-independent mechanisms, respectively. 2) If the two substances are stored in separate vesicle types (for example ACh or NA with some peptides), then differential release is possible at different impulse frequencies; the peptides released at higher frequencies modulate the role of the classical transmitter, by both prejunctional enhancement of its release and post-junctional facilitation of its action.     

Influences of temperature change on the relaxation and amplitude inhibition by noradrenaline in the rabbit jejunum.

In the rabbit jejunum, the elevation of temperature within the range of 25-37 degrees C diminished the sensitivity to noradrenaline (NA) for both the relaxation and amplitude inhibition. The relaxation by NA was mainly mediated via adrenergic beta-receptors at 25, 30 or 37 degrees C. The amplitude inhibition was mediated via alpha-receptors at 37 degrees C, and both alpha- and beta-receptors at 30 or 25 degrees C.     

The effect of the phytoalexins, lubimin, (-)-maackiain, pinosylvin, and the related compounds dehydroloroglossol and hordatine M on human lymphoblastoid cell lines

We have tested the effect of the phytoalexins lubimin, (-)-maackiain and pinosylvin and the related compounds dehydroloroglossol and hordatine M on the growth of the human lymphoblastoid cell lines Molt and Raji. (-)-maackiain, pinosylvin and dehydroloroglossol showed significant growth inhibitory action on the cells. Suppression of [3H] thymidine and [3H] leucine uptake was tested and noted in pinosylvin and dehydroloroglossol. The phytoalexins and related compounds are widespread in plants and provide a potential source of antineoplastic substances.     

Somatostatin and 3-oxy-methyl-D-glucose (3-OMG) uptake in isolated chicken intestinal epithelial cells

The direct effect of somatostatin on the absorption of 3-oxymethylglucose in epithelial cells isolated from the small intestine of chicken was studied. The presence of somatostatin in the incubation medium at concentrations of 3.5 X 10(-8) M and 7 X 10(-8) M produced significant dose-dependent increases in the accumulation of sugar in the enterocytes. This effect might be due to an increase in the cell membrane permeability caused by hormone action.     

Protective effect of N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine (PF9601N) on mitochondrial permeability transition

PF9601N, N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine, an monoamine oxidase (MAO) B inhibitor, has shown neuroprotective properties against dopaminergic toxins. To elucidate the mechanisms involved in this protection, the effect of PF9601N on mitochondria was assessed. PF9601N prevents mitochondrial swelling, drop in the electrical potential and oxidation of sulfhydryl groups, glutathione and pyridine nucleotides induced by Ca²⁺. These observations demonstrate the protective effect of PF9601N on the induction of mitochondrial permeability transition. This protection is due to the interaction of the secondary protonated amino group in the molecule with pore-forming structures and to its antioxidant property, rather than to inhibition of MAO B activity. PF9601N also prevents the release of cytochrome c from mitochondria, suggesting its potential inhibitory effect on mitochondria-mediated apoptosis. The low IC⁵⁰ value for this inhibition, in comparison with deprenyl, make it a more efficient compound than propargylamines and other amines in protecting the bioenergetic functions of mitochondria. Received 9 March 2006; received after revision 10 April 2006; accepted 21 April 2006     

Modulator role of prostaglandins (Pg) in adrenergic neurotransmission in carotid sinus]

In Rabbit carotid sinus, the presence of sympathetic nerve endings capable of releasing noradrenaline has been demonstrated. The release of NA in response to sympathetic nerve stimulation was decreased by PgE2 and a precursor of Pg (arachidonic acid) but was strongly increased by an inhibitor of Pg biosynthesis (indomethacin). The experiments carried out demonstrated that freshly synthesized Pg acts in the same way as exogenous Pg and suggested that Pg could have a regulating effect on adrenergic neurotransmission in carotid sinus. The role of this regulating mechanism in the physiology of carotid sinus has been discussed.     

Effect of large mesencephalic-diencephalic lesions on the noradrenalin,dopamine and 5-hydroxytryptamine neurons of the central nervous system

Zusammenfassung Nach Ausführung von grossen symmetrischen mesencephalisch-dicncephalischen Läsionen in Ratten konnte mit Hilfe von biochemischen und histochemischen Methoden eindeutig festgestellt werden, dass die Dopamin (DA), Noradrenalin (NA) und 5-Hydroxytryptamin (5-HT) enthaltenden Nerventerminalen im Prosencephalon zu grossen aufsteigenden DA, NA und 5-HT Neuronsystemen gehören. Die Zellkörper dieser Neuronensysteme sind im Gehirnstamm lokalisiert. Dies deutet darauf hin, dass ein einzelnes NA Neuron Gebiete innervieren kann, die weit auseinander liegen, zum Beispiel auf der einen Seite im Cerebellum, auf der anderen im Prosencephalon.     

Differential inhibitory effects of noradrenaline upon insulin secretion by the isolated perfused pancreas of the rat

Summary Responses of basal and glucose-induced secretion phases of the isolated perfused pancreas of the rat to graded doses of noradrenaline (NA) are described. Maximal inhibition of basal secretion was achieved at [NA]=40, ng/100 ml; at [NA]=80 ng/100 ml, the 1st phase of glucose induced secretion was abolished; at [NA]=100 ng/100 ml the 2nd phase was abolished. At [NA]40 ng/100 ml basal secretion was less sensitive to NA inhibition than glucose induced output.Acknowledgment. The authors are most grateful to Mr J. Stevenson for advice upon and assistance with statistical analysis of data.     

Differential interaction of 2,4,6-trinitrobenzenesulfonic (TNBS) and 2,4-dinitrobenzenesulfonic (DNBS) acids on mouse lymphocytes]

Modifications of lymphoid cells with dinitro-2,4 phenylsulfonic acid (DNBS) or trinitro-2,4,6 phenylsulfonic acid (TNBS) have been studied. TNBS action always produces an electrophoretic mobility increase in relation with the amount of amino-groups, according to the cell type. DNBS action produces an electrophoretic mobility increase for B cells of spleen and a decrease for T cells of spleen and thymic cells. The hydrophobic fluorescent probe 1-anilino-8-naphthalene sulphonate used to study conformational changes of cells revealed a slight fluorescence decrease for TNP-modified cells and an important fluorescence increase for DNP-modified cells.     

Stress-induced increase in noradrenaline release in the rat hypothalamus assessed by intracranial microdialysis

Summary The hypothalamic microdialysis of conscious rats was used to investigate the effects of immobilization stress (20 min) on extracellular noradrenaline(NA) levels. The stress significantly increased NA levels relative to basal efflux by 106% and this elevation continued for 40 min after release from stress.     

Stress-induced increase in noradrenaline release in the rat hypothalamus assessed by intracranial microdialysis

The hypothalamic microdialysis of conscious rats was used to investigate the effects of immobilization stress (20 min) on extracellular noradrenaline (NA) levels. The stress significantly increased NA levels relative to basal efflux by 106% and this elevation continued for 40 min after release from stress.     

Long-term depressor effects of catecholamine neuronal grafts in the third ventricle of the brain in normotensive rats

Summary Neuronal tissue containing A-6 group noradrenalin (NA) neurons of the locus ceruleus, or A-10 group dopamine (DA) neurons of the substantia nigra, was grafted into the third ventricle at the level of the preoptic-anterior hypothalamic region, in normotensive male rats. A significant and long-lasting depressor effect was shown in rats with either graft. In rats with an NA neuron-rich graft, plasma concentrations of arginine-vasopressin (AVP), plasma renin activity (PRA), and corticosterone (CS) decreased significantly, whereas in rats with a DA neuron-rich graft, AVP and PRA concentrations also decreased significantly but CS showed no significant change. Neither NA nor adrenalin in plasma changed significantly in rats with either graft.     

Long-term depressor effects of catecholamine neuronal grafts in the third ventricle of the brain in normotensive rats

Neuronal tissue containing A-6 group noradrenalin (NA) neurons of the locus ceruleus, or A-10 group dopamine (DA) neurons of the substantia nigra, was grafted into the third ventricle at the level of the preoptic-anterior hypothalamic region, in normotensive male rats. A significant and long-lasting depressor effect was shown in rats with either graft. In rats with an NA neuron-rich graft, plasma concentrations of arginine-vasopressin (AVP), plasma renin activity (PRA), and corticosterone (CS) decreased significantly, whereas in rats with a DA neuron-rich graft, AVP and PRA concentrations also decreased significantly but CS showed no significant change. Neither NA nor adrenalin in plasma changed significantly in rats with either graft.     

Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes

The present study examined the effect of GLP-1(1-37) on chemokine-induced CD4-positive lymphocyte migration as an early and critical step in atherogenesis. Pretreatment with GLP-1(1-37) reduced the SDF-induced migration of isolated human CD4-positive lymphocytes in a concentration-dependent manner. Similar effects were seen when RANTES was used as a chemokine. GLP-1(1-37)’s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream, GLP-1(1-37) inhibited SDF-induced phosphorylation of MLC and cofilin and limited f-actin formation as well as ICAM3 translocation. Furthermore, exendin-4 inhibited SDF-induced migration of CD4-positive lymphocytes similarly to GLP-1(1-37), and transfection of these cells with GLP-1 receptor siRNA abolished GLP-1(1-37)’s action on chemokine-induced ICAM3 translocation, suggesting an effect mediated via the GLP-1 receptor. Thus, GLP-1(1-37) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase pathway and via the GLP-1 receptor. This effect provides a potential novel mechanism for how GLP-1(1-37) may modulate vascular disease.     

Changes in the distensibility of the cat aortic arch induced by noradrenaline

Summary In the isolated preparation of the aortic arch of the cat, noradrenaline (NA) reduced at low pre-loads, and increased at high pre-loads, the arterial wall distensibility. For each dose of NA, the changes were directly related to the pressure level in the system.     

Thermogenic response as the function of extravascular influx of infused noradrenaline

Summary The dynamic and static phases of the thermogenic response to i.v. infused noradrenaline (NA) do not reflect the arterial concentration of NA; according to the equation presented here they are a function of the influx rate.     

Inhibitors of the acrosomal proteinase acrosin: Human urinary trypsin inhibitor (UTI) and 4-(2-carboxyethyl) phenyl trans 4-aminomethylcyclohexanecarboxylate hydrochloride (DV-1006)

Summary Human urinary trypsin inhibitor (UTI) and (4-(2-carboxyethyl) phenyl trans 4-aminoethylcyclohexanecarboxylate hydrochloride (DV-1006) competitively inhibited the human acrosomal proteinase acrosin; Ki values were 1.2×10^–8M and 9.4×10^–7 M, respectively.