Further studies on the properties of bile acids. I. Bile acid-induced changes of the action of drugs acting on the autonomic nervous system on the heart and blood vessels

The action of certain drugs on the autonomic system was studied under the influence of bile acids: 3,12-dihydroxycholanic acid (deoxycholic), 3,7,12-trihydroxycholanic acid (cholic), and 3,7,12-triketocholanic acid (dehydrocholic). The experiments were carried out on rat heart in vivo and on isolated rat vessel preparation. It was shown that bile acids reduced the stimulating effect of isoprenaline on rat heart and the relaxing effect on the blood vessels. An inversion of the effects of adrenaline and noradrenaline on the rat heart was observed, and an enhancement of the vasoconstrictor effect of these substances. Under the conditions of this experiment an inversion was noted of the action of acetylcholine on the heart and blood vessels.     

Mechanism of action of antipruritic drugs.

Astemizole and terfenadine, two potent non-sedative H1 antihistamines, had no effect on itch measured objectively as nocturnal scratching and subjectively on a 10 cm line. Trimeprazine, however, a more sedative but less potent H1 antihistamine, was antipruritic, as was nitrazepam, a sedative benzodiazepine. We concluded (a) that antipruritic drugs act centrally by a property related to sedation; (b) H1 receptor antagonists have a peripheral antipruritic action only when itch is due to histamine release, as in the wealing disorders. Thus the new nonsedative H1 antihistamines have no place in the treatment of itch from other causes.     

Ricin does not act as an endonuclease on L cell polysomar RNA.

The ability of ricin to act as an endonuclease was examined using labelled polysomes isolated from mouse L cells grown in [³²P] orthophosphate. No change was detected in the electrophoretic mobility of any ribosomal RNA species whether L cells were first treated with ricin or the isolated polysomes were treated with ricin. No trichloroacetic acid soluble counts over control levels were released by ricin treatment of isolated polysomes and no changes were observed in sucrose density gradient polysome profile with ricin treatment. The action of ricin on polysomes which results in inhibition of translation does not appear to involve endonuclease activity.     

An inhibitory segment of the catalytic subunit of phosphorylase kinase does not act as a pseudosubstrate.

The C terminus of the catalytic gamma subunit of phosphorylase kinase contains two autoinhibitory calmodulin binding domains designated PhK13 and PhK5. These peptides inhibit truncated gamma(1-300). Previous data show that PhK13 (residues 302-326) is a competitive inhibitor with respect to phosphorylase b, with a K(i) of 1.8 microm. This result suggests that PhK13 may bind to the active site of truncated gamma(1-300). Variants of PhK13 were prepared to localize the determinants for interaction with the catalytic fragment gamma(1-300). PhK13-1, containing residues 302-312, was found to be a competitive inhibitor with respect to phosphorylase b with a K(i) of 6.0 microm. PhK13 has been proposed to function as a pseudosubstrate inhibitor with Cys-308 occupying the site that normally accommodates the phosphorylatable serine in phosphorylase b. A PhK13-1 variant, C308S, was synthesized. Kinetic characterization of this peptide reveals that it does not serve as a substrate but is a competitive inhibitor. Additional variants were designed based on previous knowledge of phosphorylase kinase substrate determinants. Variants were analyzed as substrates and as inhibitors for truncated gamma(1-300). Although PhK13-1 does not appear to function as a pseudosubstrate, several specificity determinants employed in the recognition of phosphorylase b as substrate are utilized in the recognition of PhK13-1 as an inhibitor.     

Antiarrhythmic drugs and the modulation of autonomic control of heart rate in rabbits

A model of the components of autonomic control of heart rate was developed and used for the evaluation of quantitative contribution of sympathetic and vagal tone to cardiac function. In conscious rabbits, sequential inhibition of muscarinic and beta receptors was produced and the relative contributions of vagal and sympathetic tone were characterized. Based on the model, the magnitude of presynaptic interaction between the vagal and sympathetic nerve endings was evaluated. From data in the literature, similar analysis of the control of heart rate was performed for the rat, dog, and human subject and compared with that of the rabbit. The results show that the resting rabbit heart is under less vagal tone than sympathetic tone as compared with other species. The effects of acute administration of amiodarone on the sympathetic and parasympathetic control of heart rate as well as intrinsic heart rate were investigated. Amiodarone decreased the heart rate, which resulted from a direct effect on the sinoatrial (SA) node. In addition, it attenuated the vagal as well as the sympathetic effects on the SA node. The effect on vagal component was greater. Further, the effects of other antiarrhythmic drugs on the electrocardiographic PP and PR intervals were studied. The usefulness of this model for the analysis of the effects of antiarrhythmic drugs is presented.     

Fat facets does a Highwire act at the synapse.

Neuromuscular synapses are highly dynamic structures that respond to both intercellular and intracellular cues to manipulate synaptic form. A variety of post-translational modifications of synaptic proteins are used to regulate synaptic plasticity. A recent report by DiAntonio et al. shows that two ubiquitin pathway proteins, Highwire and Fat facets, may be mutually antagonistic regulators of presynaptic growth at the Drosophila neuromuscular junction. This work adds support to the emerging idea that ubiquitin, a polypeptide that targets proteins for proteasomal degradation, regulates synaptic development.     

The phosphatidylinositide-Ca2+ hypothesis does not apply to the steroidogenic action of corticotropin.

The hypothesis that ACTH (corticotropin) stimulates steroidogenesis by a mechanism that involves breakdown of polyphosphoinositides and increase in intracellular Ca2+ (called here the 'phosphatidylinositide-Ca2+ mechanism') was tested in Y-1 adrenal-tumour cells and in bovine fasciculata cells, by using incorporation of 32P and myo-[3H]inositol to study phospholipid metabolism, and quin-2 and fura 2 to measure intracellular Ca2+. As a positive control, we repeated experiments showing that angiotensin II stimulates glomerulosa cells by way of the phosphatidylinositide-Ca2+ mechanism, by using the same methods. With Y-1 and fasciculata cells, no change was observed in the incorporation of either of the labelled precursors into any phosphatidylinositide or into any of three major phosphoinositols, i.e. inositol phosphate, bisphosphate and trisphosphate. Moreover, no change in mass of any of these compounds was seen. No change was observed in the concentration of intracellular Ca2+ in Y-1 or fasciculata cells on addition of ACTH, by using either quin-2 or fura 2. By contrast, decreased incorporation of 32P into phosphatidylinositol bisphosphate and an increase in intracellular Ca2+ were seen when glomerulosa cells were treated with angiotensin II. It is concluded that the phosphatidylinositide-Ca2+ mechanism is not used by Y-1 adrenal or bovine fasciculata cells in the steroidogenic response to ACTH unless the mechanism is radically different from that seen with all other hormones so far tested in which this mechanism occurs.     

Pentoxifylline does not act via adenosine receptors in the inhibition of the superoxide anion production of human polymorphonuclear leukocytes.

The inhibitory effect of adenosine (ADO) and pentoxifylline (POF) was studied alone and in combination on the N-formyl-methionyl-leucyl-phenylalanine (FMLP) stimulated superoxide anion production of human polymorphonuclear leukocytes (PMNL). The pharmacological analysis of the results of these experiments demonstrated greater than additive and independent interaction of the drugs, representing potentiation. These results reflect differences between the sites of action of ADO and POF. Accordingly, the ADO receptor antagonist 8-phenyltheophylline only diminished the inhibition mediated by ADO, but totally failed to affect POF. Therefore, we hypothesize that POF acts as a phosphodiesterase inhibitor, potentiating the increase in cyclic AMP induced by ADO due to the stimulation of the adenylate-cyclase of human PMNL.     

Inert dust insecticides: Part I. Mechanism of action

The mode of action of inert dust insecticides on the grain weevil ( Calandra granaria L.) has been investigated by determination of mortality-time curves and by a detailed study of the influence of dusts on the water relations of the insects. It has been found that dusts do not depend for their action on any chemical reactivity, some highly inert substances such as diamond and carborundum being very effective. A physical process is therefore indicated.
Dusts do not penetrate into the respiratory system, and although large amounts are ingested these seem to have little harmful effect.
It has been demonstrated that effective dusts increase the rate of evaporation of water from insects to the air, and that the relative killing powers of different dusts run parallel with their capacities for promoting evaporation. The results are in harmony with the view (proposed by earlier workers) that inert dusts kill insects by inducing death by desiccation.     

Ryanodine does not produce negative chronotropic effect on action potential generation in heart pacemaker cells of young frogs Rana temporaria

The goal of the present work consisted in studying role of Ca²⁺ released via ryanodine-sensitive receptors of the sarcoplasmic reticulum in modulation of frequency of action potential (AP) generation of cells of the pacemaker type of the young and adult frog heart. Ryanodine (3 μM) decreased the AP generation frequency in adult frogs by 43%, while produced no effect in young animals. Duration of the diastolic depolarization decreased more than twice as compared with control. Ryanodine (20 μM) inhibited completely the AP generation spontaneous activity in adult frogs, whereas in young animals the negative chronotropic effect was observed, on average, by 14%. The rate of diastolic depolarization did not change. Based on analysis of our obtained data and the literature data, we have concluded that in young frogs there takes place the spatial-temporal uncoupling of the sarcoplasmic reticulum and the sarcolemmal membrane. Original Russian Text ? V. F. Golovko, 2006, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2006, Vol. 42, No. 4, pp. 335–339.     

Endogenous enkephalin does not contribute to the cerebral anti-hyperalgesic action of gabapentin

The aim of this study was to investigate the role of endogenous enkephalin in the cerebral antihyperalgesic action of gabapentin. Neuropathic pain models and antihyperalgesic effect of gabapentin were confirmed by the presentation and changes of mechanical allodynia and thermal hyperalgesia of operated mouse hind paws. The results suggested that endogenous enkephalin may not be involved in the antihyperalgesic effect of gabapentin.