Avermectin and avermectin derivatives are antagonists at the 4-aminobutyric acid (GABA) receptor on the somatic muscle cells of Ascaris; is this the site of anthelmintic action?

Parasitology ◽  
1990 ◽  
Vol 101 (2) ◽  
pp. 265-271 ◽  
Author(s):  
L. Dye-Holden ◽  
R. J. Walker
Keyword(s):  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Parasitic Nematode ◽  
Anthelmintic Activity ◽  
Muscle Cells ◽  
Aminobutyric Acid ◽  
Electrophysiological Recording ◽  
Receptor Antagonists ◽  
Somatic Muscle

The mechanism underlying the ability of the anthelmintic avermectin to paralyse the nematode Ascaris is not yet fully understood. Using conventional two-electrode electrophysiological recording techniques we have demonstrated that micromolar concentrations of ivermectin block the inhibitory GABA response on the muscle cells of the parasitic nematode Ascaris. The ability of a number of avermectin derivatives to act as receptor antagonists for the Ascaris muscle GABA receptor has been determined. This provides useful information to compare with the in vivo anthelmintic potency of these compounds. Abamectin, the most potent anthelmintic, was the most potent compound at inhibiting the GABA response whilst octahydroavermectin, a compound which lacks anthelmintic activity, did not block the GABA receptor. This is consistent with the notion that the GABA receptor antagonist properties of the avermectins could contribute to their anthelmintic action.

An ion-sensitive microelectrode study on the effect of a high concentration of ivermectin on chloride balance in the somatic muscle bag cells of Ascaris suum

Parasitology ◽  
1993 ◽  
Vol 106 (4) ◽  
pp. 421-427 ◽  
Author(s):  
H. R. Parri ◽  
M. B. A. Djamgoz ◽  
L. Holden-Dye ◽  
R. J. Walker
Keyword(s):  
Receptor Antagonist ◽  
Chloride Channel ◽  
Gaba Receptor ◽  
Parasitic Nematode ◽  
Ascaris Suum ◽  
Muscle Cells ◽  
High Concentration ◽  
Somatic Muscle ◽  
Ion Sensitive Microelectrodes ◽  
Bag Cells

SUMMARYIvermectin has been shown to increase chloride conductances of invertebrate cells. On the muscle cells of the parasitic nematode Ascaris, ivermectin acts as both a GABA receptor antagonist and a chloride channel opener. In this study, ion-sensitive microelectrodes were used to investigate the effect of ivermectin on intracellular C1− concentration of the somatic muscle bag cells of Ascaris suum. Incubation of muscle cells with ivermectin (10 μM in 1% dimethyl sulphoxide vehicle for 60 min) increased intracellular C1− by 2·9 mM or 15% compared to controls (P > 0·01, n = 6).

Novel azole derivatives are antagonists at the inhibitory GABA receptor on the somatic muscle cells of the parasitic nematodeAscaris suum

Parasitology ◽  
1996 ◽  
Vol 112 (2) ◽  
pp. 253-259 ◽  
Author(s):  
Z. Bascal ◽  
L. Holden-Dye ◽  
R. J. Willis ◽  
S. W. G. Smith ◽  
R. J. Walker
Keyword(s):  
Gaba Receptors ◽  
Gaba Receptor ◽  
Muscle Relaxation ◽  
Outward Current ◽  
Muscle Cells ◽  
Electrophysiological Recording ◽  
Mammalian Host ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Somatic Muscle

SummaryThe somatic muscle cells of the parasitic nematodeAscaris suumpossess GABA receptors that gate chloride conductances in a similar fashion to the mammalian GABAA receptor subtype. These receptors mediate muscle relaxation and are the site of action of the anthelmintic piperazine. The properties of this receptor differ from the properties of the GABA-gated chloride receptors in the mammalian host, in particular they are not as sensitive to mammalian GABA receptor antagonists such as bicuculline and picrotoxin. Using two-electrode intracellular electrophysiological recording techniques fromAscarismuscle cells, we have tested the potency of a series of azole derivatives for their ability to block the chloride-dependent GABA response. The lead compound, SN606078, 2-(2,6-dichloro-4-trifluromethylphenyl)-4-(4,5-dicyano-lH-imidazol-2-yl)-2H-l,2,3-triazoIe, and 4 structurally related compounds reversibly blocked the conductance increase elicited by 30 μM GABA with IC50s of less than 10 μM. SN606078 (10 μM) decreased the slope of the dose-response curve for GABA, suggesting a non-competitive mechanism of action. In two-electrode voltage clamp experiments, 10μM SN606078 blocked the outward current elicited by 20 μM GABA in a voltage-dependent manner with 72 ± 2% inhibition at −20 mV and 49±6% inhibition at −40 mV. These observations indicate that SN606078 may act as an open-channel blocker of the GABA-gated chloride channel inA. suum.

Antagonism of the Antinocifensive Action of Halothane by Intrathecal Administration of GABA-A Receptor Antagonists

1996 ◽  
Vol 84 (5) ◽  
pp. 1205-1214 ◽  
Author(s):  
Peggy Mason ◽  
Casey A. Owens ◽  
Donna L. Hammond
Keyword(s):  
Spinal Cord ◽  
Receptor Antagonist ◽  
Gabaa Receptor ◽  
Glycine Receptor ◽  
Intrathecal Administration ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Receptor Antagonists ◽  
Response Latencies ◽  
Halothane Concentration

Background The hind brain and the spinal cord, regions that contain high concentrations of gamma-aminobutyric acid (GABA) and GABA receptors, have been implicated as sites of action of inhalational anesthetics. Previous studies have established that general anesthetics potentiate the effects of gamma-aminobutyric acid at the GABAA receptor. It was therefore hypothesized that the suppression of nocifensive movements during anesthesia is due to an enhancement of GABAA receptor-mediated transmission within the spinal cord. Methods Rats in which an intrathecal catheter had been implanted 1 week earlier were anesthetized with halothane. Core temperature was maintained at a steady level. After MAC determination, the concentration of halothane was adjusted to that at which the rats last moved in response to tail clamping. Saline, a GABAA, a GABAB, or glycine receptor antagonist was then injected intrathecally. The latency to move in response to application of the tail clamp was redetermined 5 min later, after which the halothane concentration was increased by 0.2%. Response latencies to application of the noxious stimulus were measured at 7-min intervals during the subsequent 35 min. To determine whether these antagonists altered baseline response latencies by themselves, another experiment was conducted in which the concentration of halothane was not increased after intrathecal administration of GABAA receptor antagonists. Results Intrathecal administration of the GABAA receptor antagonists bicuculline (0.3 micrograms) or picrotoxin (0.3, 1.0 micrograms) antagonized the suppression of nocifensive movement produced by the small increase in halothane concentration. In contrast, the antinocifensive effect of the increase in halothane concentration was not attenuated by the GABAB receptor antagonist CGP 35348 or the glycine receptor antagonist strychnine. By themselves, the GABAA receptor antagonists did not alter response latency in rats anesthetized with sub-MAC concentrations of halothane. Conclusions Intrathecal administration of bicuculline or picrotoxin, at doses that do not change the latency to pinch-evoked movement when administered alone, antagonized the suppression of noxious-evoked movement produced by halothane concentrations equal to or greater than MAC. These results suggest that enhancement of GABAA receptor-mediated transmission within the spinal cord contributes to halothane's ability to suppress nocifensive movements.

Differential inflammatory modulation of canine ileal longitudinal and circular muscle cells

1999 ◽  
Vol 277 (2) ◽  
pp. G341-G350 ◽  
Author(s):  
Xuan-Zheng Shi ◽  
Sushil K. Sarna
Keyword(s):  
Receptor Antagonist ◽  
Muscarinic Receptor ◽  
Longitudinal Muscle ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Muscle Contractions ◽  
Receptor Subtypes ◽  
Relative Role

The aim of this study was to identify the subtypes of muscarinic receptors that mediate in vivo and in vitro canine ileal longitudinal muscle contractions and whether their role is modulated by inflammation. Previous studies have reported that circular muscle contractions are suppressed in ileal inflammation induced by mucosal exposure to ethanol and acetic acid. We found that inflammation had no significant effect on in vivo and in vitro spontaneous or muscarinic receptor-mediated contractions of the longitudinal muscle. The longitudinal muscle contractions were mediated primarily by the M3 receptor subtype. However, the IC50 of the M2 receptor antagonist methoctramine was only 10 times greater than that of the M3 receptor antagonist 4-DAMP in the longitudinal muscle, whereas it was 224 times greater in the circular muscle. M2receptor-coupled decrease of intracellular cAMP occurred in the longitudinal but not in the circular muscle from the normal ileum. Inflammation did not alter this coupling in the longitudinal muscle but established it in the circular muscle. In conclusion, M2 receptors may play a greater role in the mediation of longitudinal muscle contractions than circular muscle contractions. Inflammation does not alter the contractility or the relative role of muscarinic receptor subtypes in longitudinal muscle cells. However, it modulates the M2 receptor coupling to adenylate cyclase in the circular muscle.

Mechanisms of histamine-induced relaxation in bovine small adrenal cortical arteries

2005 ◽  
Vol 289 (6) ◽  
pp. E1058-E1063 ◽  
Author(s):  
David X. Zhang ◽  
Kathryn M. Gauthier ◽  
William B. Campbell
Keyword(s):  
Blood Flow ◽  
Mast Cell ◽  
Receptor Antagonist ◽  
Zona Glomerulosa ◽  
Receptor Antagonists ◽  
Vascular Events ◽  
Nitric Oxide Synthase Inhibitor ◽  
Aldosterone Production ◽  
Synthase Inhibitor

Adrenal steroidogenesis is closely correlated with increases in adrenal blood flow. Many reports have studied the regulation of adrenal blood flow in vivo and in perfused glands, but until recently few studies have been conducted on isolated adrenal arteries. The present study examined vasomotor responses of isolated bovine small adrenal cortical arteries to histamine, an endogenous vasoactive compound, and its mechanism of action. In U-46619-precontracted arteries, histamine (10−9-5 × 10−6 M) elicited concentration-dependent relaxations. The relaxations were blocked by the H1 receptor antagonists diphenhydramine (10 μM) or mepyramine (1 μM) (maximal relaxations of 18 ± 6 and 22 ± 6%, respectively, vs. 55 ± 5% of control) but only partially inhibited by the H2 receptor antagonist cimetidine (10 μM) and the H3 receptor antagonist thioperamide (1 μM). Histamine-induced relaxations were also blocked by the nitric oxide synthase inhibitor N-nitro-l-arginine (l-NA, 30 μM; maximal relaxation of 13 ± 7%) and eliminated by endothelial removal or l-NA combined with the cyclooxgenase inhibitor indomethacin (10 μM). In the presence of adrenal zona glomerulosa (ZG) cells, histamine did not induce further relaxations compared with histamine alone. Histamine (10−7-10−5 M) concentration-dependently increased aldosterone production by adrenal ZG cells. Compound 48/80 (10 μg/ml), a mast cell degranulator, induced significant relaxations (93 ± 0.6%), which were blocked by l-NA plus indomethacin or endothelium removal, partially inhibited by the combination of the H1, H2, and H3 receptor antagonists, but not affected by the mast cell stabilizer sodium cromoglycate (1 mM). These results demonstrate that histamine causes direct relaxation of small adrenal cortical arteries, which is largely mediated by endothelial NO and prostaglandins via H1 receptors. The potential role of histamine in linking adrenal vascular events and steroid secretion requires further investigation.

Epinephrine stimulates IL-6 expression in skeletal muscle and C2C12 myoblasts: role of c-Jun NH2-terminal kinase and histone deacetylase activity

2004 ◽  
Vol 286 (5) ◽  
pp. E809-E817 ◽  
Author(s):  
Robert A. Frost ◽  
Gerald J. Nystrom ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Receptor Antagonist ◽  
Histone Deacetylase ◽  
Muscle Mass ◽  
Adrenergic Receptor ◽  
Inflammatory Cytokine ◽  
Trichostatin A ◽  
Muscle Cells ◽  
Dependent Manner

Although an individual's genetic makeup is a major determinant of muscle mass, other influences, such as hormones, cytokines, nutrition, and exercise can also modulate muscle size. IL-6 is an important inflammatory cytokine. Mice that overexpress IL-6 fail to thrive and/or have reduced skeletal muscle mass. The purpose of the present study was to determine whether the stress hormone epinephrine increases inflammatory cytokine expression in skeletal muscle and muscle cells. Infusion of epinephrine in vivo for 2 h increased IL-6 protein (15-fold) and mRNA (40-fold) in skeletal muscle but not in liver. Epinephrine had a similar effect in C2C12 muscle cells, where the hormone increased IL-6 protein and mRNA in a dose- and time-dependent manner. Epinephrine-stimulated IL-6 expression was attenuated by the α-adrenergic receptor antagonist phentolamine and completely blocked by either the β1/2-adrenergic receptor antagonist propranalol or the β2-antagonist ICI-118551. The transcriptional inhibitor DRB and the synthetic glucocorticoid dexamethasone also blocked epinephrine-induced IL-6. SP-600125 (a JNK inhibitor) and SB-202190 (a p38 MAP kinase inhibitor) completely blocked epinephrine-induced IL-6 synthesis. Endotoxin and epinephrine given together had a synergistic affect on IL-6 mRNA and protein expression. Trichostatin A (a histone deacetylase inhibitor) blocked both endotoxin- and epinephrine-induced IL-6 expression. These data suggest that epinephrine induces IL-6 synthesis in skeletal muscle in vivo and myocytes in vitro. Epinephrine utilizes predominantly the β1/2-adrenergic receptors to stimulate IL-6 synthesis. Endotoxin and epinephrine synergize to increase IL-6 mRNA expression. Optimal IL-6 synthesis may require both stress kinase and histone deacetylase activity.

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