Pharmacology of Antidiarrheal Drugs

Awouters, F.; Niemegeers, C. J. E.; Janßen, Paul

doi:10.1146/annurev.pa.23.040183.001431

Cited by 96 publications

(48 citation statements)

References 46 publications

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“…Loperamide is a commonly used antidiarrheal agent whose effects are attributed in part to its agonist activity at opioid receptors (10)(11)(12). Non-opioid effects of loperamide include functional inhibition of calmodulin (12)(13)(14) and calcium channel blockade (6,12,15,16).…”

Section: Discussionmentioning

confidence: 99%

Loperamide: A positive modulator for store-operated calcium channels?

Harper

Shin²,

Daly³

1997

Proc. Natl. Acad. Sci. U.S.A.

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The depletion of inositol trisphosphatesensitive intracellular pools of calcium causes activation of store-operated calcium (SOC) channels. Loperamide at 10-30 M has no effect on intracellular calcium levels alone, but augments calcium levels in cultured cells when SOC channels have been activated. In HL-60 leukemic cells, the apparent positive modulatory effect of loperamide on SOC channels occurs when these channels have been activated after ATP, thapsigargin, or ionomycin-elicited depletion of calcium from intracellular storage sites. Loperamide has no effect when levels of intracellular calcium are elevated through a mechanism not involving SOC channels by using sphingosine. Loperamide caused augmentation of intracellular calcium levels after activation of SOC channels in NIH 3T3 fibroblasts, astrocytoma 1321N cells, smooth muscle DDT-MF2 cells, RBL-2H3 mast cells, and pituitary GH 4 C 1 cells. Only in astrocytoma cells did loperamide cause an elevation in intracellular calcium in the absence of activation of SOC channels. The augmentation of intracellular calcium elicited by loperamide in cultured cells was dependent on extracellular calcium and was somewhat resistant to agents (SKF 96365, miconazole, clotrimazole, nitrendipine, and trif luoperazine) that in the absence of loperamide effectively blocked SOC channels. It appears that loperamide augments inf lux of calcium through activated SOC channels.The depletion of intracellular stores of calcium can result in the opening of calcium channels in the plasma membranes of cells (1). Such channels have been referred to as receptor-operated calcium channels, calcium-release-activated calcium channels, capacitative calcium entry channels, and store-operated calcium (SOC) channels. The mechanism(s) whereby depletion of inositol trisphosphate (IP 3 )-sensitive stores of calcium causes opening of SOC channels remains uncertain although several hypotheses have been advanced (2). SOC channels activate after receptor-mediated generation of IP 3 , which releases calcium from intracellular stores, or after treatment of cells with either the Ca 2ϩ -ATPase inhibitor thapsigargin, which blocks re-uptake of calcium into storage sites, or with the calcium ionophore ionomycin, which directly mobilizes calcium from storage sites. SOC channels can be blocked by imidazoles such as SKF 96365, clotrimazole, and miconazole and a small selection of other agents (3-6). Recently, loperamide was found to augment levels of intracellular calcium in HL-60 cells in which SOC channels were activated after P 2Y -receptor-mediated formation of IP 3 and release of intracellular calcium (6). The augmentation by loperamide of SOC channel-mediated elevation of intracellular calcium levels now has been shown to be a general phenomenon, occurring in several cell types after receptor-, thapsigargin-, or ionomycininduced activation of SOC channels. Loperamide appears to be a novel agent for the study of SOC channels and their functional role in cells. MATERIALS AND METHODSLoperamide, econazo...

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Section: Discussionmentioning

confidence: 99%

Loperamide: A positive modulator for store-operated calcium channels?

Harper

Shin²,

Daly³

1997

Proc. Natl. Acad. Sci. U.S.A.

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“…The opioid-specific action component of loperamide has been characterized by its binding to and activation of opioid receptors in 'much the same way as do classical opiate agonists' (Awouters et al, 1983). Little if anything is known about the receptor-subtype preference of loperamide and its relation to the antisecretory/antidiarrhoeal effect.…”

Section: Introductionmentioning

confidence: 99%

Unexpected prosecretory action component of loperamide at μ–opioid receptors in the guinea‐pig colonic mucosa in vitro

Kromer

1995

British J Pharmacology

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“…Loperamide is a widely used antidiarrhoeal that primarily acts at nanomolar concentrations through activation of opioid receptors in the intestinal tract (7). At somewhat higher concentrations, loperamide blocks calmodulin activity and calcium channels (8).…”

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confidence: 99%

Loperamide Inhibits Tachykinin NK3-Receptor-Triggered Serotonin Release Without Affecting NK2-Receptor-Triggered Serotonin Release From Guinea Pig Colonic Mucosa

2005

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Abstract. The effect of loperamide on tachykinin NK 2 -and NK 3 -receptor-mediated 5-HT outflow from guinea pig colonic mucosa was investigated in vitro. The selective tachykinin NK 2 -receptor agonist [β-Ala 8 ]-neurokinin A 4-10 (βAla-NKA) or the selective NK 3 -receptor agonist senktide elicited an increase in 5-HT outflow from whole colonic strips, but not from mucosa-free muscle layer preparations. The enhancing effect of βAla-NKA and senktide was prevented by the selective NK 2 -receptor antagonist GR94800 or the selective NK 3 -receptor antagonist SB222200. Loperamide concentration-dependently suppressed the senktide-evoked 5-HT outflow, but failed to affect the βAla-NKA-evoked 5-HT outflow. The κ-opioid receptor antagonist nor-binaltorphimine or the δ-opioid receptor antagonist naltrindole displaced the concentration-response curve for the suppressant action of loperamide to the right without significant depression of the maximum. However, the µ-opioid receptor antagonist CTOP did not affect the suppressant effect of loperamide. We concluded that the NK 3 receptor-triggered 5-HT release from colonic mucosa is suppressed by loperamide-sensitive mechanisms, whereas the NK 2 -receptor-triggered 5-HT release is loperamide-insensitive. Our data also suggest that the suppressant effect of loperamide is probably mediated by the activation of κ-and δ-opioid receptors located on intrinsic neurons.

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Pharmacology of Antidiarrheal Drugs

Cited by 96 publications

References 46 publications

Loperamide: A positive modulator for store-operated calcium channels?

Loperamide: A positive modulator for store-operated calcium channels?

Unexpected prosecretory action component of loperamide at μ–opioid receptors in the guinea‐pig colonic mucosa in vitro

Loperamide Inhibits Tachykinin NK3-Receptor-Triggered Serotonin Release Without Affecting NK2-Receptor-Triggered Serotonin Release From Guinea Pig Colonic Mucosa

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