Relationship between anti-diarrheal activity and binding to calmodulin

Zavecz, James H.; Jackson, Thomas E.; Limp, Gerald L.; Yellin, Tobias O.

doi:10.1016/0014-2999(82)90042-5

Cited by 58 publications

(24 citation statements)

References 6 publications

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“…Some reports show that loperamide interacts with calmodulin and hence, suggest that it affects intestinal secretion in a similar way to trifluoperazine, (Merrit et al, 1982;Zavecz et al, 1982). We have confirmed that loperamide binds to purified calmodulin and also inhibits calmodulin-dependent phosphodiesterase activity.…”

Section: Discussionsupporting

confidence: 79%

Effects of theophylline, choleragen and loperamide on rabbit ileal fluid and electrolyte transport in vitro

Ahsan

Ilundain

Naftalin

et al. 1987

British J Pharmacology

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1The effects of theophylline and cholera toxin on water and anion movements across rabbit ileum in vitro and the reversal of these effects by the opiate action of loperamide have been investigated. Water movement across the mucosal and serosal surfaces of the tissue was measured continuously by a high resolution method. 2 Theophylline caused an increase in short circuit current and reversed the direction of net Cl1 movement, due mainly to a decrease in mucosal-serosal flux. It also caused a rapid, but transient, reversal in the direction of fluid movement across the mucosal surface. Fluid outflow across the serosal surface was decreased but not reversed. Cholera toxin caused a slow inhibition of water movement across both mucosal and serosal surfaces. 3 Theophylline increased the exit rate of"Br across the mucosal surface and decreased the exit rate of "Br across the serosal surface. Theophylline increased the exit rate of 3H-labelled mannitol across the mucosal surface. 4 Loperamide reversed the effects of theophylline and cholera toxin on water flow across the mucosal and serosal surfaces and on net transepithelial Cl-flux; it also increased the rate of "Br exit across the serosal surface of theophylline-treated tissue. These effects of loperamide could be reversed by naloxone.5 The hydraulic conductivity, Lp of the serosal surface was measured directly by determining the osmotic flow generated by low concentrations of polyethylene glycol (mol. wt. 20000 and 90000).Theophylline reduced the Lp by 57%. Loperamide added to theophylline-treated tissues increased the Lp by 340%. This effect was reversed by naloxone.6 These results indicate that modulation of intestinal smooth muscle tone affects transepithelial ion and water flows in vitro. The increase in tone induced by secretagogues increases ion and water reflux via wide shunt channels in the mucosa and thereby reduces net absorption. The increased net fluid and electrolyte absorption induced by loperamide results from the opiate-dependent inhibition of acetylcholine release from intrinsic ganglia which reduces smooth muscle tone and thereby enhances the fluid and electrolyte conductance of the submucosal layers.

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Section: Discussionsupporting

confidence: 79%

Effects of theophylline, choleragen and loperamide on rabbit ileal fluid and electrolyte transport in vitro

Ahsan

Ilundain

Naftalin

et al. 1987

British J Pharmacology

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“…2) correlates well with the known I& values for the inhibition of calmodulin activity [15], as well as with the known antidiarrhoeal activities of the drugs [19,20]; trifluoperazine, chlorpromazine and triflupromazine have greater antidiarrhoeal activities than the other drugs.…”

Section: Resultssupporting

confidence: 63%

“…The anticalmodulin activity of a drug is its ability to inhibit the c~modulin-induced activation of phosphodiesterase in vitro 1151. The ICSO values for this inhibition of 17, 28, 40, 110 and 340pM for trifluoperazine, triflupromazine, chlorpromazine, promazine and promethazine (all phenothiazines), respectively, and of 1OOpM for ~itriptyline (a di~nz~epine) [ 15,19,20], correlate well with their abilities to inhibit the diarrhoea induced by cholera toxin and other agents, such as prostaglandins and vasoactive intestinal peptide [7,18,19,21,221. Trifluoperazine, chlorpromazine and triflupromazine have a greater antidiarrhoeal activity than amitriptyline, promazine and prometh~ine.…”

Section: Introductionmentioning

confidence: 99%

Effect of antipsychotic drugs on the molecular action of cholera toxin in rabbit intestinal epithelial cells

Longbottom

Heyningen

1990

FEBS Letters

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Antipsychotic drugs of known antidiarrhoeal and anticalmodulin activity inhibited the cholera‐toxin‐catalysed ADP‐ribosylation of proteins of M r, 37000,40000 and 45000 (thought to be regulatory components of the adenylate cyclase complex) that was previously shown to occur in plasma membranes from rabbit intestinal epithelial cells [(1989) Biochim. Biophys. Acta 1014, 289‐297]. There was no obvious correlation between the different activities of the drugs. The drugs also inhibited adenylate cyclase activity, but in this case the inhibition correlated well with the known IC50 values of the drugs for anticalmodulin activity and with their antidiarrhoeal activities.

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“…Non-opioid effects of loperamide include functional inhibition of calmodulin (12)(13)(14) and calcium channel blockade (6,12,15,16). Recently, loperamide was reported to augment the levels of intracellular calcium in HL-60 cells when SOC channels were activated by depletion of IP 3 -sensitive calcium stores by ATP (6).…”

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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Relationship between anti-diarrheal activity and binding to calmodulin

Cited by 58 publications

References 6 publications

Effects of theophylline, choleragen and loperamide on rabbit ileal fluid and electrolyte transport in vitro

Effects of theophylline, choleragen and loperamide on rabbit ileal fluid and electrolyte transport in vitro

Effect of antipsychotic drugs on the molecular action of cholera toxin in rabbit intestinal epithelial cells

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

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