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Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model.

Yang ZH, Yu HJ, Pan A, Du JY, Ruan YC, Ko WH, Chan HC, Zhou WL - PLoS ONE (2008)

Bottom Line: Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC).In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion.Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model.

View Article: PubMed Central - PubMed

Affiliation: The School of Life Science, Sun Yat-sen University, Guangzhou, China.

ABSTRACT

Background & aims: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively.

Methods/principal findings: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group.

Conclusions: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation.

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Related in: MedlinePlus

Pretreatment with forskolin reduced NAR–induced ISC on rat colonic mucosa by 95.2% (A and B) [**P<0.001 vs. control].Pretreatment with MDL-12330A reduced NAR–induced Isc by 98.0% (C and D) [**P<0.001 vs. control]. Each column represents the mean±SE (n = 5).
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pone-0003348-g004: Pretreatment with forskolin reduced NAR–induced ISC on rat colonic mucosa by 95.2% (A and B) [**P<0.001 vs. control].Pretreatment with MDL-12330A reduced NAR–induced Isc by 98.0% (C and D) [**P<0.001 vs. control]. Each column represents the mean±SE (n = 5).

Mentions: As shown in Fig. 1, NAR caused a long-lasting stimulation on ISC which is more likely to be a cAMP-mediated short circuit current reaction. In the presence of forskolin (an adenylate cyclase activator), which was used to exhaust the adenylate cyclase so that there will be no further elevation in intracellular cAMP upon subsequent addition of cAMP elevating agents, the NAR induced ISC increase was almost completely abolished (n = 4, P<0.001, Fig. 4A, B). Coordinately, pretreatment with MDL-12330A (an inhibitor of adenyl cyclase) for 30 minutes dramatically reduced the NAR induced ISC compared with control (n = 4, P<0.001, Fig. 4C, D).


Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model.

Yang ZH, Yu HJ, Pan A, Du JY, Ruan YC, Ko WH, Chan HC, Zhou WL - PLoS ONE (2008)

Pretreatment with forskolin reduced NAR–induced ISC on rat colonic mucosa by 95.2% (A and B) [**P<0.001 vs. control].Pretreatment with MDL-12330A reduced NAR–induced Isc by 98.0% (C and D) [**P<0.001 vs. control]. Each column represents the mean±SE (n = 5).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553183&req=5

pone-0003348-g004: Pretreatment with forskolin reduced NAR–induced ISC on rat colonic mucosa by 95.2% (A and B) [**P<0.001 vs. control].Pretreatment with MDL-12330A reduced NAR–induced Isc by 98.0% (C and D) [**P<0.001 vs. control]. Each column represents the mean±SE (n = 5).
Mentions: As shown in Fig. 1, NAR caused a long-lasting stimulation on ISC which is more likely to be a cAMP-mediated short circuit current reaction. In the presence of forskolin (an adenylate cyclase activator), which was used to exhaust the adenylate cyclase so that there will be no further elevation in intracellular cAMP upon subsequent addition of cAMP elevating agents, the NAR induced ISC increase was almost completely abolished (n = 4, P<0.001, Fig. 4A, B). Coordinately, pretreatment with MDL-12330A (an inhibitor of adenyl cyclase) for 30 minutes dramatically reduced the NAR induced ISC compared with control (n = 4, P<0.001, Fig. 4C, D).

Bottom Line: Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC).In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion.Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model.

View Article: PubMed Central - PubMed

Affiliation: The School of Life Science, Sun Yat-sen University, Guangzhou, China.

ABSTRACT

Background & aims: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively.

Methods/principal findings: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group.

Conclusions: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation.

Show MeSH
Related in: MedlinePlus