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


RESULTS
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.
Yang
Zi-Huan
ZH
The School of Life Science, Sun Yat-sen University, Guangzhou, China.
Yu
Hai-Jie
HJ
Pan
Ao
A
Du
Jian-Yang
JY
Ruan
Ye-Chun
YC
Ko
Wing-Hung
WH
Chan
Hsiao-Chang
HC
Zhou
Wen-Liang
WL
D000818:Animals; D002460:Cell Line; D003248:Constipation / Q000188:drug therapy*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D044950:Flavanones / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D017136:Ion Transport; D054368:Laxatives / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D044950:Flavanones; D054368:Laxatives; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C005273:naringenin