The laxative effect of bisacodyl is attributable to decreased aquaporin-3 expression in the colon induced by increased PGE₂secretion from macrophages

Abstract

Ikarashi N, Baba K, Ushiki T, Kon R, Mimura A, Toda T, Ishii M, Ochiai W, Sugiyama K. The laxative effect of bisacodyl is attributable to decreased aquaporin-3 expression in the colon induced by increased PGE 2 secretion from macrophages. Am J Physiol Gastrointest Liver Physiol 301: G887-G895, 2011. First published August 25, 2011; doi:10.1152/ajpgi.00286.2011.-The purpose of this study was to investigate the role of aquaporin3 (AQP3) in the colon in the laxative effect of bisacodyl. After oral administration of bisacodyl to rats, AQP3, macrophages, cyclooxygenase 2 (COX2), and prostaglandin E 2 (PGE2) were examined in the colon. The mechanism by which bisacodyl decreases the expression of AQP3 was examined using HT-29 and Raw264.7 cells. When diarrhea occurred, a significant increase in the expression of PGE 2 and a decrease in AQP3 expression were observed. Immunostaining showed COX2 expression only in macrophages. The PGE 2 concentration increased significantly 30 min after the addition of bisacodyl to Raw264.7 cells. Thirty minutes after PGE 2 addition to HT-29 cells, the AQP3 expression level decreased to 40% of the control. When pretreated with indomethacin, bisacodyl did not induce an increase in the colon PGE 2 level, a decrease in the AQP3 expression level, or diarrhea. The results suggest that bisacodyl may decrease the expression of AQP3 in the colon, which inhibits water transfer from the luminal to the vascular side and leads to a laxative effect. This study also showed that direct activation of colon macrophages by bisacodyl increases the secretion of PGE 2, which acts as a paracrine factor and decreases AQP3 expression in colon mucosal epithelial cells. aquaporin-3; prostaglandin E 2; bisacodyl; cyclooxygenase IN RECENT YEARS, IT HAS BECOME increasingly clear that aquaporins (AQPs), water channels, are involved in water transport in the intestinal tract (20). There are currently 13 known types of AQPs in humans, AQP0 through AQP12, which are expressed in a variety of tissues (15). Several AQPs are expressed in the intestinal tract, and at least the following eight types are known to exist there: AQP1, AQP2, AQP3, AQP4, AQP7, AQP8, AQP9, and AQP10 (5, 7, 17, 23). The main AQPs expressed in the colon are AQP1, AQP2, AQP3, AQP4, and AQP8 (5,16,23). Of these, extensive research has been conducted on AQP3, which is considered to play an important role in the colon, especially regarding water transfer (13, 34). We have found that the administration of the osmotic laxative magnesium sulfate (MgSO 4 ) to rats increases the expression of AQP3 in the colon, and an increase in the expression of AQP3 plays an essential role in the laxative effect of MgSO 4 (11,12).Bisacodyl is classified as a stimulant laxative and is widely used to treat constipation. Bisacodyl increases the production of prostaglandin E 2 (PGE 2 ) in intestinal epithelial cells and inhibits the activity of Na ϩ -K ϩ -ATPase, and, as a result, the osmotic pressure in the intestinal tract increases. It is believed that this increase in osmoti...

<b>Desacetyl bisacodyl-induced epithelial Cl</b>^<b>−</b><b> secretion in rat colon and r</b><b>ectum </b>

“…These results indicate that DAB induced Cl − secretion and appears to be associated with the COX signaling pathway. The COX signaling pathway is associated with bisacodyl-induced laxative effect because the water volume increase induced by bisacodyl in feces was inhibited by indomethacin pretreatment, as shown in the previous study (11). In our results, piroxicam completely reduced the DAB-induced 2nd phase reaction but not the 1st phase reaction.…”

“…In case of suppositories, the previously reported mechanism, including prevention of fluid absorption (11,22), showed limited contribution to the laxative action. Prevention of water absorption is not effective in the distal colon and rectum because most of the wa- ous mechanisms such as inhibition of water absorption (11,22), augmentation of epithelial permeability (8), secretion of mucus (16), and that of fluids. In the case of suppositories, the laxative action may mainly contribute to bisacodyl-induced mucus and/ or fluid secretion, which could enhance defecation.…”

“…In the case of suppositories, the laxative action may mainly contribute to bisacodyl-induced mucus and/ or fluid secretion, which could enhance defecation. In a previous study, bisacodyl-induced water secretion had been evaluated by the intestinal loop method, which could measure the total amount of water transfer through the whole intestine (9,11,22). On the other hand, the Ussing chamber assay has been used to evaluate electrolyte transport in various intestinal segments and yields information regarding secretory mechanisms.…”

“…According to previous reports, oral or rectal administration of bisacodyl induces laxative effects in rats (16). Bisacodyl also induces fluid accumulation, which was demonstrated by the colonic loop method or the measurement of water content in feces (9,11,22). Oral administration of bisacodyl induced Na/KATPase inhibition and an increase in PGE 2 and adenyl cyclase activity in rat colonic mucosa (19).…”

Comparison of efficacies of vegetable oil based and polyethylene glycol based bisacodyl suppositories in treating patients with neurogenic bowel dysfunction after spinal cord injury: A meta-analysis

“…The bisacodyl (bis (p-acetoxyphenyl)-2-pyridylmethane) is a stimulant laxative widely used in treating constipation (15). It acts directly on the mucous membrane, stimulating the sensory nerves for a parasympathetic nerve reflex response, and thereby increases intestinal tract secretion and movement (16,17).…”