Sildenafil attenuates TNBS‐induced colitis in rats: possible involvement of cGMP and K_ATP channels

Abstract

The involvement of cGMP/KATP pathway in effects of sildenafil on experimental colitis was investigated. Sildenafil significantly attenuated colonic injury markers. These effects were reversed by the addition of glibenclamide or ODQ, indicating the involvement of ATP-sensitive potassium channels (KATP) and cGMP, respectively.

The pro‐inflammatory cytokineTNF‐α inhibits lymphatic pumping via activation of theNF‐κB‐iNOSsignaling pathway

“…This question could be explored with glibenclamide, as it restores TNFα-induced dysfunction. However, reports show that this blocker leads to increased severity of experimental IBD 66,67 and that the opening of K ATP channels has anti-inflammatory effects by suppressing the production of pro-inflammatory cytokines such as TNFα and IL-1β in the gut. 68,69 Anti-TNFα antibodies such as infliximab have been used for the treatment of IBD for many years.…”

Role of epithelial ion transports in inflammatory bowel disease

“…Besides, high K ϩ secretion could explain hypokalemia observed in severe cases of UC (116). Epithelial K ATP channels, as abovementioned, have not been specifically studied yet, but glibenclamide worsens colitis (35,42) and nicorandil has been proposed for the management of IBD (60). Interestingly, monochloramine (NH 2 Cl) increased basolateral Ca 2ϩ -dependent K ϩ conductance and NKA activity in healthy rat colonic epithelia and T84 cells, suggesting that it may contribute to diarrhea in IBD due to increased anion secretion rather than low sodium absorption (121, 133).…”

“…However, these results were attributed to the inhibition of lymphocytic, and not IEC, channels. K ATP channels do play a role in IBD since the blocker glibenclamide worsens colitis (35,42) whereas sildenafil (42), nicorandil (60) and H 2 S (140) have beneficial effects on this condition, but intestinal epithelial K ATP channels need further research before they can be considered therapeutic targets. Finally, it would be of high interest to test IEC BK channel blockers or inhibitors [multiple examples can be found in the review by Nardi and Olesen (101)] in experimental colitis models.…”

The effect of PRR ligands on the membrane potential of intestinal epithelial cells

“…Therefore, in Crohn's Disease, NOD2 lack-of-function would mean lower potassium extrusion, higher [K + ]i and consequently decreased sodium absorption, contributing to watery stools. In fact, glibenclamide (a KATP inhibitor) worsens colitis [41,42] and nicorandil (an KATP opener) has been proposed for the management of IBD [43]. One possible limitation of this study is the method used to measure KC channels: membrane potential is a tightly regulated cell parameter, and even though K + is the most important ion for its regulation, other less important mechanisms may intervene and compensate for KC blockade and influence the outcome.…”