Involvement of the NO-cGMP-K(ATP) channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis

Am J Physiol Gastrointest Liver Physiol. 2013 Mar 15;304(6):G623-34. doi: 10.1152/ajpgi.00392.2012. Epub 2012 Dec 28.


Mesenteric lymphatic vessels actively transport lymph, immune cells, fat, and other macromolecules from the intestine via a rhythmical contraction-relaxation process called lymphatic pumping. We have previously demonstrated that mesenteric lymphatic pumping was compromised in the guinea pig model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis, corroborating clinical and experimental observations of a dilated and/or obstructed phenotype of these vessels in inflammatory bowel disease. Many mediators released during the inflammatory process have been shown to alter lymphatic contractile activity. Among them, nitric oxide (NO), an inflammatory mediator abundantly released during intestinal inflammation, decreases the frequency of lymphatic contractions through activation of ATP-sensitive potassium (K(ATP)) channels. The objective of this study was to investigate the role of NO and K(ATP) channels in the lymphatic dysfunction observed in the guinea pig model of TNBS-induced ileitis. Using quantitative real-time PCR, we demonstrated that expression of Kir6.1, SUR2B, and inducible NO synthase (iNOS) mRNAs was significantly upregulated in TNBS-treated animals. Pharmacological studies performed on isolated, luminally perfused mesenteric lymphatic vessels showed that the K(ATP) channels blocker glibenclamide, the selective iNOS inhibitor 1400W, and the guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly improved lymphatic pumping in quiescent lymphatic vessels from TNBS-treated animals. Membrane potential measurement with intracellular microelectrodes revealed that vessels from TNBS-treated animals were hyperpolarized compared with their sham counterpart and that the hyperpolarization was significantly attenuated in the presence of glibenclamide and ODQ. Our findings suggest that NO and K(ATP) play a major role in the lymphatic contractile dysfunction that occurred as a consequence of the intestinal inflammation caused by TNBS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Disease Models, Animal*
  • Enzyme Inhibitors / pharmacology
  • Glyburide / pharmacology
  • Guanylate Cyclase / antagonists & inhibitors
  • Guinea Pigs
  • Hypoglycemic Agents / pharmacology
  • Ileitis* / chemically induced
  • Ileitis* / metabolism
  • Ileitis* / physiopathology
  • Inflammation Mediators / metabolism
  • KATP Channels / metabolism*
  • Lymphatic Vessels* / metabolism
  • Lymphatic Vessels* / physiopathology
  • Muscle Contraction* / drug effects
  • Muscle Contraction* / physiology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Oxadiazoles / pharmacology
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Quinoxalines / pharmacology
  • Receptors, Drug / metabolism
  • Sulfonylurea Receptors
  • Trinitrobenzenesulfonic Acid / pharmacology
  • Up-Regulation / physiology


  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • ATP-Binding Cassette Transporters
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Inflammation Mediators
  • KATP Channels
  • Oxadiazoles
  • Potassium Channels, Inwardly Rectifying
  • Quinoxalines
  • Receptors, Drug
  • Sulfonylurea Receptors
  • uK-ATP-1 potassium channel
  • Nitric Oxide
  • Trinitrobenzenesulfonic Acid
  • Nitric Oxide Synthase
  • Guanylate Cyclase
  • Glyburide