A major role for carbon monoxide as an endogenous hyperpolarizing factor in the gastrointestinal tract

Abstract

Carbon monoxide (CO) is proposed as a physiological messenger. CO activates cGMP and has a direct effect on potassium channels. Both actions of CO lead to hyperpolarization of a cell's resting membrane potential, suggesting that CO may function as a hyperpolarizing factor, although direct evidence is still lacking. Here we take advantage of the known membrane potential gradient that exists in the muscle layers of the gastrointestinal tract to determine whether CO is an endogenous hyperpolarizing factor. We find that heme oxygenase-2-null mice have depolarized smooth muscle cells and that the membrane potential gradient in the gut is abolished. Exogenous CO hyperpolarizes the membrane potential. Regions of the canine gastrointestinal tract that are more hyperpolarized generate more CO and have higher heme oxygenase activity than more depolarized regions. Our results suggest that CO is a critical hyperpolarizing factor required for the maintenance of intestinal smooth muscle membrane potential and gradient.A role for carbon monoxide (CO) is proposed in cell signaling and neurotransmission (1, 2), hormone release (3, 4), as a cytoprotective agent (5), and in regulation of vascular tone (6, 7). The major source of CO is from the breakdown of heme by heme oxygenase (HO); the absence of HO-2, the constitutive HO isoform, significantly impairs the production of CO in gut and other tissues (8). HO-2 is widely expressed in tissues containing smooth muscle, including blood vessels (6), the pulmonary system (9), and the gastrointestinal tract (10), suggesting that CO is continually produced in these tissues. Multiple mechanisms of action for CO have been proposed, including activation of guanylyl cyclase and direct activation of K ϩ channels (11). Both mechanisms can result in membrane hyperpolarization, raising the possibility that CO can act as an endogenous hyperpolarizing factor. To determine whether CO is an endogenous hyperpolarizing factor, we took advantage of the known membrane potential gradients that exist in the muscle layers of the gastrointestinal tract. We chose the gastrointestinal tract as our model because our previous studies in the HO-2-null mouse demonstrate that intestinal smooth muscle is depolarized in the HO-2-null mouse (2), and because of the presence of a measurable smooth muscle membrane potential gradient that has not been reported in vascular smooth muscle. We hypothesized that if CO acts as a physiologically relevant hyperpolarizing factor, then CO production should mirror the membrane potential gradient along the long axis of the stomach as well as across the gut wall and that these resting membrane potential gradients would be diminished or abolished in HO-2-null mice. In the gastrointestinal tract of all species studied, there is a large gradient (Ϸ30 mV) in membrane potential along the long axis of the stomach from the fundus (proximal stomach) to the pylorus (distal stomach) (12). There is also a membrane potential gradient across the thickness of circular muscle layer (12, 13). In the ...

Are interstitial cells of Cajal plurifunction cells in the gut?

“…An interesting series of recent studies suggests that CO generated by the ICC-MY in the stomach and the small intestine and by the ICC-SM in the colon may produce the observed gradients of the RMP in their respective circular muscle layers (55,62,162,193). Heme oxygenase (HO) activity and CO production correlate well with the observed gradients of the RMP through the thickness of the circular muscle layers in the stomach, small intestine, and the colon (55,104). These gradients are absent in HO-2 knockout mice (193).…”

Preventive Effect of <i>Lactobacillus fermentum</i> Zhao on Activated Carbon-Induced Constipation in Mice

“…To investigate the preventive effects of LF-Zhao against activated carboninduced constipation, the animals were divided into 6 groups with 20 mice each. The normal and control groups were fed normal diets for 9 d. The LF-Zhao was suspended in water to make the lactic acid bacteria suspensions at concentrations of 1310 8 and 1310 9 CFU/ mL; the L. delbrueckii subsp. bulgaricus was also made of lactic acid bacteria suspension at concentrations of 1310 9 CFU/mL.…”

“…One study had demonstrated that a large dose of activated carbon results in digestive tract obstruction (8). Therefore, in the latest study, we examined the functional effects of LF-Zhao in the alimentary tract using an activated carbon-induced constipation mouse model.…”

Kit‐like immunoreactivity in the zebrafish gastrointestinal tract reveals putative ICC

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