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TRANSLATIONAL PHYSIOLOGY

Mechanism of regulation of rabbit intestinal villus cell brush border membrane Na/H exchange by nitric oxide

¹Section of Digestive Diseases, Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia; ²The Ohio State University, Columbus, Ohio; and ³University of Rochester, Rochester, New York

Submitted 8 June 2005 ; accepted in final form 4 April 2006

ABSTRACT

In the mammalian small intestine, coupled NaCl absorption occurs via the dual operation of Na/H and Cl/HCO₃ exchange on the villus cell brush border membrane (BBM). Although constitutive nitric oxide (cNO) has been demonstrated to alter gastrointestinal tract functions, how cNO may specifically alter these two transporters to regulate coupled NaCl absorption is unknown. In villus cells, inhibition of cNO synthase (cNOS) with L-N^G-nitroarginine methylester (L-NAME) stimulated Na/H exchange whereas Cl/HCO₃ exchange was unaffected. In villus cell BBM vesicles (BBMV) prepared from rabbits treated with L-NAME, Na/H exchange was also stimulated. D-NAME, an inactive analog of L-NAME, and N⁶-(1-imonoethyl)-L-lysine dihydrochloride, a more selective inhibitor of inducible NO synthase, did not affect Na/H exchange. Kinetic studies demonstrated that the mechanism of stimulation is secondary to an increase in the maximal rate of uptake of Na, without an alteration in the affinity of the transporter for Na. Northern blot studies demonstrated an increase in the message for the BBM Na/H exchanger NHE3, and Western blot studies showed that the immunoreactive protein levels of NHE3 was increased when cNOS was inhibited. Thus these results indicate that cNO under nominal physiological states most likely maintains an inhibitory tone on small intestinal coupled NaCl absorption by specifically inhibiting BBM Na/H expression.

nitro-L-arginine methyl ester; N⁶-(1-imonoethyl)-L-lysine dihydrochloride; nitric oxide; NHE3; NH/E exchange