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Hypertonicity Inhibits Lipopolysaccharide-Induced Nitric Oxide Synthase Expression in Smooth Muscle Cells by Inhibiting Nuclear Factor B

Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois (S.C.P, D.M.H, V.R.); and Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York (J.F.S, A.L.W, S.B.M)

The expression of inducible nitric-oxide synthase (iNOS) in vascular smooth muscle cells leads to prolonged vasorelaxation in vivo and contributes to the profound vasodilation induced by bacterial lipopolysaccharide (LPS) in septic shock. This induction of iNOS depends, in large part, on activation of nuclear factor (NF)-B. Hypertonicity regulates the activity of NF-B in different cell lines; as such, we propose that it should also regulate the expression of iNOS. Thus, the goal of this study was to determine whether hypertonicity regulates iNOS expression and function in smooth muscle cells and to elucidate the mechanism(s) underlying this process. Treatment of hamster ductus deferens (DDT₁MF-2) cells and porcine aortic smooth muscle cells with either mannitol (50 mM) or NaCl (50 mM) reduced LPS-stimulated iNOS expression and nitric oxide release. Both of these agents also reduced the activation of NF-B induced by LPS, tumor necrosis factor- and interleukin-1 in smooth muscle cells. This inhibitory action was caused by suppression of IB- phosphorylation, a prerequisite for ubiquitination and degradation of this protein, and showed additivity with N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG-132), an inhibitor of proteasomal degradation of IB-. Furthermore, exposure to mannitol inhibited the activity of IB kinase, an enzyme involved in phosphorylation of IB-. Mannitol was unable to affect the induction of iNOS produced by overexpression of RelA in DDT₁MF-2 cells, suggesting that this agent does not have additional downstream inhibitory actions on this activated NF-B subunit. Taken together, these data suggest that these hypertonic solutions may prove useful as anti-inflammatory agents, especially against conditions associated with increased NF-B activity.

Received September 16, 2002; accepted February 24, 2003.

Address correspondence to: Dr. Vickram Ramkumar, SIU School of Medicine, Box 19230, Springfield, IL 62974-1222. E-mail: vramkumar{at}siumed.edu

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