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Deletion of neuronal NOS prevents impaired vasodilation in septic mouse skeletal muscle

  1. Darcy Lidingtona,b,
  2. Fuyan Lia,b and
  3. Karel Tymla,b,c,*
  1. aThe Centre for Critical Illness Research, Lawson Health Research Institute, London, Canada
  2. bDepartment of Medical Biophysics, University of Western Ontario, London, Canada
  3. cDepartment of Physiology and Pharmacology, University of Western Ontario, London, Canada
  1. *Corresponding author. The Centre for Critical Illness Research, Victoria Research Laboratory, 6th Floor, 800 Commissioners Road East, London, Canada, N6C 2V5. Tel.: +1 519 685 8300x55076; fax: +1 519 685 8341. Email address: ktyml{at}lhsc.on.ca
  • Received June 16, 2006.
  • Revision received December 11, 2006.
  • Accepted December 28, 2006.

Abstract

Objective: Sepsis-stimulated nitric oxide (NO) production impairs arteriolar responsiveness in skeletal muscle. Using wild type (WT), eNOS−/−, iNOS−/− and nNOS−/− mice, we aimed to determine the key nitric oxide synthase (NOS) isoenzyme(s) responsible for the arteriolar hyporesponsiveness to acetylcholine (ACh) in septic skeletal muscle.

Methods: Sepsis was induced by the cecal ligation and perforation procedure (24 h model). We measured the post-ACh increase in red blood cell velocity (VRBC) in a capillary fed by the stimulated arteriole as an index of vasodilation. NOS activity and protein expression in the muscle were measured by standard procedures.

Results: In all non-septic mice, ACh increased VRBC by ∼150% from baseline. Sepsis impaired this response in WT, eNOS−/− and iNOS−/− mice, but not in nNOS−/− mice. Accordingly, pharmacological inhibition of nNOS with 7-nitroindazole reversed this impairment in WT mice. cNOS (eNOS+nNOS) activity was elevated in septic WT mice; Western blots indicated that this occurred through a post-translational mechanism. iNOS protein activity/expression was negligible. ACh caused dilation via endothelial-derived relaxing factor (EDRF) in WT mice and via endothelial-derived hyperpolarizing factor (EDHF) in eNOS−/− mice. Although exogenous NO reduced EDHF-mediated dilation in eNOS−/− mice, NOS inhibition did not reverse the sepsis-impaired dilation in these mice.

Conclusions: In our 24-h mouse model of sepsis, NO in skeletal muscle is primarily derived from nNOS. Sepsis impairs both EDRF- and EDHF-mediated dilation in response to ACh. Both genetic deletion and inhibition of nNOS protect against this impairment when the dilation occurs via the EDRF but not EDHF pathway.

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    1. Cardiovasc Res (2007) 74 (1): 151-158. doi: 10.1016/j.cardiores.2006.12.022
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