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Inhibiting nitric oxide overproduction during hypotensive sepsis increases local oxygen consumption in rat skeletal muscle*

Bateman, Ryon M. PhD; Sharpe, Michael D. MD; Goldman, Daniel PhD; Lidington, Darcy PhD; Ellis, Christopher G. PhD

doi: 10.1097/01.CCM.0000295307.92027.2F
Laboratory Investigations

Objective: Although nitric oxide (NO) is a known regulator of cardiovascular function, the effect of NO overproduction during sepsis on capillary oxygen transport and local tissue oxygen consumption is not well understood. The objectives of this study were to determine whether sepsis-induced NO overproduction increased capillary stopped-flow and modulated tissue oxygen consumption in skeletal muscle.

Design: Prospective, controlled laboratory study.

Setting: Animal laboratory in a university-affiliated research institute.

Subjects: Male Sprague-Dawley rats, 165–180 g body weight.

Interventions: Rats were made septic by cecal ligation and perforation (CLP) and were then ventilated and volume resuscitated (saline). The hind limb extensor digitorum longus (EDL) skeletal muscle was blunt dissected for in vivo microvascular imaging. The inducible NO synthase (iNOS) inhibitor L-N6-(1-iminoethyl)lysine dihydrochloride (L-NIL) was infused (3 mg/kg body weight per hour) starting 1 hr post-CLP to maintain arterial blood and EDL tissue NOx (NO2 + NO3) at baseline.

Measurements and Main Results: Red blood cell hemodynamics, hemoglobin oxygen saturation, capillary geometry, and functional capillary density information were used to calculate capillary oxygen flux (the rate of oxygen diffusion from capillary to tissue) and indices of local oxygen delivery and tissue oxygen consumption. Over the first 5 hrs of septic injury, mean arterial pressure decreased while capillary stopped-flow and capillary oxygen flux both increased (p < .05). Inhibiting iNOS/NO overproduction partially restored mean arterial pressure and increased arterial pH. Within the microcirculation, inhibiting NO increased capillary red cell velocity and increased local tissue oxygen consumption (p < .05). Inhibiting NO failed, however, to prevent capillary stopped-flow.

Conclusions: During the onset of sepsis, concurrent with the onset of microvascular dysfunction, there is an iNOS/NO-mediated reduction in local skeletal muscle tissue oxygen consumption.

From the University of Western Ontario and the London Health Sciences Centre, Department of Medical Biophysics (RMB, DL, CGE) and Department of Anesthesia and Program in Critical Care Medicine (MDS), London, ON, Canada; and the Departments of Mathematical Sciences and Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ (DG).

Supported, in part, by research grant MOP-499416 from the Canadian Institutes of Health, London, ON, Canada, University of Western Ontario (CGE). Dr. Bateman is a Lewis MacDonald Research Fellow and was supported by the Spoerel Research Fellowship (London, ON, Canada) and the Heart and Stroke Foundation of Canada (postdoctoral fellowship). The authors have not disclosed any potential conflicts of interest.

Address requests for reprints to: Ryon M. Bateman, PhD, Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-Ku, Tokyo 160-8582 Japan.

© 2008 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins