Am. J. Respir. Crit. Care Med., Volume 158, Number 5, November 1998, 1656-1663

Diaphragm Sarcolemmal Injury Is Induced by Sepsis and Alleviated by Nitric Oxide Synthase Inhibition

MENG-CHIH LIN, SATORU EBIHARA, QASIM EL DWAIRI, SABAH N. A. HUSSAIN, LIYING YANG, STEWART B. GOTTFRIED, ALAIN COMTOIS, and BASIL J. PETROF

Respiratory and Critical Care Divisions, McGill University Health Centre, Respiratory Muscle Biology Group, Meakins-Christie Laboratories, McGill University, and Centre Hospitalier Université de Montreal, Montreal, Québéc, Canada

Endotoxemia is associated with impaired diaphragm contractility, and increased nitric oxide (NO) production has recently been implicated in this phenomenon. However, the precise nature of sepsis-related alterations in diaphragm myofiber function remains unclear. We tested the hypothesis that enhanced NO synthesis during sepsis produces diaphragm sarcolemmal injury with attendant abnormalities of myofiber membrane electrophysiology. Two different rat sepsis models were employed: acute (4 h) intraarterial endotoxin (LPS; 20 mg/kg) and subacute (24 h) peritonitis induced by cecal ligation and perforation (CLP). Diaphragm damage occurred after both LPS and CLP, as indicated by hyperpermeability of myofibers to a low molecular weight tracer dye, which is normally unable to penetrate the sarcolemma. Sarcolemmal injury was significantly correlated with reductions in the resting membrane potential (E_m) of single diaphragm myofibers. Western analysis revealed increased diaphragmatic expression of the inducible isoform of NO synthase (iNOS) after LPS and CLP. An inhibitor of NOS activity, LNMMA, significantly decreased morphologic as well as electrophysiologic signs of myofiber membrane injury and dysfunction. Therefore, we conclude that both acute endotoxemia and subacute peritonitis models of sepsis lead to significant sarcolemmal damage and altered E_m in diaphragm myofibers. These changes appear to be mediated, at least in part, through the pathway of increased nitric oxide production.

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