PT Schumacker, J Kazaglis, HV Connolly, RW Samsel, MF O'Connor and JG Umans
Department of Medicine, University of Chicago, Illinois 60637.

Endotoxin administration decreases intrinsic responsiveness of arteries to contractile agonists, both in vivo and in vitro. Endotoxin also impairs systemic and intestinal ability to increase microvascular O2 extraction in response to decreases in O2 delivery. During endotoxemia, contractile responsiveness can be increased by stereospecific inhibitors of nitric oxide (NO) synthase, suggesting that the hypotension and loss of microvascular function caused by endotoxin may result from increased nitric oxide biosynthesis. This study tested whether inhibition of NO synthesis could reverse the systemic and intestinal oxygen extraction defects seen after endotoxin challenge in the dog. Oxygen extraction and hemodynamic responses to progressive decreases in O2 delivery (stagnant hypoxia) were measured systemically and in isolated autoperfused intestine segments in anesthetized dogs. Systemic and intestinal O2 extractions at the onset of O2 supply dependency were significantly impaired in endotoxin-challenged (n = 6) compared with control (n = 7) animals. Inhibition of NO synthase activity with N omega-nitro-L-arginine methyl ester (L-NAME), 50 mg/kg + 100 mg/kg/h, completely inhibited endothelium-dependent vasodilation responses evaluated in vitro, and significantly but incompletely reversed the systemic hypotension in animals previously given endotoxin (n = 9). Despite this improvement, critical O2 extraction ratios remained significantly reduced. Administration of L-NAME in the absence of endotoxin (n = 8) significantly increased systemic vascular resistance and decreased cardiac output and O2 delivery, but it did not impair critical O2 extraction ratios in whole body or isolated intestine. We conclude that inhibition of NO synthesis in this model of endotoxemia can improve arterial pressure without improving those microvascular functions that may influence tissue O2 extraction efficacy.

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