This study was designed to determine whether sepsis modifies the ability to preserve vital organ O2 delivery (QO2) across a clinically relevant range of hematocrits. Ninety rats were randomly allocated to cecal ligation and perforation (CLP) or a sham (Sham) procedure. With the use of rat plasma, rat whole blood, or packed rat red blood cells, respectively, randomization into three different hematocrit subgroups followed: low (21-28%), middle (33-40%), and high (45-52%). Organ blood flow values (Q) were measured by the radioactive microsphere technique, and organ QO2 values were calculated. Twenty-four hours after laparotomy, the hematocrit grouping had not modified the interorgan distribution of Q or QO2 in either the CLP or Sham rats. To characterize overall metabolic O2 reserve, rats were then exposed to hypoxia (inspired O2 fraction, 0.08) for 20 min. Whereas cardiac output increased significantly during hypoxia in all experimental groups, myocardial QO2 failed to increase in the low hematocrit Sham subgroup and fell significantly in both the middle- and low-hematocrit CLP subgroups. There was also a lesser redistribution of QO2 away from the small intestine in the low-hematocrit compared with the high-hematocrit CLP subgroup. We conclude that myocardial QO2 is more effectively maintained in septic hypoxic rats if the hematocrit is maintained at levels >45%.
The mechanism involved in the endotoxin‐induced myocardial dysfunction is not fully understood. The purpose of the present study was to demonstrate that myocardial dysfunction in endotoxinemia is mediated via an increase in myocyte production of high mobility group box 1 protein (HMGB1). In vivo, mouse model of endotoxinemia in mice was induced by i.p. injection of LPS (10 mg/kg) and myocardial function was evaluated 24 hrs later. LPS induced a decrease in myocardial contractility (end‐systolic and end‐diastolic volume relation). The decrease in myocardial contractility was diminished when the mice were received either a HMGB1 antagonist (A‐box) or an inhibitor of HMGB1 (glycyrrhizic acid). Expression of myocardial HMGB1 was increased in the heart of mice treated with LPS (immunoflorescence staining). Further, recombinant HMGB1 (10–20 μg/mouse, i.p.) resulted in a dose dependent decrease in myocardial contractility. To confirm that the source of HMGB1 was the cardiac myocytes in the hearts, isolated cardiac myocytes were exposed to LPS (10 μg/ml). Treatment of cardiac myocytes with LPS increased in intracellular levels of HMGB1 and release HMGB1 by myocytes to the supernatant (Western). Taken together, our study suggests LPS‐induced myocardial dysfunction is a result of increase in myocyte HMGB1. (CIHR MOP 81303).
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