PROLONGED DURATION OF SEPSIS CAUSES ELEVATED ENDOTHELIN-1 AND MYOCARDIAL DYSFUNCTION CORRELATING WITH DNA FRAGMENTATION

Abstract

We tested the hypothesis that elevated myocardial endothelin correlates with DNA fragmentation and myocardial dysfunction during sepsis. Male Sprague-Dawley rats (350-400 g) were randomized into sham, 1-, 3- and 7-days sepsis groups. Sepsis and sham-sepsis was induced using 200 mg/kg cecal inoculum and 5% dextrose water i.p., respectively. Post-mortem analysis od septic animals revealed a severely inflamed peritoneum with presence of pus, which was directly proportional to the duration of sepsis. We observed 10, 33 & 42 % mortality in 1-, 3- & 7-days sepsis groups, respectively. Animals in 3-days and 7-days post sepsis exhibited pulmonary edema and increased heart weight. Plasma and myocardial endothelin (ET)-1 concentration in 7-days sepsis group were significantly elevated as compared to sham and 1-day sepsis groups. Sepsis produced a significant prolongation of left ventricular isovolumic relaxation rate constant, tau, in 1-day sepsis group as compared to sham. Three and 7-days septic groups showed a significant prolongation in tau as compared to sham as well as 1 day sepsis groups. To assess a correlation with myocardial performance and apoptosis, protein expression of Bax and TdT-FragEL™ staining was performed. Sepsis produced a significant upregulation of myocardial Bax in 3-days and 7-days sepsis groups. We observed increased number of apoptotic nuclei in 3- and 7-days septic myocardium, suggesting an increased DNA fragmentation. Sepsis-induced mortality, depressed myocardial performance and elevated ET-1 levels correlate with DNA fragmentation and elevated Bax expression. We concluded that sepsis-induced decrease in myocardial performance could be due to apoptosis. This work was supported by NHLBI # 66016 (ACS).