The role of endothelin-1 in circulatory changes during hypodynamic sepsis in the rat.

Our objective was to investigate the significance of endogenous endothelin-1-induced systemic circulatory reactions during hypodynamic sepsis. In the first part of this study, we observed the changes in global hemodynamic parameters in Wistar rats after exogenous endothelin-1 administration in order to test an intervention strategy aimed at preventing the development of hypodynamic cardiovascular derangement during intraabdominal sepsis. Cardiac output, mean arterial blood pressure, and peripheral vascular resistance were recorded, and the endothelin-A receptor antagonist BQ-610 and the endothelin-B receptor antagonist IRL-1038 were used to investigate the role of receptor subtypes in circulatory changes. In addition, the effects of treatment with the novel endothelin-A receptor inhibitor ETR-P1/fl peptide were examined in endothelin-1-treated anesthetized rats. The injection of 1 nmol/kg endothelin-1 induced a significant rise in peripheral vascular resistance, a transient increase in mean arterial pressure, and a decrease in cardiac output. Administration of the endothelin-A receptor antagonist BQ-610 and ETR-P1/fl peptide increased cardiac output and decreased systemic vascular resistance in the controls and in animals treated with exogenous endothelin. In the second part of the study, the animals were instrumented for hemodynamic monitoring and randomized to undergo cecal ligation and perforation for 8 h or control laparotomy. Septic animals with cecal ligation and puncture were normotensive and hypodynamic, with a significantly increased total peripheral resistance throughout the 8 h observation period. ETR-P1/fl peptide treatment started after the induction of sepsis significantly increased cardiac output and decreased systemic vascular resistance almost to control levels. We conclude that endogenous endothelin-1 contributes significantly to the systemic hemodynamic alterations during hypodynamic circulatory response, and the inhibition of endothelin-A receptors may improve global hemodynamic status in this phase of sepsis.