Endothelin-Dependent Myocardial Dysfunction in an Experimental Endotoxic Shock Model

OBJECTIVE: Impaired myocardial contractility is a major contributor to cardiovascular failure during septic shock; however, the underlying mechanisms remain incompletely understood. This study investigated the roles of endothelin and nitric oxide (NO) in cardiac dysfunction using the endothelin receptor antagonist tezosentan and nitric oxide synthase (NOS) inhibitors in an experimental model of endotoxic shock. METHOD: Endotoxic shock was induced in rats via intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg). Hearts were isolated four hours after LPS or saline administration and perfused using a Langendorff apparatus. Myocardial contractility, coronary perfusion pressure, and heart rate were recorded. The effects of tezosentan and NOS inhibitors (Nω-nitro-L-arginine methyl ester [L-NAME], aminoguanidine, and S-methylisothiourea sulfate [AETU]) were assessed by adding these agents to the perfusate. In parallel, atrial and papillary muscle contractility and spontaneous beating rates were evaluated using isolated tissue preparations in in vitro organ bath studies. RESULTS: Baseline myocardial contractility was significantly reduced in LPS-treated perfused hearts compared with controls (3.03 +- 0.25 vs. 4.94 +- 0.39 g, P < 0.05), whereas no significant differences were observed in isolated atrial or papillary muscle preparations. Coronary perfusion pressure was significantly increased in the LPS group (101 +- 6 vs. 79 +- 6 mmHg, P < 0.05). Tezosentan significantly attenuated the LPS-induced reduction in myocardial contractility but did not affect the increase in perfusion pressure. None of the NOS inhibitors altered myocardial contractility or perfusion pressure in LPS-treated hearts. CONCLUSION: Myocardial contractility impairment in experimental endotoxic shock occurs only in the presence of an intact coronary vasculature and is prevented by endothelin receptor blockade. These findings suggest that vascular endothelium-derived endothelin plays a key role in myocardial depression during endotoxic shock, whereas nitric oxide appears to have a limited contribution in this model.