β1-Adrenergic cardiac contractility is increased during early endotoxemic shock: Involvement of cyclooxygenases

Endothelial dysfunction is one of the earliest symptoms in septic patients and plays an important role in the cardiovascular alterations. However, the endothelial mechanisms involved in the impaired sympathetic regulation of the cardiovascular system are not clear. This study aimed to determine the role of the endocardial endothelium (EE) in the cardiac β-adrenergic (β-AR) remodeling at the early phase of endotoxemic shock. Rats received either lipopolysaccharide (LPS) or saline (control) intravenously. Three hours later, β-AR cardiac contractility was evaluated on papillary muscles with or without a functional EE. Isoproterenol-induced contractility was strongly increased in papillary muscles from LPS rats. A similar increase was observed with a β1-AR stimulation, whereas β2-AR and β3-AR produced similar contractility in control and LPS treatments. The removal of the EE did not modify β1-AR-induced contractility in controls, whereas it abolished the increased β1-AR response in LPS-treated muscles. In LPS-treated papillary muscle, the increased β1-AR-induced contractility was not modified by pretreatment with a NOS inhibitor or an endothelin receptor antagonist. Conversely, the increased β1-AR-induced contractility was abolished by indomethacin, a non-selective cyclooxygenase (COX) inhibitor, as well as by selective inhibitors of COX1 and COX2. An early treatment with indomethacin improved the survival of LPS rat. Our results suggest that the EE is involved in the increased cardiac β1-AR contractility in the early phase of endotoxemic shock. This effect is mediated through the activation of COX1 and COX2 and suggests these may be novel putative therapeutic targets during endotoxemic shock.