β 3 adrenergic receptor blockade reduces mortality in endotoxin-induced heart failure by suppressing induced nitric oxide synthase and saving cardiac metabolism.

The beta(3)-adrenergic receptor (beta(3)AR) is related to myocardial fatty acid metabolism and its expression has been implicated in heart failure. In this study, we investigated the role of beta(3)AR in sepsis-related myocardial dysfunction using lipopolysaccharide (LPS)-induced endotoxemia as a model of cardiac dysfunction. We placed mice into three treatment groups and treated each with intraperitoneal injections of the beta(3)AR agonist CL316243 (CL group), the beta(3)AR antagonist SR59230A (SR group), or normal saline (NS group). Survival rates were significantly improved in the SR group compared with the other treatment groups. Echocardiography analyses revealed cardiac dysfunction within 6-12 h of LPS injections, but the outcome was significantly better for the SR group. Myocardial ATP was preserved in the SR group but was decreased in the CL-treated mice. Additionally, quantitative PCR analysis revealed that expression levels of genes associated with fatty acid oxidation and glucose metabolism were significantly higher in the SR group. Furthermore, the expression levels of mitochondrial membrane protein complexes were preserved in the SR group. Electron microscope studies showed significant accumulation of lipid droplets in the CL group. Moreover, inducible nitric oxide synthase (iNOS) protein expression and nitric oxide were significantly reduced in the SR group. The in vitro study demonstrated that beta(3)AR has an independent iNOS pathway that does not go through the nuclear factor-kappa B pathway. These results suggest that blockading beta(3)AR improves impaired energy metabolism in myocardial tissues by suppressing iNOS expression and recovers cardiac function in animals with endotoxin-induced heart failure. NEW & NOTEWORTHY Nitric oxide production through stimulation of beta(3)-adrenergic receptor (beta(3)AR) may improve cardiac function in cases of chronic heart failure. We demonstrated that the blockade of beta(3)AR improved mortality and cardiac function in endotoxin-induced heart failure. We also determined that LPS-induced inducible nitric oxide synthase has a pathway that is independent of nuclear factor-kappa B, which worsened cardiac metabolism and mortality in the acute phase of sepsis. Treatment with the beta(3)AR antagonist had a favorable effect. Thus, the blockade of beta(3)AR could offer a novel treatment for sepsis-related heart failure.