Abstract 879: Cardiodepressant Effect of Upregulated Beta3-Adrenergic Receptors in Sepsis
Beta3 adrenoceptors (β3-AR) mediate a NO-dependent negative inotropic effect and are upregulated in the failing heart. As the role of these receptors in other cardiac diseases is unknown so far, we analyzed expressional and functional modulations of the β3-AR pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression. The causal role of the β3AR was tested in genetically-deleted mice and cardiomyocytes. β3AR and eNOS protein abundance (Western blotting) were increased (224±11.2% and 295±60.9% of controls, respectively; p=0.001) in hearts from septic patients (n=8), compared to normal hearts (n=15). The effects of BRL 37344, a β3AR-preferential agonist, with or without L-NAME (NOS inhibitor) was analyzed by videomicroscopy on the contractility of neonatal mouse ventricular myocytes (NMVM) incubated with conditioned medium from LPS-stimulated cultured macrophages (Mc-LPS+ medium). Stimulation of untreated NMVM with BRL37344 dose-dependently decreased the amplitude of contractile shortening to -36.0±7.8% of baseline (n=4; p<0.05). This response was unchanged by nadolol, a β1-β2-blocker (-47.8±7.4%,n=3), but abolished by bupranolol, a β1- β 2-β3-blocker (+17±8.8%,n=3). Incubation in Mc-LPS+ medium potentiated the depressing effect of BRL37344 to -45.3±4.8 % (n=7; p<0.05), that was partially reversed by L-NAME, to -23.71±10.83%(n=3). Accordingly, the cardiodepressant effect of BRL37344 was potentiated by Mc-LPS+ in wild-type (FVB) but not in β3-AR KO cardiomyocytes (P<0.001 by ANOVA; n=5–16). However, there was no difference in mortality after LPS injection (75mg/kg) in vivo between β3-AR KO(n=55) and FVB (n=60). We conclude that β3-AR are upregulated in the human myocardium during sepsis, and mediate an increased negative inotropic response to the β3 agonist, BRL37344, in cytokine-treated murine cardiomyocytes. Activation of the β3-AR pathway by catecholamines may contribute to the myocardial dysfunction in sepsis.