brl-37344 and Sepsis

To analyze the implication of the beta3-adrenoceptor (beta3-AR) pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression.. beta3-AR and eNOS protein abundance were increased (332+/-66.4% and 218+/-39.3; P<0.05) in hearts from septic patients. The effect of BRL37344, a beta3-AR-preferential agonist, 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 (P<0.05). This response was abolished by L-NAME (NOS inhibitor). Incubation in Mc-LPS+ medium potentiated the depressing effect of BRL37344 (P<0.05) as well as of SR58611A (P<0.05) in wild-type myocytes. Importantly, the contractile depression was abrogated in cardiomyocytes from beta3-AR KO mice.. beta3-AR are upregulated during sepsis in the human myocardium and by cytokines in murine cardiomyocytes, where they mediate an increased negative inotropic response to beta3 agonists. Activation of the beta3-AR pathway by catecholamines may contribute to the myocardial dysfunction in sepsis.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Adult; Animals; Animals, Newborn; Blotting, Western; Cells, Cultured; Culture Media, Conditioned; Disease Models, Animal; Ethanolamines; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Myocardial Contraction; Myocytes, Cardiac; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Reverse Transcriptase Polymerase Chain Reaction; RNA; Sepsis; Stereoisomerism; Up-Regulation