Moniotte S, Belge C, Sekkali B, Massion P B, Rozec B, Dessy C, Balligand J-L
Unit of Pharmacology and Therapeutics, FATH 5349, Université Catholique de Louvain, Brussels, Belgium.
Eur J Heart Fail. 2007 Dec;9(12):1163-71. doi: 10.1016/j.ejheart.2007.10.006. Epub 2007 Nov 19.
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.
分析β3-肾上腺素能受体（β3-AR）通路在人类脓毒症心肌以及脓毒症小鼠模型（一种与心肌抑制相关的病症）中的意义。
脓毒症患者心脏中β3-AR和内皮型一氧化氮合酶（eNOS）蛋白丰度增加（分别为332±66.4%和218±39.3；P<0.05）。通过视频显微镜分析β3-AR选择性激动剂BRL37344对用脂多糖刺激的培养巨噬细胞的条件培养基（Mc-LPS+培养基）孵育的新生小鼠心室肌细胞（NMVM）收缩性的影响。用BRL37344刺激未处理的NMVM可剂量依赖性降低收缩缩短幅度（P<0.05）。L-NAME（一氧化氮合酶抑制剂）可消除这种反应。在野生型心肌细胞中，在Mc-LPS+培养基中孵育可增强BRL37344（P<0.05）以及SR58611A（P<0.05）的抑制作用。重要的是，β3-AR基因敲除小鼠的心肌细胞中收缩抑制作用被消除。
在脓毒症期间，人类心肌中的β3-AR上调，在小鼠心肌细胞中细胞因子可使其上调，在这些细胞中它们介导对β3激动剂的负性肌力反应增强。儿茶酚胺激活β3-AR通路可能导致脓毒症中的心肌功能障碍。
