Department of Internal Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO 65212, USA.
Hypertension. 2010 Apr;55(4):880-8. doi: 10.1161/HYPERTENSIONAHA.109.145136. Epub 2010 Feb 22.
Insulin resistance is associated with obesity and may be accompanied by left ventricular diastolic dysfunction and myocardial remodeling. Decreased insulin metabolic signaling and increased oxidative stress may promote these maladaptive changes. In this context, the beta-blocker nebivolol has been reported to improve insulin sensitivity, increase endothelial NO synthase activity, and reduce NADPH oxidase-induced superoxide generation. We hypothesized that nebivolol would attenuate diastolic dysfunction and myocardial remodeling by blunting myocardial oxidant stress and promoting insulin metabolic signaling in a rodent model of obesity, insulin resistance, and hypertension. Six-week-old male Zucker obese and age-matched Zucker lean rats were treated with nebivolol (10 mg x kg(-) x day(-1)) for 21 days, and myocardial function was assessed by cine MRI. Compared with untreated Zucker lean rats, untreated Zucker obese rats exhibited prolonged diastolic relaxation time (27.7+/-2.5 versus 40.9+/-2.0 ms; P<0.05) and reduced initial diastolic filling rate (6.2+/-0.5 versus 2.8+/-0.6 microL/ms; P<0.05) in conjunction with increased homeostatic model assessment of insulin resistance (7+/-2 versus 95+/-21; P<0.05), interstitial and pericapillary fibrosis, abnormal cardiomyocyte histoarchitecture, 3-nitrotyrosine, and NADPH oxidase-dependent superoxide. Nebivolol improved diastolic relaxation (32.8+/-0.7 ms; P<0.05 versus untreated Zucker obese), reduced fibrosis, and remodeling in Zucker obese rats, in concert with reductions in nitrotyrosine, NADPH oxidase-dependent superoxide, and improvements in the insulin metabolic signaling, endothelial NO synthase activation, and weight gain (381+/-7 versus 338+/-14 g; P<0.05). Results support the hypothesis that nebivolol reduces myocardial structural maladaptive changes and improves diastolic relaxation in concert with improvements in insulin sensitivity and endothelial NO synthase activation, concomitantly with reductions in oxidative stress.
胰岛素抵抗与肥胖有关，可能伴有左心室舒张功能障碍和心肌重构。胰岛素代谢信号的降低和氧化应激的增加可能促进这些适应性变化。在这种情况下，β受体阻滞剂奈必洛尔已被报道可改善胰岛素敏感性、增加内皮型一氧化氮合酶活性，并减少 NADPH 氧化酶诱导的超氧生成。我们假设奈必洛尔通过阻断心肌氧化应激和促进肥胖、胰岛素抵抗和高血压啮齿动物模型中的胰岛素代谢信号，减轻舒张功能障碍和心肌重构。将 6 周龄雄性 Zucker 肥胖大鼠和年龄匹配的 Zucker 瘦大鼠用奈必洛尔（10mg×kg-1×day-1）治疗 21 天，并通过电影 MRI 评估心肌功能。与未经治疗的 Zucker 瘦大鼠相比，未经治疗的 Zucker 肥胖大鼠舒张期松弛时间延长（27.7+/-2.5 与 40.9+/-2.0ms；P<0.05），初始舒张充盈率降低（6.2+/-0.5 与 2.8+/-0.6μL/ms；P<0.05），同时胰岛素抵抗的稳态模型评估（7+/-2 与 95+/-21；P<0.05）、间质和毛细血管周围纤维化、异常的心肌细胞组织学、3-硝基酪氨酸和 NADPH 氧化酶依赖性超氧增加。奈必洛尔改善了 Zucker 肥胖大鼠的舒张松弛（32.8+/-0.7ms；P<0.05 与未经治疗的 Zucker 肥胖大鼠相比），减少了纤维化和重塑，同时降低了硝基酪氨酸、NADPH 氧化酶依赖性超氧和改善了胰岛素代谢信号、内皮型一氧化氮合酶激活和体重增加（381+/-7 与 338+/-14g；P<0.05）。结果支持以下假设：奈必洛尔降低心肌结构适应性变化并改善舒张松弛，同时改善胰岛素敏感性和内皮型一氧化氮合酶激活，同时降低氧化应激。
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