title: Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO 65212, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhou
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Roger D
authors.initials: RD
authors.lastname: Tilmon
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Brown
authors.forename: Jeong-A
authors.initials: JA
authors.lastname: Kim
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Demarco
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D004983:Ethanolamines / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000068577:Nebivolol; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D001578:Benzopyrans; D001786:Blood Glucose; D004983:Ethanolamines; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D000068577:Nebivolol; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt