title: Differential effects of heart rate reduction with ivabradine in two models of endothelial dysfunction and oxidative stress.
abstract: Heart rate reduction with the I(f)-channel-inhibitor ivabradine is a novel and appealing option in the therapy of patients with ischemic heart disease. The aim of the current study was to determine the effects of ivabradine in two different animal models of vascular disease characterized by increased oxidative stress and endothelial dysfunction. Wistar rats with angiotensin II induced hypertension and ApoE knockout mice were used as animal models of endothelial dysfunction and oxidative stress, with half of the animals receiving ivabradine 10 mg/kg/day in parallel. Ivabradine lead to a sustained 15-20% heart rate reduction, but had no effect on blood pressure. While ivabradine had no effect on endothelial function and vascular reactive oxygen species production in angiotensin II-treated rats, it improved both parameters in ApoE knockout mice. These antioxidative effects were associated with a decreased NADPH oxidase activity and the prevention of eNOS uncoupling. In addition, ivabradine treatment led to an attenuation of angiotensin II signaling and increased the expression of telomere-stabilizing proteins in ApoE knockout mice, which may explain its beneficial effects on the vasculature. The absence of these protective ivabradine effects in angiotensin II-infused rats may relate to the treatment duration or the presence of arterial hypertension.
authors.affiliation: Department of Cardiology, Johannes Gutenberg University, 55101 Mainz, Germany.
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Kleschyov
authors.forename: Marcus
authors.initials: M
authors.lastname: Hortmann
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D001552:Benzazepines / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D015151:Immunoblotting; D000077550:Ivabradine; D049449:Luminescence; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D001552:Benzazepines; D017382:Reactive Oxygen Species; D000077550:Ivabradine