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Differential effects of heart rate reduction with ivabradine in two models of endothelial dysfunction and oxidative
Swenja Kröller-Schön1, Eberhard Schulz, Philip Wenzel
1Department of Cardiology, Johannes Gutenberg University, 55101 Mainz, Germany.
Insights
Ivabradine effectively reduces heart rate in animal models, improving vascular function and reducing oxidative stress in ApoE knockout mice but not in hypertensive rats. This suggests potential benefits for vascular health, particularly in non-hypertensive conditions.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Vascular Biology
Background:
- Ivabradine is an I(f)-channel inhibitor used to reduce heart rate in ischemic heart disease.
- Oxidative stress and endothelial dysfunction are key features of vascular disease.
Purpose of the Study:
- To investigate the effects of ivabradine on oxidative stress and endothelial dysfunction in two animal models of vascular disease.
- To assess ivabradine's impact on angiotensin II-induced hypertension in Wistar rats and ApoE knockout mice.
Main Methods:
- Two animal models were used: Wistar rats with angiotensin II-induced hypertension and ApoE knockout mice.
- Animals received ivabradine (10 mg/kg/day) or a placebo.
- Endothelial function, reactive oxygen species (ROS) production, NADPH oxidase activity, eNOS uncoupling, and angiotensin II signaling were assessed.
Main Results:
- Ivabradine consistently reduced heart rate by 15-20% without affecting blood pressure.
- In ApoE knockout mice, ivabradine improved endothelial function and reduced ROS production by decreasing NADPH oxidase activity and preventing eNOS uncoupling.
- These benefits were not observed in angiotensin II-treated rats, possibly due to hypertension or treatment duration.
Conclusions:
- Ivabradine demonstrates potential antioxidative and endothelial-protective effects in ApoE knockout mice, linked to reduced NADPH oxidase activity and eNOS uncoupling.
- The lack of similar effects in hypertensive rats suggests that arterial hypertension may interfere with ivabradine's vascular benefits.
- Further research is needed to clarify the role of treatment duration and hypertension in mediating ivabradine's vascular effects.
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.
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