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Heart Rate Reduction by Ivabradine Improves Aortic Compliance in Apolipoprotein E-Deficient Mice

  • Background: Impaired vascular compliance is associated with cardiovascular mortality. The effects of heart rate on vascular compliance are unclear. Therefore, we characterized effects of heart rate reduction (HRR) by I(f) current inhibition on aortic compliance and underlying molecular mechanisms in apolipoprotein E-deficient (ApoE<sup>–</sup>/<sup>–</sup>) mice. Methods: ApoE<sup>–</sup>/<sup>–</sup> mice fed a high-cholesterol diet and wild-type (WT) mice were treated with ivabradine (20 mg/kg/d) or vehicle for 6 weeks. Compliance of the ascending aorta was evaluated by MRI. Results: Ivabradine reduced heart rate by 113 ± 31 bpm (∼19%) in WT mice and by 133 ± 6 bpm (∼23%) in ApoE<sup>–</sup>/<sup>–</sup> mice. Compared to WT controls, ApoE<sup>–</sup>/<sup>–</sup> mice exhibited reduced distensibility and circumferential strain. HRR by ivabradine increased distensibility and circumferential strain in ApoE<sup>–</sup>/<sup>–</sup> mice but did not affect both parameters in WT mice. Ivabradine reduced aortic protein and mRNA expression of the angiotensin II type 1 (AT1) receptor and reduced rac1-GTPase activity in ApoE<sup>–</sup>/<sup>–</sup> mice. Moreover, membrane translocation of p47<sup>phox</sup> was inhibited. In ApoE<sup>–</sup>/<sup>–</sup> mice, HRR induced anti-inflammatory effects by reduction of aortic mRNA expression of IL-6, TNF-alpha and TGF-beta. Conclusion: HRR by ivabradine improves vascular compliance in ApoE<sup>–</sup>/<sup>–</sup> mice. Contributing mechanisms include downregulation of the AT1 receptor, attenuation of oxidative stress and modulation of inflammatory cytokine expression.

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Metadaten
Author: Florian Custodis, Peter Fries, Andreas Müller, Christoph Stamm, Markus Grube, Heyo K. Kroemer, Michael Böhm, Ulrich Laufs
URN:urn:nbn:de:gbv:9-opus-32423
DOI:https://doi.org/10.1159/000339547
ISSN:1018-1172
ISSN:1423-0135
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/22759927
Parent Title (English):Journal of Vascular Research
Publisher:S. Karger AG
Place of publication:Basel, Switzerland
Document Type:Article
Language:English
Date of first Publication:2012/07/03
Release Date:2020/10/08
Tag:Aortic compliance; Apolipoprotein E knockout mice; Heart rate reduction; Ivabradine
GND Keyword:-
Volume:49
Issue:5
First Page:432
Last Page:440
Faculties:Universitätsmedizin / Institut für Pharmakologie
Licence (German):License LogoUrheberrechtlich geschützt