title: Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis.
abstract: OBJECTIVE
  Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth.
  
  
  RESULTS
  The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments.
  
  
  CONCLUSIONS
  Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.
authors.affiliation: Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Kirrberger Straße, Homburg/Saar, Germany. stephan.schirmer@uks.eu
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Schirmer
authors.forename: Achim
authors.initials: A
authors.lastname: Degen
authors.forename: Magnus
authors.initials: M
authors.lastname: Baumhäkel
authors.forename: Florian
authors.initials: F
authors.lastname: Custodis
authors.forename: Lisa
authors.initials: L
authors.lastname: Schuh
authors.forename: Michael
authors.initials: M
authors.lastname: Kohlhaas
authors.forename: Erik
authors.initials: E
authors.lastname: Friedrich
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Bahlmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kappl
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000378:metabolism; D001158:Arteries / Q000187:drug effects; D050197:Atherosclerosis / Q000503:physiopathology*; D001552:Benzazepines / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects; D003097:Collateral Circulation / Q000187:drug effects*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006937:Hypercholesterolemia / Q000503:physiopathology*; D000077550:Ivabradine; D008026:Ligation; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000889:Anti-Arrhythmia Agents; D001057:Apolipoproteins E; D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; D016207:Cytokines; D017382:Reactive Oxygen Species; D000077550:Ivabradine; D052250:Nitric Oxide Synthase Type III