© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Enhancement of Rho/Rho-kinase system in regulation of vascular smooth muscle contraction in tachycardia-induced heart failure
The Department of Biomedical Regulation/Cardiovascular Medicine (Second Department of Internal Medicine), Yamaguchi University School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
* Corresponding author. Tel.: +81-836-22-2248; fax: +81-836-22-2246 masunori{at}po.cc.yamaguchi-u.ac.jp
Objective: The Rho/Rho-kinase system regulates Ca2+ sensitivity in vascular smooth muscle. A new drug, Y-27632, specifically inhibits Rho-kinase and hence decreases the phosphorylation of myosin light chain, thus reducing contraction. Here, we compare the effects of Y-27632 and nifedipine on the vasoconstrictor response of the femoral artery in heart failure. Methods: Heart failure (HF) was produced by chronic rapid RV pacing (250 bpm, 28 days, six dogs). Indo1-AM was loaded into endothelium-denuded femoral artery segments for measuring intracellular [Ca2+]. Tension and changes in intracellular [Ca2+] [the change in the ratio (418 nm/468 nm) of Indo1 fluorescence (Fratio)] were simultaneously measured in Krebs–Ringer solution. Results: In HF: (i) norepinephrine (10 µM) produced greater tension (784±52 g/cm2) than in control (502±64 g/cm2) despite a similar increase in Fratio, indicating increased Ca2+ sensitivity in vascular smooth muscle; (ii) nifedipine attenuated this enhanced response by only a maximum of 27% at 1 µmol/l with a 56% reduction in Fratio; (iii) Y-27632 attenuated it by a maximum of 80% at 100 µmol/l without a significant change in Fratio; (iv) RhoA protein and mRNA expression levels in the femoral artery were up-regulated by +110% and +56%, respectively, while those of Rho-kinase were unchanged. Conclusions: The Ca2+-sensitizing mechanism involving the Rho/Rho-kinase system may be deeply involved in the enhanced arterial vasoconstriction seen in HF. Since Y-27632 attenuated this response in small arteries, it shows potential as a novel, potent vasodilator for the treatment of HF.
KEYWORDS HF, heart failure; CHF, congestive heart failure; MLC, myosin light chain; GEFs, guanine–nucleotide exchange factors; GDI, guanine–nucleotide dissociation inhibitor; GTP
S, guanosine 5'-O-(-thiotriphosphate); GDPβS, guanosine 5'-O-(-thiodiphosphate; GEFs, guanine–nucleotide exchange factors; GDI, guanine–nucleotide dissociation inhibitor; RAS, renin–angiotensin system; RT-PCR, reverse transcription polymerase chain reaction amplification; PMSF, phenylmethanesulfonyl fluoride; Tris, tris[hydroxymethyl]aminomethane; ANP, atrial natriuretic-peptide
1 These authors contributed equally to this work.
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