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Research ArticleCARDIOVASCULAR

Enhanced Cardiac L-Type Calcium Current Response to β2-Adrenergic Stimulation in Heart Failure

Zhu-Shan Zhang, Heng-Jie Cheng, Tomohiko Ukai, Hideo Tachibana and Che-Ping Cheng
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 188-196;
Zhu-Shan Zhang
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Heng-Jie Cheng
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Tomohiko Ukai
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Hideo Tachibana
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Che-Ping Cheng
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Abstract

The β2-adrenergic receptor (β2-AR)-mediated increase in cardiac L-type Ca2+ current (ICa,L) has been documented in normal subjects. However, the role and mechanism of β2-AR activation on ICa,L in heart failure (HF) are unclear. Accordingly, we compared the effect of zinterol (ZIN), a highly selective β2-AR agonist, on ICa,L in isolated left ventricular cardiomyocytes obtained from normal control and age-matched rats with HF induced by left coronary artery ligation (4 months). ICa,L was measured by using the whole-cell voltage-clamp technique. In normal myocytes, superfusion of ZIN (10−5 M) caused a 21% increase in ICa,L (9.21 ± 0.24 versus 7.59 ± 0.20 pA/pF) (p < 0.05). In HF myocytes, the same concentration of ZIN produced a significantly greater increase (30%) in ICa,L (6.20 ± 0.24 versus 4.75 ± 0.17 pA/pF) (p < 0.01). This ZIN-induced increase in ICa,L was further augmented in both normal and HF myocytes (normal: 59 versus 21%; HF: 71 versus 30%) after the incubation of myocytes with pertussis toxin (PTX, 2 μg/ml, 36°C, 6 h). These effects were not modified by the incubation of myocytes with CGP-20712A (3 × 10−7 M), a β1-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551 (10−7 M), a β2-AR antagonist. In addition, all of the effects induced by ZIN were completely prevented in the presence of an inhibitory cAMP analog, Rp-cAMPS (100 μM, in the patch-pipette solution). In conclusion, β2-AR activation stimulates L-type Ca2+ channels and increases ICa,L in both normal and HF myocytes. In HF, β2-AR activation-induced augmentation of ICa,L was increased. These effects are likely to be mediated through a cAMP-dependent mechanism and coupled with both stimulatory G protein and PTX-sensitive G protein.

Footnotes

  • This study was supported in part by grants from the National Institutes of Health (HL45258, HL53541, and HL12335-01A1) and the American Heart Association (9640189N). Dr. C. P. Cheng is an established investigator of the American Heart Association. An abstract of this work was presented at the 1999 American Heart Association Meeting.

  • Abbreviations:
    AR
    adrenergic receptor
    ICa,L
    L-type Ca2+ current
    HF
    heart failure
    PKA
    protein kinase A
    LV
    left ventricular
    LV dp/dtmax and dp/dtmin
    maximum and minimum time derivative of LVP, respectively
    PTX
    pertussis toxin
    MI
    myocardial infarction
    ZIN
    zinterol
    CGP
    CGP-20712A
    ISO
    isoproterenol
    ICI
    ICI-118551
    Ach
    acetylcholine
    NE
    norepinephrine
    [Ca2+]i
    intracellular calcium
    • Received December 26, 2000.
    • Accepted March 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleCARDIOVASCULAR

Enhanced Cardiac L-Type Calcium Current Response to β2-Adrenergic Stimulation in Heart Failure

Zhu-Shan Zhang, Heng-Jie Cheng, Tomohiko Ukai, Hideo Tachibana and Che-Ping Cheng
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 188-196;

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Research ArticleCARDIOVASCULAR

Enhanced Cardiac L-Type Calcium Current Response to β2-Adrenergic Stimulation in Heart Failure

Zhu-Shan Zhang, Heng-Jie Cheng, Tomohiko Ukai, Hideo Tachibana and Che-Ping Cheng
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 188-196;
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