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Research ArticleCELLULAR AND MOLECULAR

Carbachol Inhibits the L-Type Ca2+ Current Augmented by 1,2-bis(2-Aminophenoxy)ethane-N,N,N′,N′-Tetraacetic Acid in Guinea Pig Ventricular Myocytes: Calcium-Sensitivity Hypothesis for Muscarinic Inhibition

Jian-Bing Shen and Achilles J. Pappano
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 857-864;
Jian-Bing Shen
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Achilles J. Pappano
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Abstract

The L-type Ca2+ current [ICa(L)] increases with time after patch rupture in guinea pig ventricular myocytes dialyzed with pipette solutions containing ≥20 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid ([BAPTA]pip). ICa(L)progressively increases because BAPTA chelates subsarcolemmal Ca2+ to disinhibit cardiac adenylyl cyclase (AC) activity. We studied inhibition by carbachol (CCh) of ICa(L)(22–24°C). At 40 mM [BAPTA]pip, 100 μM CCh reversibly suppressed ICa(L) maximally by 42%; half-maximal inhibition (20%) required 1 μM. Atropine antagonized the CCh effect on BAPTA-stimulated ICa(L), as did dialysis with 50 μM guanosine-5′-O-(3-thio)triphosphate. At 20, 30, and 40 mM [BAPTA]pip, ICa(L) increased by 6.7 ± 1.8, 10.1 ± 1.4, and 11.3 ± 1.2 pA/pF, respectively. Inhibition by 100 μM CCh averaged −1.8 ± 0.6, −2.3 ± 0.4, and −4.1 ± 0.4 pA/pF at 20, 30, and 40 mM [BAPTA]pip, respectively. Dialysis of the AC inhibitor 2′-dAMP (100 μM) suppressed ICa(L) run up in 40 mM BAPTA and its inhibition by CCh. Replacing 1.8 mM external Ca2+ with Ba2+, which lacks high-affinity regulatory sites on AC, suppressed CCh-induced inhibition. Neither ICa(L) run up nor its inhibition by CCh occurred when 40 mM EGTA, a slower chelator, replaced BAPTA. Our results support the AC disinhibition hypothesis for BAPTA. We propose that CCh inhibits ICa(L) in BAPTA by increasing either AC sensitivity to inhibition by ambient Ca2+ or the activity of the inhibitory guanine nucleotide binding protein.

Footnotes

  • This work was supported by U.S. Public Health Service Grant HL-13339.

  • Abbreviations:
    mAChR
    muscarinic acetylcholine receptor
    ICa(L)
    L-type calcium current
    IBa(L)
    L-type barium current
    IK(Ach)
    inwardly rectifying K+current
    AC
    adenylyl cyclase
    P-site
    purine site
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    PKA
    protein kinase A
    GTPγS
    guanosine-5′-O-(3-thio)triphosphate
    Giα
    inhibitory guanine nucleotide binding protein
    [Ca]sm
    subsarcolemmal calcium
    τ1
    time constant of fast inactivating component
    τ2
    time constant of slow inactivating component
    CCh
    carbachol
    ACh
    acetylcholine
    ISO
    isoproterenol
    I-V
    current-voltage
    PDE
    phosphodiesterase
    CaM
    Ca/calmodulin
    ICl(cAMP)
    cAMP-induced Ca− current.
    • Received December 18, 2000.
    • Accepted May 9, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Carbachol Inhibits the L-Type Ca2+ Current Augmented by 1,2-bis(2-Aminophenoxy)ethane-N,N,N′,N′-Tetraacetic Acid in Guinea Pig Ventricular Myocytes: Calcium-Sensitivity Hypothesis for Muscarinic Inhibition
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Research ArticleCELLULAR AND MOLECULAR

Carbachol Inhibits the L-Type Ca2+ Current Augmented by 1,2-bis(2-Aminophenoxy)ethane-N,N,N′,N′-Tetraacetic Acid in Guinea Pig Ventricular Myocytes: Calcium-Sensitivity Hypothesis for Muscarinic Inhibition

Jian-Bing Shen and Achilles J. Pappano
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 857-864;

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Research ArticleCELLULAR AND MOLECULAR

Carbachol Inhibits the L-Type Ca2+ Current Augmented by 1,2-bis(2-Aminophenoxy)ethane-N,N,N′,N′-Tetraacetic Acid in Guinea Pig Ventricular Myocytes: Calcium-Sensitivity Hypothesis for Muscarinic Inhibition

Jian-Bing Shen and Achilles J. Pappano
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 857-864;
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