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OtherCARDIOVASCULAR PHARMACOLOGY

Carbachol Increases Contractions and Intracellular Ca++ Transients in Guinea Pig Ventricular Myocytes

Lev Protas, Jian-Bing Shen and Achilles J. Pappano
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 66-74;
Lev Protas
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Jian-Bing Shen
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Achilles J. Pappano
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Abstract

We tested hypotheses concerning the muscarinic receptor subtype and the involvement of L-type Ca current (ICa) in the stimulation of contractions by carbachol (CCh) in single guinea pig ventricular myocytes. When superfused with Tyrode’s solution (36°C, 5.4 mM [Ca++]o) and stimulated at 0.2 Hz, CCh (EC50 ≈18 μM) increased the early component of isotonic contractions by acting at muscarinic receptors indistinguishable from the M2 subtype because AF-DX 116 (M2-selective) was more potent than pirenzepine (M1-selective) as an antagonist of the CCh effect. Action potential duration decreased slightly and ICa was not increased when CCh increased contractions. Carbachol increased intracellular Ca++transients and contractions reversibly, which indicated an effectvia sarcoplasmic reticulum (SR) Ca stores. Ryanodine (1–10 μM) blocked the early contraction component increased by CCh, another indication that CCh action depends on SR Ca stores. We previously found that CCh increased a background Na+current by occupancy of M2 receptors. We now report that the increased contractions by CCh can also originate at M2receptors and that SR Ca stores are involved in the CCh effect. Because CCh did not significantly increase ICa, the initial increase of intracellular Na+ by CCh may eventually act through Na-Ca exchange to enhance excitation-contraction coupling.

Footnotes

  • Send reprint requests to: Dr. Achilles J. Pappano, Department of Pharmacology, University of Connecticut Health Center, Farmington, CT 06030.

  • ↵1 This work was supported by USPHS Grant HL-13339.

  • ↵2 Present address: Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.

  • Abbreviations:
    ACh
    acetylcholine
    PTX
    pertussis toxin
    CCh
    carbachol
    Gi
    inhibitory guanine nucleotide binding protein
    AF-DX 116
    (11[[2-[diethylamino)methyl]-1- piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3–6][1,4]benzodiazepine-6-)one
    mAChR
    muscarinic receptor
    SR
    sarcoplasmic reticulum
    InsP3
    inositol 1,4,5- trisphosphate
    Ica
    L-type calcium current
    INa-Ca
    sodium-calcium exchange current
    HEPES
    N-(2-hydroxyethyl) piperazine-N-(2- ethanesulfonic acid)
    cAMP
    cyclic adenosine monophosphate
    cGMP
    cyclic guanosine monophosphate
    IK(ACh)
    acetylcholine-induced potassium current
    fura-2AM
    fura-2-acetoxymethyl ester
    EC50
    effective concentration for 50% maximum effect
    APD50
    action potential duration at 50% amplitude
    PKC
    protein kinase C
    TTX
    tetrodotoxin
    • Received April 8, 1997.
    • Accepted September 2, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

Carbachol Increases Contractions and Intracellular Ca++ Transients in Guinea Pig Ventricular Myocytes

Lev Protas, Jian-Bing Shen and Achilles J. Pappano
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 66-74;

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OtherCARDIOVASCULAR PHARMACOLOGY

Carbachol Increases Contractions and Intracellular Ca++ Transients in Guinea Pig Ventricular Myocytes

Lev Protas, Jian-Bing Shen and Achilles J. Pappano
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 66-74;
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