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Research ArticleCARDIOVASCULAR

Cyclosporine and FK506 Differentially Regulate the Sarcolemmal Na+-K+ Pump

Mahidi Mardini, Anastasia S. Mihailidou, Angela Wong and Helge H. Rasmussen
Journal of Pharmacology and Experimental Therapeutics May 2001, 297 (2) 804-810;
Mahidi Mardini
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Anastasia S. Mihailidou
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Angela Wong
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Helge H. Rasmussen
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Abstract

Cyclosporine A (CsA) and FK506, important immunosuppressants, have been shown to inhibit the enzymatic equivalent of the Na+-K+ pump (Na+, K+-ATPase) in renal tissue. A similar effect in the heart may contribute to the adverse effects of these agents that include calcification, contractile dysfunction, and altered calcium handling. However, inhibition of the pump has not been demonstrated in cardiac myocytes. We isolated single ventricular myocytes from control rabbits and from rabbits administered CsA or FK506 for 1 week. Na+-K+ pump current (Ip) was measured using the whole-cell patch-clamp technique. When patch pipettes contained Na+ in a concentration ([Na]pip) near physiological intracellular levels mean Ip of cardiac myocytes from rabbits with serum CsA levels within the therapeutic range was significantly lower than mean Ip of cardiac myocytes from controls. Treatment had no effect on Ip measured using a [Na]pipexpected to nearly saturate intracellular binding sites. The CsA-induced inhibition of Ip was dependent on the K+ concentration in pipette solutions. Mean Ipin myocytes from rabbits with serum levels of FK506 within the therapeutic range was similar to mean Ip in myocytes from controls, whereas FK506 in a dose inducing serum levels severalfold above the therapeutic range caused significant pump inhibition. Using ion-sensitive microelectrodes we showed the intracellular Na+ activity in papillary muscles isolated from rabbits treated with CsA was significantly higher than in papillary muscles from control rabbits, indicating that CsA causes pump inhibition in intact myocytes with a physiological intracellular milieu.

Footnotes

  • Send reprint requests to: Dr. Mahidi Mardini, Department of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, New South Wales, Australia 2065.

  • This study was supported by the North Shore Heart Research Foundation. M.M. was a recipient of a Postgraduate Medical Research Scholarship from the National Heart Foundation of Australia. Part of this work is presented in abstract form in Circulation(1999) 100 (Suppl):I-223.

  • Abbreviations:
    CsA
    cyclosporine
    Na+-K+-ATPase
    enzymatic equivalent of Na+-K+ pump
    Ip
    Na+-K+ pump current
    Vm
    test potential
    [Na]pip
    pipette Na+concentration
    [K]pip
    pipette K+concentration
    Ih
    holding current
    Ip-Vm
    pump current-voltage relationship
    • Received October 19, 2000.
    • Accepted January 23, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 2
1 May 2001
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Research ArticleCARDIOVASCULAR

Cyclosporine and FK506 Differentially Regulate the Sarcolemmal Na+-K+ Pump

Mahidi Mardini, Anastasia S. Mihailidou, Angela Wong and Helge H. Rasmussen
Journal of Pharmacology and Experimental Therapeutics May 1, 2001, 297 (2) 804-810;

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Research ArticleCARDIOVASCULAR

Cyclosporine and FK506 Differentially Regulate the Sarcolemmal Na+-K+ Pump

Mahidi Mardini, Anastasia S. Mihailidou, Angela Wong and Helge H. Rasmussen
Journal of Pharmacology and Experimental Therapeutics May 1, 2001, 297 (2) 804-810;
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