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Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle.
- Source :
-
The American journal of physiology [Am J Physiol] 1998 Dec; Vol. 275 (6), pp. H2041-52. - Publication Year :
- 1998
-
Abstract
- FK-506 increases the cytosolic Ca2+ concentration transient in rat ventricular myocytes by prolonging the action potential through inhibition of the K+ currents Ito and IK [J. Physiol. (Lond.) 501: 509-516, 1997]. Physiological and biochemical techniques were used in parallel to examine the electrophysiological mechanisms and the role of calcineurin inhibition in these effects. FK-506 prolonged the recovery of Ito from inactivation. Thus Ito inhibition was frequency dependent, with no decrease at 0.2 Hz (recorded at +50 mV from -70 mV) but a 40% decrease at 2.0 Hz. In contrast, inhibition of IK ( approximately 60%) was time and voltage independent. At 25 microM, FK-506 (by 65%) and cyclosporin A (by 57%) inhibited calcineurin activity in myocyte extracts. However, only FK-506 increased the cytosolic Ca2+ concentration transient in field-stimulated myocytes. Furthermore, FK-506 was still active on K+ currents when cells were dialyzed with 10 mM EGTA. These results demonstrate that calcineurin inhibition is not responsible for the functional effects of FK-506 in heart and suggest that IK and Ito are modulated by FK-506-binding proteins or directly by FK-506.
- Subjects :
- Animals
Calcineurin physiology
Calcium metabolism
Cell Separation
Cyclosporine pharmacology
Electric Conductivity
Heart Ventricles
Homeostasis
Intracellular Membranes metabolism
Myocardium cytology
Myocardium metabolism
Osmolar Concentration
Potassium physiology
Rats
Rats, Sprague-Dawley
Calcineurin Inhibitors
Heart drug effects
Immunosuppressive Agents pharmacology
Potassium antagonists & inhibitors
Tacrolimus pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9513
- Volume :
- 275
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The American journal of physiology
- Publication Type :
- Academic Journal
- Accession number :
- 9843803
- Full Text :
- https://doi.org/10.1152/ajpheart.1998.275.6.H2041