FK506 alters sarcoplasmic reticulum calcium release in neonatal piglet cardiac myocytes.
Tacrolimus (FK506) is a potent immunosuppressive drug that, when complexed to a family of immunophilin proteins known as FK binding proteins, inhibits calcineurin in T lymphocytes. Although i.v. use of FK506 in pediatric transplant recipients has been linked to development of cardiomyopathies, its mechanism of cardiotoxicity has not been examined in a neonatal animal model. In our study the effects of FK506 were investigated in cardiac myocytes isolated from newborn piglets. The peak amplitude of electrically triggered fura-2 Ca2+ transients was increased in FK506-treated myocytes, but Ca2+ transient duration and baseline fura-2 Ca2+ ratios were not altered. 45Ca2+ uptake by digitonin-lysed piglet cells decreased at pCa < or = 6.0, indicating that sarcoplasmic reticulum efflux channels were leaky. The results suggest that elevated release of sarcoplasmic reticulum Ca2+ during systole contributes to cardiotoxic effects observed in children.
Hohl
C M
CM
Department of Medical Biochemistry, Ohio State University, Columbus 43210, USA.
Altschuld
R A
RA
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D005456:Fluorescent Dyes; D016257:Fura-2; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013552:Swine; D016559:Tacrolimus / Q000494:pharmacology*
D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D002118:Calcium; D016257:Fura-2; D016559:Tacrolimus