Acute cardiovascular effects of tacrolimus in the isolated guinea pig heart

Abstract

Tacrolimus is an immunosuppressive, macrolide antibioticfrequently used to minimize transplant rejections. It has alsobeen used as a topical ointment to treat atopic dermatitis (Kappet al., 2003), and as an immunosuppressant in kidney trans-plants in dogs (Griffin et al., 1992). Macrolide antibiotics areknown to prolong ventricular repolarization, and to produce thepotentially fatal arrhythmia torsade de pointes (TdP).Reports by Johnson et al. (1992) and Hodak et al. (1998)describe TdP in patients receiving tacrolimus. TdP is a rapid,polymorphic, ventricular tachycardia produced most often bydrugs that lengthen the duration of depolarization and repolar-ization measured as the QT duration in the electrocardiogram(ECG). Tacrolimus has been shown to increase QTc (QT correctedfor heart rate) dispersion in patients with kidney transplants,implying a risk for TdP (Gerhart et al., 2001). A second study byGonza´lez et al. (1999) reported shortening of QTc in patientswith liver transplants treated with tacrolimus. The QTc disper-sion refers to the difference in durations of QTcs from numerousleads, and is thought to reflect heterogeneity of ventricularrepolarization, an electrophysiological substrate for early afterdepolarizations and re-entrant ventricular arrhythmias. Minem-atsu et al. (1999) demonstrated lengthening of QTc in a use-dependent manner showing counterclockwise hysteresis inanesthetized guinea pigs. Thus, the QTc lengthened more athigher heart rates than at lower heart rates – a pattern oppositeto that of most torsadogenic agents, which lengthen QTc in areverse-use dependent manner.There are two mechanisms by which tacrolimus may retardventricular repolarization. Tacrolimus blocks intermediate-con-ductance K