Cardioprotective effects of the calcineurin inhibitor FK506 and the PAF receptor antagonist and free radical scavenger, EGb 761, in isolated ischemic/reperfused rat hearts

Effects of the calcineurin inhibitor FK506, the platelet-activating factor (PAF) antagonist, and free radical scavenger Ginkgo biloba extract, EGb 761 , and their combination on reperfusion-induced ventricular fibrillation (VF ), ventricular tachycardia (VT), and recovery of cardiac function were stud ied after 30 min of global ischemia followed by 2 h of reperfusion in isola ted rat hearts. In the first series of studies, rats received a daily (oral ) dose of 0, 1, 5, 10, 20, or 40 mg/ kg/day FK506 for 10 days. FK506 dose-d ependently reduced the incidence of reperfusion-induced total (irreversible plus reversible) VF from a value of 92% for untreated animals to 92% (NS), 83% (NS), 67% (NS), 33% (p < 0.05), and 25% (p < 0.05), for doses of 1-40 mg/kg/day, respectively, with effects on incidence of VT showing the same p attern. FK506, between 20 and 40 mg/kg/day, also resulted in significant re covery of postischemic cardiac function. In the second series of studies, r ats were treated with EGb 761 alone or in combination with FK506. Whereas n o significant reduction in arrhythmias or improvement in cardiac function r esulted from a single intervention of EGb 761 at 25 mg/kg/day, combined tre atment of rats with 25 mg/kg/day of EGb 761 and 1 or 5 mg/kg/day of FK506 r esulted in a reduction in total and irreversible VF of 92% and 92% to 42% ( p < 0.05) and 33% (p < 0.05), 25% (p < 0.05) and 8% (p < 0.05), respectivel y, versus untreated control animals, paralleled by similar effects on the i ncidence of VT and accompanied by significant improvements in postischemic cardiac function. Our results demonstrate a novel cardioprotective characte ristic of FK506 and suggest that combination therapy by using FK506 plus EG b 761 synergistically improves postischemic cardiac function, while reducin g the incidence of reperfusion-induced VF and VT, which may expand the clin ical utility of FK506 and allow therapy with FK506 at lower doses than are currently useful.