Protective Effect of FK506 on Ischemia/Reperfusion-Induced Myocardial Damage in Canine Heart

Abstract

We investigated the cardioprotective effect of FK506, a newly developed immunosuppressive agent, on ischemia-reperfusion-induced myocardial damage and the inhibitory effect of FK506 on superoxide radical formation by neutrophils. Open-chest anesthetized dogs were divided into two groups: group 1, 2-h occlusion of the coronary artery followed by 1-h reperfusion; and group 2, 2-h occlusion followed by 1-h reperfusion with preadministration of FK506 (0.5 mg/kg). After reperfusion, heart mitochondria were prepared from the normal and reperfused areas and mitochondrial function and mitochondrial GSH (the reduced form of glutathione) and GSSG (the oxidized form of glutathione) concentrations were measured. In addition, neutrophils were collected from normal healthy dogs, and the inhibitory effect of FK506 on superoxide radical formation by neutrophils was also investigated. One-hour reperfusion after 2-h coronary occlusion induced significant mitochondrial dysfunction associated with a marked depletion of mitochondrial GSH concentration. FK506 reduced mitochondrial dysfunction, depletion of mitochondrial GSH concentration, and development of reperfusion arrhythmias. FK506 also reduced stimulant-induced superoxide radical formation by normal neutrophils dose dependently. Radical scavenging activity decreased in association with reperfusion, and FK506 reduced superoxide radical formation by neutrophils, which might contribute to lessening ischemia-reperfusion damage.