Yasuto Nishinaka

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

We investigated the cardioprotective effect of FK506, a newly developed immunosuppressive agent, on ischemia-reperfusion-induced myocardial damage and the inhibitory effect of FK.506 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 ische-mia-reperfusion damage.

The cardioprotective effect of γ-glutamylcysteine ethyl ester during coronary reperfusion in canine hearts

1 The cardioprotective effect of γ‐glutamylcysteine ethyl ester was investigated on ischaemia‐reperfusion‐induced myocardial damage in anaesthetized dogs. 2 Open chest anaesthetized dogs were divided into four groups: 2 h occlusion of the left anterior descending coronary artery (LAD); 2 h LAD occlusion followed by 1 h reperfusion; 2 h LAD occlusion followed by 1 h reperfusion with administration of γ‐glutamylcysteine ethyl ester (10 mg kg−1 just before reperfusion); 2 h LAD occlusion followed by 1 h reperfusion with administration of GSH (the reduced form of glutathione, 10 mg kg−1 just before reperfusion). 3 After occlusion or reperfusion, heart mitochondria were prepared from the normal area and the occluded or the reperfused area, and mitochondrial function (rate of oxygen consumption in State III, and respiratory control index) was measured polarographically. 4 Mitochondrial GSH and GSSG (the oxidized form of glutathione) concentrations, and activities of glutathione peroxidase and glutathione reductase were measured. 5 Two h of LAD occlusion induced mitochondrial dysfunction with depletion of mitochondrial GSH concentration. One h of reperfusion after 2 h LAD occlusion induced significant mitochondrial dysfunction associated with a marked depletion of mitochondrial GSH concentration. 6 γ‐Glutamylcysteine ethyl ester reduced mitochondrial dysfunction and depletion of mitochondrial GSH concentration after 2 h LAD occlusion and 1 h reperfusion. In contrast, GSH did not prevent depletion of mitochondrial GSH concentration and mitochondrial dysfunction after 2 h LAD occlusion followed by 1 h reperfusion. 7 The activities of glutathione peroxidase and glutathione reductase did not change significantly in each group. 8 One h of reperfusion after 2 h occlusion of LAD induced ventricular arrhythmias. γ‐Glutamylcysteine ethyl ester markedly reduced the development of reperfusion arrhythmias, whilst GSH showed no protective effect. 9 γ‐Glutamylcysteine ethyl ester maintained mitochondrial GSH concentration, prevented reperfusion myocardial damage, and reduced reperfusion arrhythmias.

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts

SummaryThe cardioprotective effects of a high dose of ascorbate on ischemia-reperfusion-induced myocardial damage were investigated using open chest anesthetized dogs. Two-hour occlusion of the left anterior descending coronary artery (LAD) induced mitochondrial dysfunction with a depletion of mitochondrial glutathione (GSH) concentration. Two-hour LAD occlusion followed by 1-h reperfusion worsened the ischemia-induced mitochondrial dysfunction together with a marked depletion of mitochodrial GSH concentration. Ascorbate reduced the mitochondrial dysfunction and prevented the depletion of mitochondrial GSH concentration after 2-h LAD occlusion and 1-h reperfusion. Activities of mitochondrial glutathione peroxidase and glutathione reductase did not change significantly in each group. Administration of ascorbate also prevented reperfusion arrhythmias without affecting blood pressure or heart rate. These results suggest that coronary reperfusion induces mitochondrial dysfunction and a depletion of mitochondrial GSH concentration, and that a high dose of ascorbate prevents reperfusion damage.

Hemodynamic mechanisms of the antianginal action of a novel vasodilator FK409 in dynamic exercise-induced angina.

FK409 is a novel vasodilator with a unique chemical structure. We wished to elucidate the mechanisms of antianginal action of FK409 in dynamic exercise-induced angina. Twelve patients with stable effort angina pectoris were studied before and after a single 40-mg oral dose of FK409. Chest pain was induced in all of 12 patients during the control multistage bicycle ergometer exercise. After FK409 administration, the same workload did not induce chest pain in 6 patients. The ST segment at peak exercise showed less severe depression from 0.15 ± 0.02 to 0.05 ± 0.01 mV (p < 0.001). Left ventricular (LV) filling estimated by the Doppler method was reduced, and pulmonary artery wedge pressure decreased significantly (p < 0.001) throughout exercise testing after FK409. Myocardial oxygen uptake and coronary sinus flow throughout exercise testing decreased significantly (p < 0.05) after FK409 administration. The results of the present study demonstrate that decrease in myocardial oxygen demand may be caused by pre- and afterload reduction and that it could be a major mechanism of the antianginal action of FK409. However, other mechanisms such as redistribution of coronary blood flow to the subendocardium, direct dilatation of the stenotic parts of the epicardial arteries, and an increase in collateral blood flow should be considered additional possible mechanisms of the antianginal action of FK409.