Masahiko Morihira

Oral Pretreatment with Ebselen Enhances Heat Shock Protein 72 Expression and Reduces Myocardial Infarct Size

Reactive oxygen species (ROS) enhance myocardial ischemia-reperfusion (I/R) injury. Ebselen, a seleno-organic glutathione peroxidase (GPx) mimetic, has a protective effect against tissue injury induced by ROS. However, the cardio-protective effect of orally administered ebselen has never been investigated in cardiac I/R injury. We investigated the effects and mechanisms of orally administered ebselen on experimental myocardial infarction. Isolated perfused rabbit hearts underwent 30 min of global ischemia and 60 min of reperfusion, with or without oral administration of ebselen 24 h before I/R, with or without enhanced oxidative stress by H2O2 infusion for the first 1 min of reperfusion. The recovery of left ventricular developed pressure (LVDP) was significantly improved, and the myocardial infarct size was significantly reduced by ebselen. The recovery of LVDP and the myocardial infarct size were markedly aggravated by H2O2 infusion. These enhancements by H2O2 were dose-dependently suppressed by ebselen, along with a reduction in myocardial 8-hydroxydeoxyguanosine levels, a marker for oxidative DNA damage. The myocardial reduced glutathione (GSH) level was preserved by ebselen. Ebselen markedly enhanced myocardial heat shock protein (HSP) 72 expression. The cardioprotective effect of ebselen-induced HSP72 was confirmed by MTT assay in isolated cardiomyocytes using KNK437, a novel HSP inhibitor. In conclusion, an oral administration of ebselen 24 h before I/R provided excellent cardioprotective effects, at least in part through HSP72 induction and GSH preservation.

Effect of inhaled nitric oxide on cardiovascular response to catecholamine in heart failure.

We examined the dose responses to continuous infusion of isoproterenol (ISO) and norepinephrine (NE) in normal (control) and procainamide-induced heart failure dogs with or without inhalation of 70 ppm nitric oxide (NO). Inhaled NO affected neither left ventricular (LV) function nor hemodynamics at baseline in both control and heart failure dogs. There were no significant differences in the responses to ISO and NE with or without inhaled NO in the control. The responses of LV dP/dt to ISO and NE were significantly enhanced in heart failure; however, they were not affected by inhaled NO. In contrast, LV pressure and dimension at end diastole were significantly increased, and pulmonary vascular resistance (PVR) was significantly decreased by inhaled NO during infusion of both ISO and NE in heart failure. In conclusion, the positive inotropic response to cathecholamine is not affected by inhaled NO even in heart failure. Inhaled NO decreases PVR, but potentially increases LV preload in the presence of additional stress of cathecholamine in heart failure.