Involvement of γ-Glutamyl Transpeptidase in Ischemia/Reperfusion-Induced Cardiac Dysfunction in Isolated Rat Hearts.

GGsTop is a highly potent and specific, and irreversible γ-glutamyl transpeptidase (GGT) inhibitor without any influence on glutamine amidotransferases. The aim of the present study was to investigate the involvement of GGT in ischemia/reperfusion-induced cardiac dysfunction by assessing the effects of a treatment with GGsTop. Using a Langendorff apparatus, excised rat hearts underwent 40 min of global ischemia without irrigation and then 30 min of reperfusion. GGT activity was markedly increased in cardiac tissues exposed to ischemia, and was inhibited by the treatment with GGsTop. Exacerbation of cardiac functional parameters caused by ischemia and reperfusion, namely the reduction of left ventricular (LV) developed pressure and the maximum and negative minimum values of the first derivative of LV pressure, and the increment in LV end-diastolic pressure was significantly attenuated by GGsTop treatment. The treatment with GGsTop suppressed excessive norepinephrine release in the coronary perfusate, a marker for myocardial dysfunction, after ischemia/reperfusion. In addition, oxidative stress indicators in myocardium, including superoxide and malondialdehyde, after ischemia/reperfusion were significantly low in the presence of GGsTop. These observations demonstrate that enhanced GGT activity contributes to cardiac damage after myocardial ischemia/reperfusion, possibly via increased oxidative stress and subsequent norepinephrine overflow. GGT inhibitors have potential as a therapeutic strategy to prevent myocardial ischemia/reperfusion injury in vivo.

Role of superoxide production in post-ischemic cardiac dysfunction and norepinephrine overflow in rat hearts.

Reactive oxygen species and norepinephrine are known as physiological active substances which cause cell damage and cardiac dysfunction in myocardial ischemia/reperfusion injury. We investigated the role of reactive oxygen species, especially superoxide (O2(-)), in ischemia-induced norepinephrine overflow and cardiac dysfunction using superoxide scavengers tempol and tiron. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Tempol (10 and 100 µM) and tiron (100 and 500 µM) were perfused 15 min before ischemia and during reperfusion. Cardiac levels of oxidative stress markers such as O2(-) and malondialdehyde were notably increased during ischemia and following reperfusion, which were suppressed by the administration of tempol or tiron. These agents significantly improved ischemia/reperfusion-induced cardiac dysfunction such as decreased left ventricular developed pressure and the maximum and minimum value of the first derivative of left ventricular pressure and increased left ventricular end-diastolic pressure. Furthermore, norepinephrine overflow in the coronary effluent after ischemia/reperfusion was significantly suppressed by the administration of each agent. These results suggest that endogenously increased O2(-) is involved in norepinephrine overflow and cardiac dysfunction after myocardial ischemia/reperfusion.