The role of ATP sensitive K+ channels and of nitric oxide synthase on myocardial ischemia/reperfusion-induced apoptosis

Gok S., Vatansever S., Vural K., Sekuri C., Izanli A., Tezcan A., ...More

ACTA HISTOCHEMICA, vol.108, no.2, pp.95-104, 2006 (SCI-Expanded) identifier

  • Publication Type: Article / Article
  • Volume: 108 Issue: 2
  • Publication Date: 2006
  • Doi Number: 10.1016/j.acthis.2006.01.005
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.95-104
  • Keywords: apoptosis, nitric oxide, KATP channels, ischemia-reperfusion, isolated rat heart, POTASSIUM CHANNELS, CYTOCHROME-C, RAT HEARTS, DIAZOXIDE, ISCHEMIA, MITOCHONDRIA, REPERFUSION, EXPRESSION, ACTIVATION, PROTECTION
  • Dokuz Eylül University Affiliated: Yes


During ischemia, ATP-sensitive K+ channels (KATP channels) open, and this triggers necrotic processes and apoptosis. In this study, we investigated whether selective sarcoplasmic and mitochondrial KATP channel blockers affected myocardial apoptosis and nitric oxide synthase (NOS) activity in a rat model of myocardial ischemia/reperfusion in vitro. Isolated rat hearts were subjected to 30 min of coronary artery occlusion followed by 30 min of reperfusion. A selective sarcKATP channel blocker, HMR1098 and a selective mitoKATP channel blocker, 5-hydroxydecanoate, were added to the perfusion fluid 10 min before occlusion. Myocardial apoptosis was detected immunohistochemically using the TUNEL method. Myocardial inducible NOS (iNOS) and endothelial NOS (eNOS) were determined immunohistochemically. In control hearts, apoptosis induction was associated with a greater immunoreactivity of iNOS than eNOS. Treatment with HMR1098, at a concentration of 3 mu mol/l, significantly reduced the TUNEL-positive cardiomyocytes and this was associated with decreased iNOS and increased eNOS immunoreactivity. When this drug was administered at a higher concentration, at 30 mu mol/l, a more marked reduction in apoptosis was observed but, in contrast to the effects observed at the lower drug concentration, eNOS immunoreactivity was almost completely abolished while iNOS was strong. Moreover, ischemia-induced cardiac dysfunction (e.g. contractile force and recovery of coronary flow) was increased by the higher concentration of HMR 1098. In hearts treated with 5-hydroxydecanoate, myocyte apoptosis was slightly reduced, and this was associated with an almost equal increase in both iNOS and eNOS immunoreactivity. These findings suggest that iNOS appears to be more important than eNOS in the reduction of apoptosis. However, the further inhibition of apoptosis by the higher concentration of HMR 1098 was associated with poorer cardiac function. (C) 2006 Elsevier GmbH. All rights reserved.