p38-MAPK is involved in restoration of the lost protection of preconditioning by nicorandil in vivo.
Nicorandil, a selective mitochondrial K(ATP) channel opener, reinstates the waned protection after multiple cycles of preconditioning. In this study, we determined the signal transduction activated in heart after 3 or 8 cycles of preconditioning and prolonged ischemia in rabbits treated with placebo or nicorandil. In a first series (eight groups) we evaluated the (%) infarct to risk ratio after 30 min ischemia/3 h reperfusion and in a second series (six groups), we assessed the intracellular levels of cyclic GMP (c-GMP), protein kinase C (PKC) activity and p38-mitogen activated protein kinase (p38-MAPK) phosphorylation from heart samples taken during the long ischemia. Cardioprotection by 3 cycles of preconditioning (11.7+/-3.8% vs 45.9+/-5.2% in the control, P<0.001) was lost after 8 cycles (43.9+/-5.1%, P=NS vs control). Nicorandil restored it to the levels of classic preconditioning (13.7+/-2.4% vs 40.8+/-3.5% in respective controls, P<0.001). This was reversed by the p38-MAPK inhibitor SB203580 (48.8+/-5.1%) which had no protective effect in the control group (44.6+/-5.8%). In the placebo-treated rabbits, intracellular c-GMP and PKC were increased only in the group subjected to 3 cycles of preconditioning. Despite that nicorandil equalizes the intracellular levels of c-GMP, PKC and activated p38-MAPK at the long ischemia, specific alterations of p38-MAPK phosphorylation differentiate the protected groups. Our data delineate the signal transduction mechanism mediating the beneficial effect of nicorandil and imply that the recapture of the lost protection is due to a dynamic process of the intracellular mediators accompanied by an increase in p38-MAPK phosphorylation and not to an instantaneous event.
Iliodromitis
Efstathios K
EK
2nd University Department of Cardiology, Medical School, Attikon General Hospital, University of Athens, Athens, 124 62, Greece.
Aggeli
Ioanna-Katerina S
IK
Gaitanaki
Catherine
C
Tsiafoutis
Ioannis
I
Zoga
Anastasia
A
Beis
Isidoros
I
Kremastinos
Dimitrios Th
DT
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control; D020108:Nicorandil / Q000494:pharmacology*; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D015221:Potassium Channels; D011725:Pyridines; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP; C093642:SB 203580