Pharmacological and ischemic preconditioning of the human myocardium: mitoK(ATP) channels are upstream and p38MAPK is downstream of PKC.
BACKGROUND
These studies investigate the role of mitoK(ATP) channels, protein kinase C (PKC) and Mitogen activated protein kinase (p38MAPK) on the cardioprotection of ischemic (IP) and pharmacological preconditioning (PP) of the human myocardium and their sequence of activation.


RESULTS
Right atrial appendages from patients undergoing elective cardiac surgery were equilibrated for 30 min and then subjected to 90 min of simulated ischemia followed by 120 min reoxygenation. At the end of each protocol creatinine kinase leakage (CK U/g wet wt) and the reduction of MTT to formazan dye (mM/g wet wt) were measured. Similar protection was obtained with alpha1 agonist phenylephrine, adenosine and IP and their combination did not afford additional cardioprotection. Blockade of mitoK(ATP) channels with 5-hydroxydecanoate, PKC with chelerythrine, or p38MAPK with SB203580 abolished the protection of IP and of PP. In additional studies, the stimulation of mitoK(ATP) channels with diazoxide or activation of PKC with PMA or p38MAPK with anisomycin induced identical protection to that of IP and PP. The protection induced by diazoxide was abolished by blockade of PKC and by blockade of p38MAPK. Furthermore, the protection induced by PMA was abolished by SB203580 but not by 5-hydroxydecanoate, whereas the protection induced by anisomycin was unaffected by either 5-hydroxydecanoate or chelerythrine.


CONCLUSIONS
Opening of mitoK(ATP) channels and activation of PKC and p38MAPK are obligatory steps in the signal transduction cascade of IP and PP of the human myocardium with PKC activation being downstream of the opening of mitoK(ATP) channels and upstream of p38MAPK activation.
Department of Integrative Human Cardiovascular Physiology and Functional Genomics, Division of Cardiac Surgery, University of Leicester, Glenfield Hospital, Groby Road, Leicester. mahmoud.loubani@ntlworld.com
Mahmoud
M
Loubani
Manuel
M
Galiñanes
D058668:Adrenergic alpha-1 Receptor Antagonists; D006348:Cardiac Surgical Procedures / Q000379:methods; D002316:Cardiotonic Agents / Q000494:pharmacology; D017558:Elective Surgical Procedures / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000601:surgery; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008929:Mitochondria, Heart / Q000201:enzymology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000517:prevention & control*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D058915:Purinergic P1 Receptor Antagonists; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D058668:Adrenergic alpha-1 Receptor Antagonists; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D058915:Purinergic P1 Receptor Antagonists; C117780:mitochondrial K(ATP) channel; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases