Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways.
OBJECTIVE
An in situ model was used to test whether and how multiple occlusions at reperfusion can protect rabbit myocardium.


BACKGROUND
Recently it was demonstrated that postconditioning in dogs salvaged ischemic myocardium.


METHODS
Control hearts underwent 30-min regional ischemia/3-h reperfusion, whereas in experimental hearts four postconditioning cycles of 30-s occlusion/30-s reperfusion starting 30 s after release of the index coronary occlusion were added in the presence or absence of various cell signaling antagonists.


RESULTS
Postconditioning decreased infarction from 35.4 +/- 2.7% of the risk zone in control hearts to 19.8 +/- 1.8% (p < 0.05). Six cycles did not result in greater protection. If postconditioning cycles were begun after 10 min of reperfusion, protection was no longer evident. Either the non-selective K(ATP) channel closer glibenclamide or the putatively selective mitochondrial K(ATP) channel antagonist 5-hydroxydecanoate administered 5 min before reperfusion blocked the protection afforded by postconditioning, indicating involvement of the mitochondrial K(ATP) channel. PD98059, a mitogen-activated protein/extracellular-signal regulated kinase (MEK) 1/2 and therefore extracellular-signal regulated kinase (ERK) inhibitor, and N(omega)-nitro-L-arginine methyl ester, an antagonist of nitric oxide synthase, infused shortly before reperfusion also aborted the protection afforded by postconditioning. Combined ischemic postconditioning and preconditioning resulted in significantly greater protection than either alone.


CONCLUSIONS
Multiple, short, regional coronary occlusions immediately after prolonged myocardial ischemia are an effective cardioprotective intervention in the rabbit, and the mechanism of protection involves activation of ERK, production of nitric oxide, and opening of mitochondrial K(ATP) channels. These observations suggest that a similar approach could be applied in the cardiac catheterization laboratory to protect reperfused myocardium after primary angioplasty in patients with acute myocardial infarction.
Yang
Xi-Ming
XM
Department of Physiology, University of South Alabama, College of Medicine, Mobile 36688, USA.
Proctor
J Bradley
JB
Cui
Lin
L
Krieg
Thomas
T
Downey
James M
JM
Cohen
Michael V
MV
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics; D006880:Hydroxy Acids / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009203:Myocardial Infarction / Q000473:pathology; D015425:Myocardial Reperfusion; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D002121:Calcium Channel Blockers; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D015221:Potassium Channels; C052853:5-hydroxydecanoic acid; D020928:Mitogen-Activated Protein Kinases; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester