Attenuated cardioprotection by ischemic preconditioning in coronary stenosed heart and its restoration by carvedilol.
OBJECTIVE
Infarct size (IS) reduction by ischemic preconditioning (IPC) has been assessed in the heart in which coronary stenosis (CS)-induced chronic ischemia was not present. The aim of this study is to assess whether and how IS reduction by IPC is modified in the heart in which CS has occurred, and how further therapeutics, if any, modify it.


METHODS
We assessed the IS produced by a 30-minute acute coronary occlusion and a 24-hour reperfusion (COR) in rat hearts in which CS had developed for 1-12 weeks. Modifications of IS by IPC and the mitochondrial KATP channel (mitoKATP) opener and blocker, and the effects of daily beta-blocker treatment with carvedilol on them, were also assessed. Myocardial protein kinase C (PKC)-epsilon activities in the risk areas were measured by Western blotting.


RESULTS
One to 4 weeks after CS induction, myocardial PKC-epsilon was activated in the risk area of CS even without IPC, but such CS-induced PKC activation as well as that by IPC was attenuated 8-12 weeks after CS. The IS reductions by the mitoKATP opener as well as by IPC were attenuated 8-12 and 4-12 weeks after CS, respectively. Daily carvedilol treatment after inducing CS restored the malfunctioning PKC-mitoKATP signal cascade and the attenuated IPC and mitoKATP effect on IS.


CONCLUSIONS
CS activates the PKC-mitoKATP signal cascade, mimicking the IPC effect, whereas this cardioprotective effect is attenuated late after CS via their downregulation. Restoration of these changes may be a novel mechanism for cardioprotection by carvedilol in the CS-induced ischemic heart.
Watanabe
Kenichi
K
First Department of Internal Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima 960-1295, Japan.
Yaoita
Hiroyuki
H
Ogawa
Kazuei
K
Oikawa
Masayoshi
M
Maehara
Kazuhira
K
Maruyama
Yukio
Y
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D023921:Coronary Stenosis / Q000150:complications* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D015221:Potassium Channels / Q000378:metabolism; D011412:Propanolamines / Q000627:therapeutic use*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D015221:Potassium Channels; D011412:Propanolamines; C117780:mitochondrial K(ATP) channel; D000077261:Carvedilol; C497257:Prkce protein, rat; D051744:Protein Kinase C-epsilon