[Cardioprotective mechanism of ischemic preconditioning is impaired by postinfarct ventricular remodeling through angiotensin II type 1 receptor activation].
BACKGROUND
Activation of protein kinase C-linked receptors and subsequent opening of the mitochondrial adenosine triphosphate-sensitive K+ (mitoKatp) channel is crucial in preconditioning. This study examined whether post-infarct ventricular remodeling interferes with the preconditioning mechanism.


RESULTS
Two weeks before isolation of hearts, rabbits underwent a sham operation or coronary ligation (COL) to induce remodeling. Isolated buffer perfused hearts were subjected to 30-min global ischemia/2-hr reperfusion, and infarct size was expressed as a percentage of the left ventricle (%I/LV), from which the scarred infarct by COL was excluded. Although %I/LV was similar in sham-operated and remodeled hearts (52.9 +/- 6.5% vs 45.8 +/- 5.2%), preconditioning with 2 episodes of 5-min ischemia protected sham-operated but not remodeled hearts (%I/LV = 18.1 +/- 2.5% vs 54.8 + 2.9%, p < 0.05). Infusion of valsartan (10 mg/kg/day; Val), an angiotensin II type 1 receptor blocker, for 2 weeks after COL prevented the ventricular remodeling and preserved the response to preconditioning (%I/LV = 27.4 +/- 3.8%), though Val alone did not change %I/LV. Diazoxide, a mitoKatp channel opener, protected both sham-operated and remodeled hearts (%I/LV = 14.1 +/- 3.1% and 8.3 +/- 3.6%).


CONCLUSIONS
The myocardium remodeled after infarction is refractory to preconditioning, which is probably due to interruption of cellular signaling by preconditioning upstream of mitoKatp channels. An angiotensin II type 1 receptor blocker is beneficial not only for suppression of ventricular remodeling but also for preservation of the preconditioning mechanism.
Second Department of Internal Medicine, Sapporo Medical University, Sapporo.
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T
Miki
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T
Miura
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Tsuchida
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Nakano
T
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Hasegawa
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Fukuma
K
K
Shimamoto
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000503:physiopathology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000502:physiology*
D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine