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EXPERIMENTAL STUDIES

Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A₁ receptor activation

Tetsuji Miura, MD, PhD^* , Yongge Liu, PhD, Hiroyuki Kita, MD, PhD^* , Takashi Ogawa, MD, PhD^* and Kazuaki Shimamoto, MD, PhD^*

^* Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
Otsuka America Pharmaceutical Inc., Rockville, Maryland, USA

Manuscript received March 29, 1999; revised manuscript received July 23, 1999, accepted September 13, 1999.

Reprint requests and correspondence: Dr. Tetsuji Miura, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-0061, Japan
miura{at}sapmed.ac.jp

OBJECTIVES

This study intended to assess the role of mitochondrial ATP-sensitive potassium (mitoKATP) channels and the sequence of signal transduction with protein kinase C (PKC) and adenosine A₁ receptors in rabbits.

BACKGROUND

To our knowledge, the link between trigger receptors of preconditioning, PKC and mitoKATP channels has not been examined in a whole heart model of infarction.

METHODS

In the first series of experiments, myocardial infarction was induced in isolated buffer-perfused rabbit hearts by 30-min global ischemia and 2-h reperfusion. Infarct size in the left ventricle was determined by tetrazolium staining and expressed as a percentage of area at risk (i.e., the whole left ventricle) (%IS/AR). In the second series of experiments, mitochondria were isolated from the heart, and their respiratory function was examined using glutamate as a substrate.

RESULTS

Pretreatment with R-phenylisopropyladenosine (R-PIA, 1 µmol/liter), an A₁-receptor agonist, reduced %IS/AR from 49.8 ± 6.5% to 13.4 ± 2.9%. This protection was abolished by calphostin C, a PKC inhibitor, and by 5-hydroxydecanoate (5-HD), a selective inhibitor of mitoKATP channels. A selective mitoKATP channel opener, diazoxide (100 µmol/liter), mimicked the effect of R-PIA on infarct size (%IS/AR = 11.6 ± 4.0%), and this protective effect was also abolished by 5-HD. However, calphostin C failed to block the infarct size–limiting effect of diazoxide. Neither calphostin C nor 5-HD alone modified %IS/AR. State III respiration (QO₂) and respiratory control index (RCI) were reduced after 30 min of ischemia (QO₂ = 147.3 ± 5.3 vs. 108.5 ± 12.3, RCI = 22.3 ± 1.1 vs. 12.1 ± 1.8, p < 0.05). This mitochondrial dysfunction was persistent after 10 min of reperfusion (QO₂ = 96.1 ± 15.5, RCI = 9.5 ± 1.9). Diazoxide significantly attenuated the respiratory dysfunction after 30 min of ischemia (QO₂ = 142.8 ± 9.7, RCI = 16.2 ± 0.8) and subsequent 10-min reperfusion (QO₂ = 135.3 ± 7.2, RCI = 19.1 ± 0.8).

CONCLUSIONS

These results suggest that mitoKATP channels are downstream of PKC in the mechanism of infarct-size limitation by A₁-receptor activation and that the anti-infarct tolerance afforded by opening of mitoKATP channels is associated with preservation of mitochondrial function during ischemia/reperfusion.

Abbreviations and Acronyms   5-HD = 5-hydroxydecanoate   %IS/AR = infarct size as a percentage of area at risk   KATP channel = ATP-sensitive potassium channel   LVDP = left ventricular developed pressure   mitoKATP channel = mitochondrial ATP-sensitive potassium channel   PKC = protein kinase C   QO2 = the rate of oxygen consumption in state III respiration   RCI = respiratory control index   R-PIA = R-phenylisopropyladenosine

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