摘要：

OBJECTIVES This study intended to assess the role of mitochondrial ATP-sensitive potassium (mitoK atp) channels and the sequence of signal transduction with protein kinase C (PKC) and adenosine A 1 receptors in rabbits. BACKGROUND To our knowledge, the link between trigger receptors of preconditioning, PKC and mitoK atp 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 A 1-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 mitoK atp channels. A selective mitoK atp 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 (Q o 2) and respiratory control index (RCI) were reduced after 30 min of ischemia (Q o 2 = 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 (Q o 2 = 96.1 ± 15.5, RCI = 9.5 ± 1.9). Diazoxide significantly attenuated the respiratory dysfunction after 30 min of ischemia (Q o 2 = 142.8 ± 9.7, RCI = 16.2 ± 0.8) and subsequent 10-min reperfusion (Q o 2 = 135.3 ± 7.2, RCI = 19.1 ± 0.8). CONCLUSIONS These results suggest that mitoK atp channels are downstream of PKC in the mechanism of infarct-size limitation by A 1-receptor activation and that the anti-infarct tolerance afforded by opening of mitoK atp channels is associated with preservation of mitochondrial function during ischemia/reperfusion.

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