Abstract | OBJECTIVES: 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 micromol/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 mitoK ATP channels. A selective mitoK ATP channel opener, diazoxide (100 micromol/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 mitoK ATP 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 mitoK ATP channels is associated with preservation of mitochondrial function during ischemia/reperfusion.
|
Authors | T Miura, Y Liu, H Kita, T Ogawa, K Shimamoto |
Journal | Journal of the American College of Cardiology
(J Am Coll Cardiol)
Vol. 35
Issue 1
Pg. 238-45
(Jan 2000)
ISSN: 0735-1097 [Print] United States |
PMID | 10636286
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Potassium Channels
- Receptors, Purinergic P1
- Adenosine Triphosphate
- Protein Kinase C
|
Topics |
- Adenosine Triphosphate
(physiology)
- Animals
- Electron Transport
(physiology)
- Male
- Mitochondria, Heart
(pathology, physiology)
- Myocardial Infarction
(pathology, physiopathology)
- Myocardial Reperfusion Injury
(pathology, physiopathology)
- Potassium Channels
(physiology)
- Protein Kinase C
(physiology)
- Rabbits
- Receptors, Purinergic P1
(physiology)
- Signal Transduction
(physiology)
|