| Abstract | Trimetazidine (TMZ) affects mitochondrial function during ischemia. Mitochondrial permeability transition is a pivotal event in cardiomyocyte death following acute ischemia. The aim of the present study was to determine whether the anti-ischemic agent TMZ might modulate mitochondrial permeability transition pore (mPTP) opening and limit lethal ischemia-reperfusion injury. Anesthetized NZW rabbits underwent 30 min of coronary artery occlusion followed by 4 hours of reperfusion. Prior to this, they underwent either no intervention (control, C), ischemic preconditioning (PC), or an IV injection of 5 mg kg(-1) TMZ 10 min before ischemia (TMZ). Additional rabbits (Sham group) underwent no ischemia/reperfusion throughout the experiment. Infarct size was assessed by triphenyltetrazolium staining, and apoptosis via measurement of caspase 3 activity. Ca(2+)-induced mPTP opening was assessed in mitochondria isolated from ischemic myocardium. TMZ and PC significantly reduced infarct size that averaged 34 +/- 4% and 21 +/- 4% of the risk region respectively, versus 63 +/- 6% in controls (P<0.005). Caspase 3 activity was reduced in both TMZ and PC groups: 37 +/- 11 and 29 +/- 7 respectively, versus 68 +/- 9 nmol min(-1) mg(-1) mitochondrial protein in controls (P=0.01 versus TMZ and PC). In controls, Ca(2+) load required for mPTP opening averaged 11 +/- 4 microM mg(-1) mitochondrial protein versus 116 +/- 6 in shams (P<0.0001). Pre-treatment by TMZ or PC attenuated this, with Ca(2+) loads averaging 45 +/- 4 and 46 +/- 4 microM mg(-1) mitochondrial proteins, respectively (P<0.005 versus C). These data suggest that TMZ inhibits mPTP opening and protects the rabbit heart from prolonged ischemia-reperfusion injury. |
| Authors | Laurent Argaud, Ludovic Gomez, Odile Gateau-Roesch, Elisabeth Couture-Lepetit, Joseph Loufouat, Dominique Robert, Michel Ovize
(Affiliation: Inserm, E0226, 69003 Lyon, France.)
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| Journal | Journal of molecular and cellular cardiology
(J Mol Cell Cardiol)
Vol. 39
Issue 6
Pg. 893-9
(Dec 2005)
ISSN: 0022-2828 England |
| PMID | 16243351
(Publication Type: Journal Article)
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| Chemical References |
- Ion Channels
- Mitochondrial Membrane Transport Proteins
- Vasodilator Agents
- mitochondrial permeability transition pore
- Trimetazidine
- Calcium
|
| Topics |
- Animals
- Calcium
(metabolism)
- Calcium Signaling
(drug effects)
- Ion Channels
(metabolism)
- Male
- Mitochondria, Heart
(metabolism)
- Mitochondrial Membrane Transport Proteins
- Permeability
(drug effects)
- Rabbits
- Reperfusion Injury
(metabolism, prevention & control)
- Trimetazidine
(administration & dosage)
- Vasodilator Agents
(administration & dosage)
|
