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5-HD abolishes ischemic preconditioning independently of monophasic action potential duration in the heart
J Munch-Ellingsen1, J E Løkebø, E Bugge
1Department of Medical Physiology, Institute of Medical Biology, University of Tromsø, Norway. jensme@fagmed.uit.no
Insights
5-hydroxydecanoate (5-HD) abolished the infarct-reducing effects of ischemic preconditioning (IPC) in rat and rabbit hearts. This suggests the mitochondrial KATP channel, not the sarcolemmal KATP channel, is key to IPC
Area of Science:
- Cardiovascular Physiology
- Cellular Electrophysiology
- Ischemic Heart Disease Research
Background:
- Ischemic preconditioning (IPC) protects the heart from ischemia-reperfusion injury.
- The role of ATP-sensitive potassium (KATP) channels in IPC remains debated, with conflicting results across species.
- 5-hydroxydecanoate (5-HD) is a known blocker of mitochondrial KATP channels.
Purpose of the Study:
- To investigate the effect of 5-HD on IPC-induced cardioprotection in rat and rabbit models.
- To determine if IPC or IPC with 5-HD affects action potential duration in rabbit hearts.
Main Methods:
- Isolated rat hearts and in situ rabbit hearts underwent regional ischemia and reperfusion.
- IPC was induced using short cycles of ischemia and reperfusion.
- 5-HD was administered before IPC; infarct size and monophasic action potential duration (MAPD50) were measured.
Main Results:
- 5-HD abolished the infarct-reducing effect of IPC in both rat and rabbit hearts.
- In rabbits, 5-HD did not abolish the ischemia-induced shortening of MAPD50.
- IPC and IPC + 5-HD both shortened MAPD50 compared to control in rabbits.
Conclusions:
- 5-HD abolishes IPC-induced cardioprotection in rat and rabbit hearts.
- The findings suggest a role for the mitochondrial KATP channel in the protective mechanism of IPC.
- The sarcolemmal KATP channel is unlikely to be involved in the protective effects of IPC.
Objective:
Blocking of the KATP channel with either glibenclamide or 5-hydroxydecanoate (5-HD) has been shown to abolish the infarct reducing effect of ischemic preconditioning (IPC) in hearts from several species, but the results in rat and rabbit have been equivocal. In this study we investigated if 5-HD could abolish IPC in rat and rabbit and further if IPC or IPC + 5-HD were affecting action potential duration in the rabbit heart.
Methods:
The rat hearts were isolated and retrogradely perfused on a Langendorff perfusion apparatus with Krebs-Henseleit buffer. The rabbit experiments were performed in an in situ model. Rat and rabbit hearts were subjected to 30 min regional ischemia by ligating a coronary artery followed by 120 min (rat) or 150 min (rabbit) of reperfusion. The preconditioning protocol was one or three cycles of 5 min ischemia plus 5 min reperfusion in the rat and one cycle of 5 min ischemia plus 10 min reperfusion in the rabbit. In the rat 5-HD was added to the reservoir before ischemic preconditioning in different concentrations, and in the rabbit 5-HD was given as a bolus 5 mg/kg intraventricularly 2 min before the preconditioning ischemia. In the rabbit epicardial monophasic action potential duration at 50 % repolarization (MAPD50) was measured at 1, 2 and 5 min in each of the ischemic periods using a contact pressure electrode. Infarcts were measured with tetrazolium staining and risk zone volumes with fluorescent microspheres.
Results:
All data are presented as infarct size in % of risk zone volume (mean +/- SEM). In the rat 200 microM of 5-HD abolished the protective effect of one cycle of IPC (28.6 +/- 4.7 versus 8.4 +/- 0.8) and 500M of 5-HD abolished three cycles of IPC (50.7 +/- 7.8 versus 8.4 +/- 2.0). Control was 40.9 +/- 2.8. In the rabbit 5-HD abolished IPC (41.2 +/- 7.2 versus 8.1 +/- 3.2). Control was 53.5 +/- 12.4. MAPD50 were significantly more shortened compared to control at 1 and 2 min into the 30 min ischemia for the IPC and IPC+5-HD.
Conclusions:
We conclude that 5-HD abolishes ischemic preconditioning when given before the preconditioning ischemia in both rat and rabbit but does not abolish the ischemia induced shortening of the action potential duration in the rabbit; thus, a role for the mitochondrial KATP channel and not the sarcolemmal KATP channel in the protective mechanism behind IPC is probable.