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Mitochondrial KATP channels participate in the limitation of infarct size by cariporide
Ignacio Pérez Nuñez1, Juliana Fantinelli, Luisa F González Arbeláez
1Fellowship of CONICET, Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina.
Abstract:
The objective of this study is to assess the participation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels in the cardioprotective effects of the Na(+)/H(+) exchanger (NHE-1) blocker cariporide in isolated rat hearts. Regional ischemia was induced by occlusion of left anterior descending coronary artery during 40 min followed by 2-h reperfusion (IC). Cariporide (C, 10 μΜ), or C plus 5-hydroxydecanoate (5-HD, 100 μM, a selective mitoK(ATP) channel inhibitor), or C plus chelerythrine (Chele, 1 μM, a PKC inhibitor), or an opener of mitoK(ATP) channels, diazoxide (Dz, 100 μM) was applied at the onset of reperfusion. Infarct size (IS) and myocardial function were evaluated. The calcium-induced permeability transition pore (mPTP) opening was determined by measuring the light scattering decrease (LSD, a.u.) in isolated mitochondria in the absence and presence of C, C + 5-HD and Dz. IS was 33 ± 2% of the risk area in IC and was significantly diminished by C (15 ± 2%, p < 0.05), which also improved myocardial function [LVDP = 58 ± 5% (IC) vs 80 ± 5% (C)] and blunted LSD [0.80 ± 0.04 (IC) vs 0.51 ± 0.04 (C) a.u.]. 5-HD and Chele were both able to abolish the cardioprotective effects of C on IS. Dz treatment decreased IS and LSD to a similar extent to that produced by C (15 ± 4% and 0.52 ± 0.04 a.u., respectively). The present data suggest that attenuation of mPTP opening after PKC-mediated mitoK(ATP) channel activation is a crucial step for the cardioprotective effects of cariporide.
Insights
Cariporide protects isolated rat hearts by activating mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels, which inhibits the mitochondrial permeability transition pore (mPTP) opening. This mechanism is crucial for cariporide
Area of Science:
- Cardiovascular Research
- Mitochondrial Physiology
- Pharmacology
Background:
- The Na(+)/H(+) exchanger (NHE-1) plays a role in cardiac protection.
- Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels are implicated in cardioprotection.
- Cariporide is an NHE-1 blocker with potential cardioprotective effects.
Purpose of the Study:
- To investigate the role of mitoK(ATP) channels in cariporide-induced cardioprotection.
- To determine if cariporide's effects involve the mitochondrial permeability transition pore (mPTP).
Main Methods:
- Isolated rat heart model of regional ischemia-reperfusion.
- Administration of cariporide, mitoK(ATP) channel inhibitors (5-hydroxydecanoate), PKC inhibitors (chelerythrine), and mitoK(ATP) channel openers (diazoxide).
- Assessment of infarct size, myocardial function, and mitochondrial light scattering decrease (LSD) to evaluate mPTP opening.
Main Results:
- Cariporide significantly reduced infarct size and improved myocardial function.
- Cariporide attenuated mPTP opening, as indicated by reduced LSD.
- Inhibition of mitoK(ATP) channels or PKC abolished cariporide's cardioprotective effects.
- Diazoxide mimicked cariporide's protective effects on infarct size and mPTP opening.
Conclusions:
- Cariporide exerts cardioprotection through activation of mitoK(ATP) channels.
- This activation leads to the attenuation of mPTP opening, likely mediated by PKC.
- MitoK(ATP) channel participation is a critical step in cariporide's cardioprotective mechanism.
