- Record: found
- Abstract: found
- Poster: found
Characterization of Two Novel Pharmacological ATP-Sensitive Potassium Channels Modulators in Isolated Rat Heart Mitochondria
Alexandra Petrus, Oana Duicu, Adrian Sturza, Lavinia Noveanu, István Baczkó, Danina Muntean, Norbert Jost
2014-10-14
This work has been published open access under Creative Commons Attribution License CC BY 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com.
mitochondrial ATP-sensitive potassium channels, cardiac arrhythmias, mild uncoupling
Abstract
Background Mitochondrial dysfunction plays a major role in the pathogenesis of ischemia/reperfusion injury and cardiac arrhythmias. Mitochondrial ATP-sensitive potassium channel (mitoKATP) openers such as diazoxide and pinacidil have been reported to elicit cardioprotective effects via mild uncoupling and/or respiratory chain inhibition. The aim of the present study was to characterize the effects of two novel mitoKATP modulators (KL-1488 and KL 1495) on the respiratory rates and calcium retention capacity of isolated rat heart mitochondria. Methods Mitochondrial respiratory function was assessed by high-resolution respirometry (Oxygraph-2k Oroboros Ltd.) at 370C according to the Substrate-Uncoupler-Inhibitor Titration (SUIT) protocol, as follows: complex I (CI) and complex II (CII) dependent respiration was stimulated by glutamate + malate and rotenone + succinate, respectively (State 2) and subsequent ADP (State 3, OXPHOS state) addition; cytochrome c addition evaluated the intactness of the outer mitochondrial membrane; ATP synthase was inhibited by oligomycin (State 4); uncoupled respiration was obtained by FCCP titration; respiration was inhibited with antimycin A. Calcium retention capacity (CRC) was determined by spectrofluorimetry and calculated as the amount of calcium taken by mitochondria before opening of the mitochondrial permeability transition pore (mPTP) in the presence of the pharmacological agents. Results For both C I and C II-supported respiration, 150 µM of KL 1495 (but not of KL 1488) significantly increased respiratory rates in State 2 and 4, and decreased State 3 respiration, respectively. No inhibition of mPTP opening was observed in the presence of either compound. Conclusion The mitochondrial uncoupling and respiratory chain inhibition induced by KL 1495 could play a role in cardioprotection during the postischemic reperfusion. The research was funded by the POSDRU grant no. 159/1.5/S/136893 titled “Parteneriat strategic pentru creșterea calității cercetării științifice din universitățile medicale prin acordarea de burse doctorale și postdoctorale – DocMed.Net_2.0” (A.P.).
Content
Author and article information
Journal
10.14293/P2199-8442.1.SOP-MED.PIIL0I.v1