[The influence of the fluorine-containing activators of mitochondrial adenosine triphosphate sensitive potassium channels on the oxidative phosphorilation]

Abstract

The cardioprotective mechanism of KATP channel openers and especially their influence on mitochondrial respiration has not been clarified yet. In this article we investigated the effect of DiazoFm and DiazoFp, the new fluor-containing analogues of diazoxide and the potential mitochondrial KATP channel openers, on the oxidative phosphorylation in the isolated mitochondria. It was shown that the influence of KATP channel openers on ADP-stimulated oxygen consumption (State 3) depended on the substrates we used (succinate or 2-oxoglutarate sodium). We have shown that the depression of State 3 was less when we used DiazoFm (30 MM) and DiazoFp (30 MM) in comparison with Diazoxide in experiments where succinate was used. The fluor-containing KATP, channels openers did not significantly change the activity of succinate dehydrogenase in comparison with diazoxide (it decreased succinate dehydrogenase activity by 27%). Thus, the fluor-containing analogues of diazoxide did not significant influence on the complex II of the respiratory chain. In the other experiments when we used 2-oxoglutarate sodium as an oxidative substrate, DiazoFp increased ADP-stimulated oxygen consumption by 33%. All the studied KATP openers have an uncoupling effect, regardless the substrates we used. This effect was more significant when we used succinate as a substrate. We have shown that the uncoupling effect of oxidative phosphorylation is a consequence of K channels activation. This statement was proved by 5-hydroxydecanoate (200 MM) with depressed influence of Diazoxide and its fluoring-containing analogues. Conclusion. The fluor-containig KATP channels openers had not direct influence on the respiratory chain in mitochondria, but activation mitochondrial KATP channels by them lead to uncoupling phosporylation and respiration.