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PhD Tkachenko H., Prof., DSci Kurhalyuk N. 1
Department of Hygiene and Toxicology, Danylo Halytskiy Lviv National Medical University , Lviv , Ukraine , 1 Department of Animals Physiology , Institute of Biology and Environment Protection, Pomeranian University , S?upsk , Poland ;
Opening of K ATP Channel Induces Cardioprotective Effect during Stress : Role of Intermittent Hypoxia
Stress condition seems to be quite capable of causing oxidative stress in many organs, includes cardiovascular system. Opening of K ATP channel was found to preserve mitochondria l function and the normal mitochondria l oxygen consumption rate, and lowering Ca 2+ overloading of mitochondria during hypoxia in ischemic rat heart (Iwai et al., 2000; Tkachenko , Kurhalyuk , 2006, 2007).
Intermittent hypoxia (IH) improves the enhancement of energy support producing by increasing formation of mitochondria, activating electron flux through mitochondrial respiratory complex I, and increasing efficiency of oxidative phosphorylation ( Manukhina et al., 2006). The association of oxidative stress with reduce of mitochondrial respiration suggests that an openers of the K ATP channel may enhance the cell protection under oxidative damage ( Zhuo et al., 2005). The hypoxic training may influence nitric oxid (NO) production, NO tissue concentration, and NO- synthase expression ( Manukhina et al., 2006 ) . The protective effects of NO have been linked directly to mitochondrial K ATP activation ( Ockaili et al., 1999). Thus, an ideal treatment for stress condition should encompass both openers of the K ATP channel and IH actions. Therefore, it was of particular interest to ascertain whether pinacidil , the opener of the K ATP channel, and IH also possess protective properties and whether their coadministration could offer additional beneficial effects on mitochondrial respiration processes during stress condition.
Accordingly, the goals of the present study were 1 ) to show that the pharmacological opening of the K ATP channel with pinacidil induces cardioprotection during stress, 2 ) to investigate the protective effect of adaptation to IH in mitochondrial function, 3) to determine whether the protective role of pinacidil is dependent on effect of adaptation to IH.
Role of � ATP channel opener pinacidil , blocker glibenclamide and IH on the mitochondrial function during stress were evaluated in six groups of rats. Mitochondria respi rat ion and oxidative phosphorylation were studied with polarographic methods using a Clark oxygen electrode by the method of Chance and Williams (1956). Succinate ( 0.35 mM final concentration) and ?- ketoglutarate (1mM) were used as oxidative substrates. ADP (phosphate acceptor) was administered in concentration 0.2 mM . Inhibitory analysis with rotenone and malonic acid was used for the estimation of the role of NAD- and FAD-generated substrates in mitochondrial oxidation. Concentration of NO 2 � and NO 3 � in the serum and erythrocytes was estimated by the method of Green et al. (1982). The data were statistically analyzed using t-test of Student.
In this study we report 3 findings. First, we have demonstrated that exposure of rats to IH induces protection against stress. Adaptation of rats to IH stimulated NO production as indicated by doubled plasma concentrations of nitrite and nitrate and significantly improved the rat e of oxidative phosphorylation and the respiratory ratio by Chance in heart mitochondria. Therefore, t he protective effect of IH induced by oxidation of NADH-generating substrates in heart mitochondria. Therefore, the hypoxic training in our experiments caused elevation of mitochondrial oxidative processes functioning (respiratory control ratio and rate of phosphorylation ) during oxidation of NADH-generated substrates (?- ketoglutarate ).
Second, we demonstrated the protective effect of pinacidil on mitochondrial functioning in rat�s heart during stress. Consequently, the negative effects of oxidative stress caused the decrease the role of NADH-generating substrates in mitochondria l oxidization. Administration of the pinacidil also induces protection against stress injury via activation of oxidative phosphorylation (the rate ADP-induced mitochondrial respiration , the efficiency of phosphorylation , the respiratory control ratio, and the rat e of oxidative phosphorylation ) in the presence of ?- ketoglutarate .
Third, the treatment of stress-exposed animals with a combination of IH and pinacidil was significantly more effective than either of them alone in reversing the mitochondrial respiration data and lipid peroxidation level in rat�s heart. However, the actions of pinacidil by enhancing of all mitochondrial respiration parameters in the presence of ?- ketoglutarate can provide some beneficial effects during stress independent of preexposed rats with an IH method. Thus it appears that both the pinacidil and IH have complimentary roles in the cardioprotection afforded by stress condition, and they may act together to elicit beneficial effects on the heart.
References :
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