[Cardioprotective effects of flokalin: relative role of activation of sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels].

In experiments on isolated Langendorff perfused hearts of guinea pig with modeling of ischemia (20 min) and reperfusion (40 min) the cardioprotective effects of flokalin were shown. Preliminary preischemic perfusion of isolated heart with flokalin (5 mM) for 5 minutes has significantly improved the recovery of contractive function ofischemic myocardium at repcrfusion. Particularly, recovery of systolic and developed pressure was improved and the increasing of end-diastolic pressure in left ventricle was prevented. The vasoconstriction of coronary vessels was prevented and number of extrasystols at reperfusion of ischemic heart was decreased. Morphological studies have shown that flokalin prevents the significant damage of myocardial structure and the development of hypercontraction of myofibrils at ischemia-reperfusion of myocardium. It also preserves the intact sarcolemma and intracellular organelles. The intact structure of mitochondria also was saved by flokalin that maintains the energy potential of myocardium. Using the selective blocker of mitochondrial K(ATP) channels 5-hydroxydecanoate (200 mM) allows to determine the relative role of sarcolemmal and mitochondrial K(ATP) channels activation in these effects. It was shown that mitochondrial as well as sarcolemmal K(ATP) channels play role in the recovery of ischemic myocardium functions: first are responsible for recovery of contractive function and second are responsible for coronary blood flow recovery.

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

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.

[Effect of adenosine triphosphate-sensitve potassium channel activator flokalin on the isolated heart functions].

In the experiments, using isolated, perfused according to Langendorff heart of guinea pig, was investigated the effect of flokalin, a new fluor-containing opener of ATP sensitive channels (K(ATP)), upon the functioning of the heart. It was shown, that flokalin in a dose dependent manner dilates coronary vessels, decreases final diastolic pressure in the left ventricle and the rate of extrasystoles. Flokalin does not significantly affect the developing pressure in the left ventricle, max and min dP/dt, the frequency of cardiac contractions. 5-hydroxydecanoic acid (5-HD), an inhibitor of KATP in the mitochondrial membranes, increases the developing pressure in the left ventricle, max and min dP/dt, perfusion pressure in the coronary vessels. Simultaneously the final diastolic pressure in the left ventricle is decreased. Inhibition of K(ATP) channels in the mitochondrial membrane does not affect the vasodilatory effects of flokalin in the coronary vessels. This data, under the condition of specific action of 5-HD, permits us to suppose the participation of sarcolemmal KATP channels in the mentioned processes. It was shown that inhibition of mitochondrial K(ATP) channels results in decrease of the final diastolic pressure in the left ventricle and can enhance the effect of flokalin upon the final diastolic pressure, thus urging the idea of the leading role of sarcolemmal K(ATP) channels in the mentioned above processes.

[Fluorine-containing analog of diazoxide prevented apoptosis in neonatal cardiomyocytes during anoxia-reoxygenation]. / Ftorovanyi analoh diazoksydu poperedzhuie apoptoz neonatal'nykh kardiomiotsytiv pid chas anoksiï--reoksyhenatsiï.

In experiments on the primary culture of isolated neonatal rat cardiomyocytes it was established that anoxia-reoxygenation activated the process of programmed cell death, apoptosis. The amount of apoptotic cells (defined by fragmentation of a nucleus with Hoechst 33342 staining) during anoxia-reoxygenation was increased in 2.1 fold (P < 0.05). The amount of living and necrotic cells was not changed significantly. Apoptosis of neonatal cardiomyocytes during anoxia-reoxygenation was prevented by activation of ATP-dependent potassium (K(ATP)) channels with diazoxide. Synthesized by us the fluorine-containing analogue of diazoxide had the similar effect: the amount of apoptotic cells was decreased to 3.7% that was similar to control meaning. Application of glybenclamide, which completely abrogated the action of diazoxide and its fluorine-containing analogue, allows us to assert that antiapoptotic effect of the substances mentioned above depends on K(ATP) channels opening.

[Study of the mechanism of action of novel fluoro-containing analogs of diazoxide on the vascular tonus]. / Doslidzhennia mekhanizmu diï novykh ftorvmisnykh analohiv diazoksydu na sudynnyi tonus.

On the isolated preparations of rat aorta it was shown that the new fluoro-containing analogues of diazoxide (DiazoFp and DiazoFm) elicit vasodilatatory effects related to the activation of ATP-sensitive potassium channels. It was established that DiazoFp is a more powerful vasodilator than DiazoFm and diazoxide. It was proposed that DiazoFp action consists of two components: direct activation of sarcKATP channels and activation of sarcKATP channels, through activation of mitoKATP channels.

[Effect of modification in cell membrane fatty acid composition on adrenergic cardiac and vascular reactivity]. / Vplyv modyfikatsiï zhyrnokyslotnoho skladu klitynnykh membran na adrenerhichnu reaktyvnist' sertsia ta sudyn.

The work is dedicated to examination of the effect an omega-3 polyunsaturated fatty acids (PUFA) on vascular and cardiac reactivity in intact animals. In experiments on isolated perfused rat hearts and isolated rings of rat aorta it was shown that reactivity in rats with modified membranes was lesser than in control animals after adding norepinephrine in raising concentrations. Use of omega-3 PUFA resulted in the decrease of omega-6 PUFAs (arachidonic acid (AA)) content, while omega-3 PUFAs (EPA, DHA) content in cardiomyocytes membranes increased. Besides that it was shown that after omega-3 PUFA enriched diet NO3- content increased in cardiac tissues and blood.

[ATP-sensitive potassium channels and changes in their functional activity during streptozocin-induced diabetes mellitus]. / ATF-chutlyvi kaliievi kanaly ta zmin ïkh funktsional'noï aktyvnosti pry tsukrovomu diabeti, vyklykanomu vvedenniam streptozototsynu.

Attenuation in the vasodilatory effects of a new synthesized opener of ATP-sensitive K' channels on isolated aorta strips of rat has been shown under experimental (streptozocin-induced) diabetes mellitus. The level of that attenuation depended on the nature of initial vasoconstriction. The most pronounced decrease--43.34% as compared to the control responses in healthy rats, we observed after norepinephrine-induced vasoconstriction. Following preliminary angiothensin-induced vasoconstriction and potassium depolarization, attenuation in vasoconstriction was 20.37% and 22.4%, respectively. Norepinephrine inhibited vasodilator effects of phlocalin in the aorta of diabetic rats much more significantly, as compared to those after potassium depolarization. Inhibitory effects of angiothensin II in rats with diabetes mellitus did not differ from those in the control rats. At the same time, constrictory responses to biological active agents were preserved and they did not differ from those in control rats. We suggest that impairment in vascular reactivity under diabetes mellitus, at least in part, depends on the changes in the functioning of ATP-sensitive potassium channels.