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Some of highly effective antiepileptic substances share the polymodal pharmacological action which determines the possibility of their use for treatment of pathogenetically similar diseases. Inhibitory mediator systems influence for example, suggests the combination in the pharmacological spectrum such actions as antiepileptic, analgesic (antineuropathic) and other actions. The aim of the study was evaluation of anticonvulsant effect of 7-bromo-5-(o-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one (propoxazepam) on the model of 4-aminopyridine (4-AP) – induced myoclonic seizures and characterization of its possible participation in modulation of the function of voltage-dependent potassium channels. 4-AP (10.3 mg/kg, subcutaneously) was administered 30 minutes after intraperitoneal administration of propoxazepam different doses (20, 28, 40, 60 and 80 mg/kg) and the time and quantity of myoclonic and tonic convulsions as well as total time to the lethal effect were evaluated. It was found that in this model, propoxazepam possess moderate activity (ED50 = 37,3 ± 7.9 mg/kg) Even at high doses (80 mg/kg) of the test compound, anticonvulsive action did not reach 100%. The quantity of myoclonic seizures and the latency time of their onset have no statistically significant differences in comparison with the data of animals of the control group. On the contrary, the number (and percentage representation) of tonic convulsions in the common seizure episode increased, which is due to the possible inhibitory effect of propoxazepam, which is carried out primarily through GABA-ergic mechanisms.

The NO-synthase activity (mtNOS) in mitochondria of uterine smooth muscle was studied. The mitochondrial localization of NO synthesis in myocytes was proved using laser confocal microscopy method and specific fluorescent probes MitoTracker Orange (specific to mitochondria) and DAFFM (NO-sensitive fluorescent probe). It was demonstrated using flow cytometry that nitric oxide biosynthesis in isolated mytochondria decreased in the presence of a constitutive NOsynthase blocker 2-aminopyridine (100 μmol/l, 50% inhibition) and monoclonal antibodies (2.5 μg anti-Letm1/50 μg protein) against the H+-Ca2+-exchanger (Letm1 protein), but was't sensitive to the mitochondrial permeability transition pore inhibitor cyclosporin A (5 μmol/l). A decrease of potassium ions concentration in the incubation medium and the presence of various types of potassium channel inhibitors significantly inhibited the NO-synthase reaction. We have concluded that potassium permeability of the inner mitochondrial membrane plays important role in the regulation of mtNOS activity. [ABSTRACT FROM AUTHOR]

Omega-3 polyunsaturated fatty acids (PUFA) provide protection against myocardial damage in ischemia-reperfusion. However, the mechanisms that provide cardioprotection are not fully understood. In this study, we investigated the effect of docosahexaenoic acid (DHA), a member of omega -3 PUFA, on mitochondrial respiration parameters and the role of mitochondrial calcium-dependent potassium channels of large conductance (ВКСа) in the implementation of these effects. Using the patch-clamp method, it was shown that functional ВКСа channels are expressed in the inner mitochondrial membrane of cardiac cells and their activity increases with the addition of DHA. We investigated the role of mitochondrial ВКСа channels in the regulation of mitochondrial respiratory processes. In experiments with isolated mitochondria from rat hearts, we showed that DHA prevented an increase in the respiratory rate of mitochondria in the V4 state and a decrease in the respiratory control elicited by addition of 10 μM Ca2+. Qualitatively the same effect was caused by NS1619, the ВКСа opener. In the presence of 10 μM Ca2+, the ВКСа channel inhibitor paxilin (1 μM) prevented the protective effect of DHA and NS1619 on the parameters of respiratory control. We conclude that mitochondrial ВКСа channels are involved in the implementation of the effects of DHA on mitochondrial respiration. [ABSTRACT FROM AUTHOR]

ATP-sensitive potassium channels (KATP-channels) have an exclusive cardioprotective role in endogenous heart protection from ischemic damage and regulate vascular tone. KCNJ11 (Kir6.2) polymorphisms I337V (rs5215) and G23L (rs5219, E23K), and ABCC8 (SUR1) polymorphisms S1369A (rs757110) was genotyped in 529 patients with myocardial infarction, acute and chronic heart failure, in adolescents with primary hypertension, and as control group in clinically healthy subjects of Ukraine population by the real-time polymerase chain reaction (RT-PCR). It was shown that the frequency of genotypes Glu/Glu, Glu/Lys and Lys/Lys of polymorphism E23K, and genotypes Ser/Ser, Ser/Ala and Ala/Ala of polymorphism S1369A was as follows: in 107 patients with myocardial infarction - 40.2, 43.9 and 15.9%; in 96 patients with acute heart failure - 41.7, 42.7 and 15.6%; in 99 patients with chronic heart failure - 43.4, 44.4 and 12.1%; in 104 adolescents with primary hypertension - 41.4, 46.2 and 12.5% respectively. The distribution of these genotypes in the control group in 98 clinically healthy people was 37.8, 46.9 and 15.3% respectively. Inheritance of SNPs E23K and S1369A were linked. The frequency of genotypes Ile/Ile, Ile/Val and Val/Val of polymorphism I337V was as follows: in 102 patients with myocardial infarction - 32.4, 51.0 and 16.7%; in 93 patients with acute heart failure - 37,6, 43,0 and 19,4%; in 98 patients with chronic heart failure - 40,8, 44,9 and 14,3%; in 90 clinically healthy people - 35.6, 45.6 and 18.9% respectively. Incidence of allelic polymorphisms I337V, E23K and S1369A corresponds to Hardy-Weinberg principle. By criterion χ², no significant differences were found between the groups. Thus, the frequency of allele polymorphisms I337V, E23K, and S1369A in patients with myocardial infarction, acute and chronic heart failure, and primary hypertension in adolescents was determined, and it has been shown that it does not significantly differ from the frequency in clinically healthy residents of Ukraine. [ABSTRACT FROM AUTHOR]

In the experiments on the anesthetized dogs, the effects of ATP-sensitive potassium (KATP) channels activation by flocalin on the activity of endothelial and inducible NO-synthases (iNOS), heme oxygenase reaction, blood oxygenation and free radical processes were studied. Changes in biochemical parameters in arterial blood were determined after 20 and 60 minutes after intravenous administration of flocalin in doses of 0.1, 0.5, 1.0 and 1.5 mg/kg. It is shown that the opening of KATP-channels dose-dependent increases the level of protective constitutive synthesis of nitric oxide and, conversely, inhibits inducible synthesis (at 2.8 and 2.1 times at a dose of flocalin 1.5 mg/kg, respectively). The activation of the above channels is a powerful antihypoxic mechanism - greatly enhances the oxygenation of arterial blood and the content of nitrite anion (at 3.7 and 3.0 times at a dose of 1,0 mg/kg, respectively). Flocalin significantly reduced the content of the products of the heme oxygenase reaction - iron and bilirubin (with a maximum effect of 2.9 and 1.9 times respectively), which may indicate inhibition of the activity of the enzyme heme oxygenase. Аctivation of KATP-channels dose-dependently suppresses free radical processes (decrease in the generation of superoxide anion and hydrogen peroxide (5.3 and 7.2 times at a dose of 1.5 mg/kg, respectively) and exhibits antioxidant properties (decrease in the content of diene conjugates by 6.3 times at a dose of 1.5 mg/kg), inhibits the formation of peroxynitrite by reducing the generation of superoxide anion (uric acid content) and inducible nitric oxide. Thus, the activation of KATP-channels by flocalin increases the constitutive synthesis of NO and, conversely, reduces the inducible synthesis of NO, greatly enhances the oxygenation of arterial blood, suppresses free radical processes and the activity of heme oxygenase. [ABSTRACT FROM AUTHOR]

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.