A class of drugs known as KATP-channel openers induce cardioprotection. This study examined the effects of the novel KATP-channel opener, the fluorine-containing pinacidil derivative, flocalin, on cardiac-specific KATP-channels, excitability of native cardiac myocytes and on the ischaemic heart. EXPERIMENTAL APPROACHThe action of flocalin was investigated on: (i) membrane currents through cardiac-specific KATP-channels (IKATP) formed by KIR6.2/SUR2A heterologously expressed in HEK-293 cells (HEK-2936.2/2A); (ii) excitability and intracellular Ca 2+ ([Ca 2+ ]i) transients of cultured rat neonatal cardiac myocytes; and (iii) functional and ultrastructural characteristics of isolated guinea-pig hearts subjected to ischaemia-reperfusion. KEY RESULTSFlocalin concentration-dependently activated a glibenclamide-sensitive IKATP in HEK-2936.2/2A cells with an EC50 = 8.1 Ϯ 0.4 mM. In cardiac myocytes, flocalin (5 mM) hyperpolarized resting potential by 3-5 mV, markedly shortened action potential duration, reduced the amplitude of [Ca 2+ ]i transients by 2-3-fold and suppressed contraction. The magnitude and extent of reversibility of these effects depended on the type of cardiac myocytes. In isolated hearts, perfusion with 5 mmol·L -1 flocalin, before inducing ischaemia, facilitated restoration of contraction during reperfusion, decreased the number of extrasystoles, prevented the appearance of coronary vasoconstriction and reduced damage to the cardiac tissue at the ultrastructural level (state of myofibrils, membrane integrity, mitochondrial cristae structure). CONCLUSION AND IMPLICATIONSFlocalin induced potent cardioprotection by activating cardiac-type KATP-channels with all the benefits of the presence of fluorine group in the drug structure: higher lipophilicity, decreased toxicity, resistance to oxidation and thermal degradation, decreased metabolism in the organism and prolonged therapeutic action. Abbreviations

Background Ageing is accompanied by a decrease in endogenous hydrogen sulphide (H2S) synthesis and the development of mitochondrial dysfunction. The aim of our work was to study the possible participation of exercise training‐induced regulation of endogenous H2S production in the restoration of mitochondrial function in old rats. Materials and Methods Male rats were divided into three groups: adult, old and exercise‐trained old. Exercise training of old rats was performed for 4 weeks. The mRNA expression cystathionine‐γ‐lyase (CSE) and 3‐mercaptopyruvate sulfurtransferase (3‐MST) were determined using reverse transcription and real‐time polymerase chain reaction analysis. Mitochondrial dysfunction was determined by mPTP opening, which was investigated by spectrophotometric registration of the swelling of mitochondria isolated from the rat heart. We also studied the effect of exercise on H2S content, oxidative stress and mtNOS activity. Results Exercise training in old animals significantly increased the expression of H2S‐synthesizing enzymes CSE and 3‐MST and restored endogenous H2S production in cardiac tissue and cardiac mitochondria to levels of adult animals. In addition, the training significantly reduced oxidative stress in old rats, in particular the rate of formation of •O2− and H2O2, diene conjugates and malondialdehyde levels in the mitochondria of the heart. Simultaneously, in the hearts of these animals, resistance of mPTP to the inducer of its opening of calcium ions was increased. Conclusions Thus, exercise training restores endogenous H2S production, and significantly reduces oxidative stress in cardiac mitochondria of old rats that are associated with the inhibition of calcium‐induced mPTP opening as an indicator of mitochondrial dysfunction.

Одним із головних ендогенних механізмів захисту при зниженні енергоресурсів клітини є система АТФ-чутливих калієвих (К АТФ) каналів, яку вважають центральним метаболічним сенсором щодо її енергозабезпечення. Ці канали мають нейро-, церебро-, кардіо-, нефропротекторні та інші захисні ефекти, в основі яких лежить пригнічення збудливості і метаболізму, та нормалізація біоенергетичних процесів зі збереженням високого вмісту АТФ. У цій статті розглядаються основні механізми кардіопротекторної дії активації К АТФ-каналів та можливе застосування їх активаторів для корекції патологічних станів. Ключові слова: АТФ-чутливі калієві канали; кардіопротекція.

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