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Sarcolemmal cardiac K ATP channels as a target for the cardioprotective effects of the fluorine‐containing pinacidil analogue, flocalin
Author(s) -
Voitychuk Oleg I,
Strutynskyi Ruslan B,
Yagupolskii Lev M,
Tinker Andrew,
Moibenko Olexiy O,
Shuba Yaroslav M
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01072.x
Subject(s) - pinacidil , cardioprotection , myocyte , chemistry , cardiac action potential , cardiac myocyte , sarcolemma , membrane potential , potassium channel , hek 293 cells , medicine , contraction (grammar) , pharmacology , biophysics , endocrinology , glibenclamide , ischemia , electrophysiology , biochemistry , repolarization , biology , receptor , diabetes mellitus
BACKGROUND AND PURPOSE A class of drugs known as K ATP ‐channel openers induce cardioprotection. This study examined the effects of the novel K ATP ‐channel opener, the fluorine‐containing pinacidil derivative, flocalin, on cardiac‐specific K ATP ‐channels, excitability of native cardiac myocytes and on the ischaemic heart. EXPERIMENTAL APPROACH The action of flocalin was investigated on: (i) membrane currents through cardiac‐specific K ATP ‐channels (I KATP ) formed by K IR 6.2/SUR2A heterologously expressed in HEK‐293 cells (HEK‐293 6.2/2A ); (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 RESULTS Flocalin concentration‐dependently activated a glibenclamide‐sensitive I KATP in HEK‐293 6.2/2A cells with an EC 50 = 8.1 ± 0.4 µM. In cardiac myocytes, flocalin (5 µM) 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 µmol·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 IMPLICATIONS Flocalin induced potent cardioprotection by activating cardiac‐type K ATP ‐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.