Document Detail

Sarcolemmal cardiac K(ATP) channels as a target for the cardioprotective effects of the fluorine-containing pinacidil analogue, flocalin.
MedLine Citation:
PMID:  20942816     Owner:  NLM     Status:  MEDLINE    
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 Ca²(+) ([Ca²(+) ](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 EC₅₀= 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 [Ca²(+) ](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.
Oleg I Voitychuk; Ruslan B Strutynskyi; Lev M Yagupolskii; Andrew Tinker; Olexiy O Moibenko; Yaroslav M Shuba
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  162     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-13     Completed Date:  2011-07-26     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  701-11     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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MeSH Terms
Cardiotonic Agents / chemistry,  pharmacology*
Cells, Cultured
Fluorine / analysis
Glyburide / pharmacology
Guinea Pigs
HEK293 Cells
Heart / drug effects,  physiopathology
KATP Channels / metabolism*
Membrane Potentials / drug effects
Membrane Transport Modulators / chemistry,  metabolism,  pharmacology*
Myocardium / metabolism
Myocytes, Cardiac / drug effects*,  metabolism
Patch-Clamp Techniques
Pinacidil / analogs & derivatives*,  chemistry,  pharmacology
Reperfusion Injury / drug therapy*,  metabolism
Sarcolemma / drug effects*,  metabolism
Grant Support
RG/10/10/28447//British Heart Foundation
Reg. No./Substance:
0/Cardiotonic Agents; 0/KATP Channels; 0/Membrane Transport Modulators; 0/N-(4-difluoromethoxyphenyl)-N'-pinacolyl-N''-cyanoguanidine; 284SYP0193/Fluorine; 7B0ZZH8P2W/Pinacidil; SX6K58TVWC/Glyburide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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