Inhibitory effect of 2,3‐butanedione monoxime (BDM) on Na<sup>+</sup>/Ca<sup>2+</sup>exchange current in guinea‐pig cardiac ventricular myocytes

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<jats:p><jats:list list-type="explicit-label"><jats:list-item><jats:p>The effect of 2,3‐butanedione monoxime (BDM), a ‘chemical phosphatase’, on Na<jats:sup>+</jats:sup>/Ca<jats:sup>2+</jats:sup>exchange current (<jats:italic>I</jats:italic><jats:sub>NCX</jats:sub>) was investigated using the whole‐cell voltage‐clamp technique in single guinea‐pig cardiac ventricular myocytes and in CCL39 fibroblast cells expressing canine NCX1.</jats:p></jats:list-item><jats:list-item><jats:p><jats:italic>I</jats:italic><jats:sub>NCX</jats:sub>was identified as a current sensitive to KB‐R7943, a relatively selective NCX inhibitor, at 140 m<jats:sc>M</jats:sc>Na<jats:sup>+</jats:sup>and 2 m<jats:sc>M</jats:sc>Ca<jats:sup>2+</jats:sup>in the external solution and 20 m<jats:sc>M</jats:sc>Na<jats:sup>+</jats:sup>and 433 n<jats:sc>M</jats:sc>free Ca<jats:sup>2+</jats:sup>in the pipette solution.</jats:p></jats:list-item><jats:list-item><jats:p>In guinea‐pig ventricular cells, BDM inhibited<jats:italic>I</jats:italic><jats:sub>NCX</jats:sub>in a concentration‐dependent manner. The IC<jats:sub>50</jats:sub>value was 2.4 m<jats:sc>M</jats:sc>with a Hill coefficients of 1. The average time for 50% inhibition by 10 m<jats:sc>M</jats:sc>BDM was 124±31 s (<jats:italic>n</jats:italic>=5).</jats:p></jats:list-item><jats:list-item><jats:p>The effect of BDM was not affected by 1 μ<jats:sc>M</jats:sc>okadaic acid in the pipette solution, indicating that the inhibition was not<jats:italic>via</jats:italic>activation of okadaic acid‐sensitive protein phosphatases.</jats:p></jats:list-item><jats:list-item><jats:p>Intracellular trypsin treatment<jats:italic>via</jats:italic>the pipette solution significantly suppressed the inhibitory effect of BDM, implicating an intracellular site of action of BDM.</jats:p></jats:list-item><jats:list-item><jats:p>PAM (pralidoxime), another oxime compound, also inhibited<jats:italic>I</jats:italic><jats:sub>NCX</jats:sub>in a manner similar to BDM.</jats:p></jats:list-item><jats:list-item><jats:p>Isoprenaline at 50 μ<jats:sc>M</jats:sc>and phorbol 12‐myristate 13‐acetate (PMA) at 8 μ<jats:sc>M</jats:sc>did not reverse the inhibition of<jats:italic>I</jats:italic><jats:sub>NCX</jats:sub>by BDM.</jats:p></jats:list-item><jats:list-item><jats:p>BDM inhibited<jats:italic>I</jats:italic><jats:sub>NCX</jats:sub>in CCL39 cells expressing NCX1 and in its mutant in which its three major phosphorylatable serine residues were replaced with alanines.</jats:p></jats:list-item><jats:list-item><jats:p>We conclude that BDM inhibits<jats:italic>I</jats:italic><jats:sub>NCX</jats:sub>but the mechanism of inhibition is not by dephosphorylation of the Na<jats:sup>+</jats:sup>/Ca<jats:sup>2+</jats:sup>exchanger as a ‘chemical phosphatase’.</jats:p></jats:list-item></jats:list></jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic>(2001)<jats:bold>132</jats:bold>, 1317–1325; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0703926">10.1038/sj.bjp.0703926</jats:ext-link></jats:p>

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