Nickel inhibits β-1 adrenoceptor mediated activation of cardiac CFTR chloride channels

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Cardiac ventricular myocytes exhibit a protein kinase A-dependent Cl(-) current (ICl.PKA) mediated by the cystic fibrosis transmembrane conductance regulator (CFTR). There is conflicting evidence regarding the ability of the divalent cation nickel (Ni(2+)), which has been used widely in vitro in the study of other cardiac ionic conductances, to inhibit ICl.PKA. Here the action of Ni(2+) on ICl.PKA activated by β-adrenergic stimulation has been elucidated. Whole-cell patch-clamp recordings were made from rabbit isolated ventricular myocytes. Externally applied Ni(2+) blocked ICl.PKA activated by 1 μM isoprenaline with a log IC50 (M) of -4.107 ± 0.075 (IC50=78.1 μM) at +100 mV and -4.322 ± 0.107 (IC50=47.6 μM) at -100 mV. Thus, the block of ICl.PKA by Ni(2+) was not strongly voltage dependent. Ni(2+) applied internally via the patch-pipette was ineffective at inhibiting isoprenaline-activated ICl,PKA, but in the same experiments the current was suppressed by external Ni(2+) application, indicative of an external site of Ni(2+) action. In the presence of 1 μM atenolol isoprenaline was ineffective at activating ICl.PKA, but in the presence of the β2-adrenoceptor inhibitor ICI 118,551 isoprenaline still activated Ni(2+)-sensitive ICl.PKA. Collectively, these data demonstrate that Ni(2+) ions produce marked inhibition of β1-adrenoceptor activated ventricular ICl.PKA at submillimolar [Ni(2+)]: an action that is likely to involve an interaction between Ni(2+) and β1-adrenoceptors. The concentration-dependence for ICl.PKA inhibition seen here indicates the potential for confounding effects on ICl,PKA to occur even at comparatively low Ni(2+) concentrations, when Ni(2+) is used to study other cardiac ionic currents under conditions of β-adrenergic agonism.
Original languageEnglish
Pages (from-to)46-51
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number1
Publication statusPublished - 1 Mar 2013

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