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

Cardiac ventricular myocytes exhibit a protein kinase A-dependent Cl(−) current (I(Cl.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 I(Cl.PKA). Here the action of Ni(2+) on I(Cl.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 I(Cl.PKA) activated by 1 μM isoprenaline with a log IC(50) (M) of −4.107 ± 0.075 (IC(50) = 78.1 μM) at +100 mV and −4.322 ± 0.107 (IC(50) = 47.6 μM) at −100 mV. Thus, the block of I(Cl.PKA) by Ni(2+) was not strongly voltage dependent. Ni(2+) applied internally via the patch-pipette was ineffective at inhibiting isoprenaline-activated I(Cl,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 I(Cl.PKA), but in the presence of the β2-adrenoceptor inhibitor ICI 118,551 isoprenaline still activated Ni(2+)-sensitive I(Cl.PKA). Collectively, these data demonstrate that Ni(2+) ions produce marked inhibition of β1-adrenoceptor activated ventricular I(Cl.PKA) at submillimolar [Ni(2+)]: an action that is likely to involve an interaction between Ni(2+) and β1-adrenoceptors. The concentration-dependence for I(Cl.PKA) inhibition seen here indicates the potential for confounding effects on I(Cl,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.