Pharmacological actions of monovalent ionophores on spontaneously beating rabbit sino-atrial nodal cells

Abstract

The effects of sodium (monensin) and potassium (nigericin and lonomycin A) ionophores on the spontaneous activity in rabbit sino-atrial (SA) nodal cells were investigated using microelectrode and whole-cell voltage-clamp techniques. In the multicellular preparations, the ionophores produced a negative chronotropic effect in a concentration-dependent manner, and at 3 × 10 −5 M significantly decreased the amplitude and duration of action potentials and enhanced the maximum rate of depolarization. The ionophores elicited dysrhythmias and then a sinus arrest often occurred. These responses were reversible. In whole-cell clamp experiments, monensin enhanced the L-type Ca 2+ current (I Ca), whereas lonomycin A and nigericin inhibited I Ca. The fast component of the inactivation phase for I Ca was decreased by the ionophores, but the slow component was unaffected. The activation and inactivation kinetics (d ∞ and f ∞) were not altered. The ionophores did not affect the hyperpolarization-activated inward current. Monensin inhibited the delayed rectifier K + current (I K), but lonomycin A and nigericin increased I K. Its activation kinetics shifted in the depolarizing direction. The effects on the ionic currents were irreversible. Monensin (30 μM) increased cellular Ca 2+ concentration ([Ca 2+] i), using Ca 2+-sensitive fluorescent dye (fura-2). These results indicate that the monovalent ionophores depress the action potentials and produce a negative chronotropic effect due to direct and indirect modulations of the ionic currents and the [Ca 2+] i level in rabbit SA nodal cells.