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

摘要

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 3x10(-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 Ca2+ current (ICa), whereas lonomycin A and nigericin inhibited ICa. The fast component of the inactivation phase for ICa was decreased by the ionophores, but the slow component was unaffected. The activation and inactivation kinetics (d infinity and f infinity) 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 microM) increased cellular Ca2+ concentration ([Ca2+]i), using Ca2+ -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 [Ca2+]i level in rabbit SA nodal cells.