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(1) The depression of slow inward calcium current (ICa) induced by organic or inorganic inhibitors in voltage clamped dog ventricular preparations unmasks an early transient outward current (Ito). (2)Ito is depressed by 4-aminopyridine (1 mM) in a voltage dependent manner. (3)Ito appears in reponse to voltage steps above 40 mV (from holding voltage=resting voltage) and increases with raising the amplitude of clamp steps. (4) Within physiological range of membrane voltageIto is smaller and decays several times faster thanICa. Time course of the decline is approximately exponential (t=25±6 ms at 80 mV above resting voltage). (5) Shifts of the holding voltage by 20 mV from the level of resting voltage alters the peak amplitude ofIto. It is increased by hyperpolarization and reduced by depolarization. (6) The recovery ofIto from inactivation at resting voltage was approximated by a single exponential. Time constant (390 ms) is about 15 times longer than the time constant of inactivation at 80 mV positive to the resting voltage.

A quantitative model of Ca-turnover in cardiac cells that incorporates negative feedback modulation of sarcolemmal calcium transport (via Ca channels and Na/Ca exchange) has been designed. The Na/Ca exchange current was expressed as INaCa = INaCar + ?Naca. The component INaCar reflects slow changes of Ca2+ and Na+ concentrations and depends on the Na/K pump. ?INaCa is the fast component related to the Ca2+ transient. The single input to the model is an arbitrary sequence of intervals between excitations; outputs are sequences of calcium amounts transferred among the compartments during individual intervals. The model operates with a combination of discrete variables (amounts of Ca transferred during contraction, relaxation and rest) and continuous variables — slow changes in ionic concentrations. Since the model is not formalistic but respects the nature of the underlying elements of the system, it enables us to simulate the known effects of cardiotropic drugs or to predict their unknown mechanisms by visualizing the changes in individual Ca compartments. By altering the parameters, the model also simulates the known species and tissue differences in rate-dependent phenomena.

The use-dependent features of 4-aminopyridine-induced block of the transient outward current were investigated under voltage clamp conditions in dog ventricular myocardial bundles. The block depended strongly on the pattern of voltage clamp pulses. Its level (settled in rested membranes) became deeper at early time during depolarization. In contrast, prolonged depolarization (above 50 to 100 ms) produced relief of block. Our results suggest that the block strongly depends on the state of the channel gating system.