Characterization of the electrophysiological effects of metoprolol on isolated feline ventricular myocytes.

Metoprolol is considered to be a class II antiarrhythmic agent that is highly specific for cardiac beta-1 adrenergic receptors, yet long-term administration can produce prolongation of the rate-corrected Q-T interval in humans. Action potentials and sodium (INa), "L"-type calcium (ICa) and transient outward (Ito) or inward rectifying potassium (IKl) currents were recorded from isolated cat ventricular myocytes using the whole-cell-patch technique to determine if metoprolol can directly affect cellular electrophysiological activity. External and pipette solutions, holding potentials and voltage-clamp protocols appropriate to isolate and examine INa, IKl, Ito and ICa were used. Metoprolol reversibly decreased both the duration and voltage of the action potential plateau but had no effect on upstroke velocity, the repolarization rate during phase 3 or the resting potential. Confirming previous reports suggesting that metoprolol appears to have little or no local anesthetic activity, INa was not affected by metoprolol at concentrations up to 100 microM during voltage-clamp pulses applied at less than 1 Hz when holding potential was negative to -110 mV. However, when trains of pulses to -10 mV from a holding potential of -110 mV were applied at 1 to 5 Hz, use-dependent inhibition of INa occurred, suggesting that 100 microM metoprolol may interact with inactivated Na channels to inhibit INa. Metoprolol (10 and 100 microM) also caused a concentration-dependent decrease in peak inward IKl elicited in response to hyperpolarizing from -40 mV to potentials negative to the IKl reversal potential. In addition, during strong hyperpolarizations (i.e., less than or equal to -150 mV) an inward (i.e., downward) droop in current was observed during the inactivation phase approximately 20 to 30 msec after pulse onset. Metoprolol (10 microM) also reduced peak Ito and ICa without altering the time courses of inactivation of either current or the level of the steady-state outward current elicited positive to -40 mV; steady-state ICa, on the other hand, was reduced. The sensitivity to block by metoprolol was: IKl greater than ICa greater than or equal to Ito greater than INa.