Effects of metoprolol on action potential and membrane currents in guinea-pig ventricular myocytes.

Abstract

The effects of the beta-adrenoceptor antagonist metoprolol on action potentials and membrane currents were studied in single guinea-pig ventricular myocytes. The experiments were carried out using the nystatin-method of whole-cell technique. This method was used in order to prevent the run-down of the calcium current. Metoprolol at concentrations of 10-100 mumol/l shortened action potential in a dose-dependent way. The drug only decreased resting membrane potential at a concentration of 100 mumol/l in two out of five cells. Under voltage-clamp conditions, metoprolol blocked the high threshold calcium current at concentrations of 30 and 100 mumol/l to 82 +/- 4% and 73 +/- 5% from control, respectively. The drug decreased the inward rectifying potassium current in a concentration-dependent manner. This effect was evident for inward current at voltages negative to the apparent reversal potential and for outward current at voltages between -30 and -80 mV. This blocking effect on the inward rectifying potassium current can explain the effect on resting membrane potential. At voltages positive to -30 mV metoprolol increased a time-independent outward current. This metoprolol-enhanced outward current was blocked by barium and cesium. This result suggests that the metoprolol-enhanced current is carried by potassium. The current component enhanced by metoprolol was not sensitive to glibenclamide and tetraethylammonium applied externally, which suggests that the adenosine triphosphate-sensitive channel is not the target of metoprolol. The activation of this time-independent outward current by metoprolol and the blocking effects on the calcium current seem to explain the shortening in action potential induced by the drug.