Propranolol effects on membrane repolarization time in isolated canine Purkinje fibers: threshold tissue content and the influence of exposure time.

This study has examined the relationship between the Purkinje fiber content of propranolol and effects on membrane repolarization time during prolonged exposure to low concentrations of propranolol in vitro. Canine Purkinje fibers were exposed to both dl-propranolol, 3.4 X 10(-7) M (0.1 microgram/ml) and 1.7 X 10(-6) M (0.5 micrograms/ml), and to d-propranolol, 3.4 X 10(-7) M (0.1 micrograms/ml), in Tyrode's solution for 90 to 180 min. Purkinje fibers exhibited continuous decreases in repolarization time throughout the exposure periods and fibers analyzed for propranolol content demonstrated continuous cumulation of the drug with time. A maximum 8% decrease in repolarization time was observed after 3.4 X 10(-7) M and a 30% decrease after 1.7 X 10(-6) M propranolol. A 40-fold cumulation of propranolol by the Purkinje fibers was found after both concentrations at or near equilibrium. A high degree of correlation (r = 0.98; P < .001) existed between changes in electrical activity and tissue content of propranolol. Extrapolation to zero effect showed a threshold tissue content of propranolol of approximately 1.0 microgram/g, which corresponds to a bath concentration of 25 ng/ml (8 X 10(-8) M). Changes in membrane potentials were the result of direct membrane effects of propranolol, based on the fact that d-propranolol produced membrane alterations and tissue cumulation identical to those produced by the racemic drug.