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We compared the effects of a low (0.09 microgram/ml) concentration of propranolol expected to produce only beta-adrenoceptor blockade and a high concentration (0.9 microgram/ml) expected to produce additional direct local anesthetic-like electrophysiological effects on basic and premature action potentials. Both isolated dog cardiac Purkinje and ventricular muscle fibers were examined using conventional microelectrode techniques. The low concentration of propranolol produced no significant electrophysiological change in either fiber type. The high concentration of propranolol shortened the action potential duration and refractoriness while decreasing the maximal upstroke velocity (Vmax) in both Purkinje and ventricular muscle fibers at a constant basic cycle length. In Purkinje fibers, the high concentration also slowed the kinetics of restitution of the action potential duration (tau c from 124.6 +/- 6.5 to 201.4 +/- 16.0 ms, p less than 0.01, n = 7), slowed the recovery kinetics of Vmax, and shifted the early portion of the normalized restitution curve toward longer action potential duration values in both fiber types. The range of premature action potential durations, defined as the difference between action potential durations during the first 100 ms of restitution, was decreased by the high concentration of propranolol in both Purkinje and ventricular muscle fibers by 39.5% and 33.9%, respectively. These findings indicate that (a) low concentrations of propranolol produced no direct electrophysiological effect, and (b) high concentrations of propranolol produced several potential antiarrhythmic effects in addition to the previously reported effects on Vmax and the action potential duration.

We examined the steady-state action potential duration (APD) within a wide range of cycle lengths (CL) in cardiac dog Purkinje (P) and ventricular (V) muscle fibers in the presence of: lidocaine (L) 4 and 8 micrograms/ml, mexiletine (M) 4 and 8 micrograms/ml, flecainide (F) 1 and 4 micrograms/ml, disopyramide (D) 3.1 and 10 micrograms/ml, quinidine (Q) 2.5, 5, and 10 micrograms/ml, bretylium tosylate (B) 5 and 10 micrograms/ml, and sotalol (S) 5 micrograms/ml. In the P fibers, all drugs except for B and S shortened plateau duration, increased slope of phase 2 and decreased slope of phase 3 repolarization, and either shortened (L, M, Q, F) or prolonged (D) APD. B and S lengthened APD and did not change significantly the slopes of phase 2 and 3 of repolarization. Each drug altered the relation between APD and Cl according to one of the following three patterns: (a) L, M, Q, and F shortened APD more at long than at short CL; (b) D lengthened APD more at short than at long CL; (c) B and S lengthened APD more at long that at short CL. In the V fibers, APD was lengthened by F, Q, and B, and shortened by L and M. The drug-induced changes in the relation between APD and CL were as in the P fibers. The results suggest that the drug-induced changes in the relation between APD and CL can be predicted from the drug effects on the course of repolarization.

Vmax of the action potential upstroke in canine cardiac Purkinje fibers was studied in the presence of seven class I antiarrhythmic drugs--lidocaine (4 micrograms/ml), mexiletine (4 micrograms/ml), propranolol (0.9 micrograms/ml), procainamide (30 micrograms/ml), quinidine (5 micrograms/ml), flecainide (4 micrograms/ml), and disopyramide (3.1 micrograms/ml)--at constant cycle lengths (CCL) and after abrupt changes in cycle length (ACCL). The time constant of Vmax recovery after ACCL at a basic cycle length of 500 ms was 0.09 +/- 0.01 s for lidocaine, 0.18 +/- 0.03 s for mexiletine, 1.35 +/- 0.20 s for propranolol, 4.4 +/- 0.8 s for procainamide, 8.3 +/- 1.2 s for quinidine, 11.0 +/- 0.9 s for flecainide, and 37.9 +/- 9.4 s for disopyramide. These values were similar to those reported by others in guinea pig papillary muscle, and, with the exception of flecainide, conformed to the scheme proposed by Courtney (J Mol Cell Cardiol 1980; 12:1273-86) based on the molecular weight and lipid solubility hypothesis. Each drug altered the Vmax differently at CCL from after ACCL at the same diastolic intervals. The magnitude of these differences and the range of diastolic intervals at which they were present varied among different drugs. These observations explain differences in the drug effects on the Vmax of the regularly and prematurely occurring depolarizations. In the presence of lidocaine and mexiletine, the recovery kinetics of Vmax were not altered by CCL within the 300-1,500-ms range, and the magnitude of Vmax depression was not influenced by action potential duration within the 200-270-ms range.

The purpose of this study was to elucidate the mechanism of the upward shift of the electrical restitution curve, i.e., the lengthening of premature action potential duration (APDt) expressed as percentage of basic APD, induced by class I antiarrhythmic drugs in dog Purkinje fibers. In this study, six class I antiarrhythmic drugs lengthened APDt at a diastolic interval of 20 ms by 2.5-14.1%. The drugs also decreased the ratio of APD at 50% to APD at 90% of repolarization from 70.8 +/- 1.8% (n = 60) to 47.4-60.8%. The relation between the decrease in the ratio of APD50 to APD90 of the basic AP and lengthening of the normalized APDt was linear (r = 0.92; p less than 0.01). We attributed the lengthening of normalized APDt to the decreased ratio of APD50 to APD90, and applied repolarizing current pulses in short (less than or equal to 2 mm) fibers to simulate the drug-induced decrease in the ratio of APD50 to APD90. The altered repolarization course of basic AP by the current pulse during late plateau and early phase 3 caused APDt lengthening. The relation between the current-induced decrease in the ratio of APD50 to APD90 of the basic AP and the lengthening of normalized APDt was linear (r = 0.91; p less than 0.01). The slope of regression line describing this relation was similar to that in the presence of drugs. These results suggest that lengthening of the normalized APDt by class I antiarrhythmic drugs results from a more rapid repolarization during phase 2 of the preceding basic AP, possibly due to lesser influence of the delayed outward rectifying current. The lengthening of APDt by class I drugs may contribute to their antiarrhythmic action.

The range of premature action potential duration (APDs) during the first 100 ms of electrical restitution was determined in canine ventricular muscle fibers (VM) in the presence of lidocaine (4 and 8 micrograms/ml), mexiletine (8 micrograms/ml), flecainide (2 and 4 micrograms/ml), procainamide (50 micrograms/ml), quinidine (10 micrograms/ml), and disopyramide (10 micrograms/ml). The drug effects on the characteristics of action potential at the basic cycle lengths (BCLs) of 500 and 1,000 ms were similar to those reported previously. At control, the range of premature APDs was approximately 40 ms at BCL of 1,000 ms and approximately 30 ms at BCL of 500 ms. It was decreased 26-52% by lidocaine, mexiletine, and flecainide, not changed significantly by procainamide, and increased 17-53% by quinidine and disopyramide. The range of premature APDs at control and in the presence of drugs in ventricular muscle was smaller than in Purkinje fibers at the same or lower drug concentrations (Varro et al., J Pharmacol Exp Ther 1985;233:304). The four factors influencing the premature APD range in the Purkinje fibers operated in the VM as follows: The difference between the duration of effective refractory period (ERP) and the APD at BCL (APDb) (i.e., the ERP-APDb interval) was increased by lidocaine, mexiletine, and flecainide; normalized restitution curve was shifted toward longer premature APD values only by flecainide; the kinetics of restitution were slowed only by procainamide; and APD at BCL of 1,000 ms was shortened by lidocaine and mexiletine, and prolonged at BCLs of 1,000 and 500 ms by the other four drugs.(ABSTRACT TRUNCATED AT 250 WORDS)