Use‐dependent effects of pirmenol on and conduction in guinea‐pig ventricular myocardium

Abstract

1 The use-dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise (V,) of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea-pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles. 2 Pirmenol decreased V,,,x and the overshoot of action potentials in a dose-dependent fashion. Also, doses of pirmenol greater than 1 mm abolished the generation of action potentials. Low concentrations of pirmenol (3 and 1OpM) prolonged the action potential duration, while concentrations greater than 0.1 mm shortened it markedly.3 The resting block of V,,.x in the presence of 10 and 30M pirmenol was 9.48 + 3.12 and 20.36 + 3.61%, and that of conduction velocity 2.87 + 1.52 and 6.58 + 2.09%, respectively. 4 The degree of use-dependent block induced by 10 and 30M pirmenol during 0.2, 1, 2 and 3Hz stimulations was dose-and rate-dependent. 5 In the presence of 30Mm pirmenol, mean values of time constants for the onset of the use-dependent inhibition of V,,,x and conduction velocity during a 2Hz stimulation were 1.32 + 0.15 and 1.28 + 0.09s, respectively. The recovery time constants averaged 15.83 + 2.14 (for V,,.x) and 27.80 + 8.74 (for conduction velocity) s in the presence of 30 gM pirmenol.6 These results showed that the characteristics of the use-dependent inhibition of V,,mx and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.

Profiles of Aprindine, Cibenzoline, Pilsicainide and Pirmenol in the Framework of the Sicilian Gambit

“…97,100 APD of the ventricular muscle was slightly prolonged (5-10%) at low concentrations (3-10 mol/L), but shortened at high concentrations of pirmenol (30-100 mol/L). 97,98,100,101 Prolongation of APD (13-30%) by pirmenol (5-10 mol/L) also was reported in single atrial and ventricular myocytes obtained from rabbits. 94,102 Vmax inhibition by pirmenol in Purkinje fibers and ventricular muscles was enhanced in a frequency-or usedependent manner.…”

“…94,96 Pirmenol also was shown to concentration-dependently reduce Vmax in ventricular muscles of guinea pigs and rabbits. [96][97][98][99][100][101] IC50 for Vmax inhibition was about 30 mol/L in guinea pig papillary muscles stimulated at 1.0 Hz. 97,100 APD of the ventricular muscle was slightly prolonged (5-10%) at low concentrations (3-10 mol/L), but shortened at high concentrations of pirmenol (30-100 mol/L).…”

“…94,102 Vmax inhibition by pirmenol in Purkinje fibers and ventricular muscles was enhanced in a frequency-or usedependent manner. 93,95,[97][98][99][100] Onset and offset kinetics of use-dependent Vmax inhibition are slow. 93,95,[97][98][99][100] The R of Vmax from use-dependent blockade was reported as 27-34 s in experiments by Nakaya et al using guinea pig papillary muscles.…”

“…93,95,[97][98][99][100] Onset and offset kinetics of use-dependent Vmax inhibition are slow. 93,95,[97][98][99][100] The R of Vmax from use-dependent blockade was reported as 27-34 s in experiments by Nakaya et al using guinea pig papillary muscles. 97,99,100 Comparable values (16-18 s) were reported by other investigators in experiments on ventricular muscle or Purkinje fibers.…”

“…97,99,100 Comparable values (16-18 s) were reported by other investigators in experiments on ventricular muscle or Purkinje fibers. 95,98 Reichardt et al examined voltageand time-dependence of Vmax inhibition in rabbit Purkinje fibers using a double-microelectrode voltage-clamp method. 93 Application of a single conditioning depolarization to -45 mV from an HP at -105 mV in the presence of pirmenol (50 mol/L) resulted in a significant decrease in Vmax of the test action potential elicited 100 ms after the conditioning clamp.…”