Class I and III antiarrhythmic actions of prazosin in guinea‐pig papillary muscles

1 The electrophysiological effects of prazosin, a highly specific α 1 ‐adrenoceptor antagonist, on transmembrane action potential characteristics were studied in guinea‐pig papillary muscles. 2 At concentrations between 10 −6 m and 10 −5 m , prazosin produced a concentration‐dependent decrease in the maximum upstroke velocity ( V̇ max ) and a progressive lengthening of the action potential duration at 50% (APD50) and 90% (APD90) of repolarization. The prolongation of the APD50 and APD90 values was independent of the frequency of stimulation. The prolongation of the APD90 was accompanied by a parallel lengthening of the effective refractory period (ERP) and thus, the ERP/APD 90 ratio remained unaltered at all drug concentrations tested. 3 In the presence of prazosin, 5 × 10 −6 m , the percentage of V̇ max block increased with the frequency of stimulation, the inhibitory effect being more marked at fast driving rates (frequency‐dependent V̇ max block). At 3 Hz, the onset kinetics of the frequency‐dependent V̇ max block was better fitted by a biexponential function, the K values of the fast ( K 1 ) and slow components ( K 2 ) being 0.254 ± 0.037 AP −1 and 0.045 ± 0.010 AP −1 , respectively. However, prazosin did not produce tonic V̇ max block. 4 The recovery time constant (τ re ) from the frequency‐dependent V̇ max block was prolonged from 19.6 ± 2.5 ms to 24.4 ± 5.5 s. This result indicated that prazosin can be considered as a slow kinetics Na channel blocker. 5 Prazosin, 5 × 10 −6 m , shifted the membrane responsiveness curve in a hyperpolarizing direction, which indicated that the blockade of sodium channels increased at less negative potentials (voltage‐dependent V̇ max block). 6 It is concluded that in guinea‐pig papillary muscles, prazosin inhibited the V̇ max and lengthened the duration of the action potentials, thus exhibiting both class I and class III antiarrhythmic actions, respectively, that were possibly unrelated to blockade of myocardial α 1 ‐adrenoceptors.