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

Abstract

1. The electrophysiological effects of prazosin, a highly specific alpha 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 (Vmax) 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 ADP90 was accompanied by a parallel lengthening of the effective refractory period (ERP) and thus, the ERP/APD90 ratio remained unaltered at all drug concentrations tested. 3. In the presence of prazosin, 5 x 10(-6) M, the percentage of Vmax block increased with the frequency of stimulation, the inhibitory effect being more marked at fast driving rates (frequency-dependent Vmax block). At 3 Hz, the onset kinetics of the frequency-dependent Vmax block was better fitted by a biexponential function, the K values of the fast (K1) and slow components (K2) being 0.254 +/- 0.037 AP-1 and 0.045 +/- 0.010 AP-1, respectively. However, prazosin did not produce tonic Vmax block. 4. The recovery time constant (tau re) from the frequency-dependent Vmax 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 x 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 Vmax block). 6. It is concluded that in guinea-pig papillary muscles, prazosin inhibited the Vmax 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 alpha l-adrenoceptors.