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

Abstract

1 The electrophysiological effects of prazosin, a highly specific ax-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 (V,,,.) and a progressive lengthening of the action potential duration at 50% (APDm) and 90% (APD90) of repolarization. The prolongation of the APD5o and APD91 values was independent of the frequency of stimulation. The prolongation of the APD9o was accompanied by a parallel lengthening of the effective refractory period (ERP) and thus, the ERP/APD9( ratio remained unaltered at all drug concentrations tested. 3 In the presence of prazosin, 5 x 10-6 M, the percentage of 1,, block increased with the frequency of stimulation, the inhibitory effect being more marked at fast driving rates (frequency-dependent V,,,C,, 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 APà nd 0.045 ± 0.010 AP-', respectively. However, prazosin did not produce tonic V,.. block. 4 The recovery time constant (Tre) from the frequency-dependent V.,.z 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 (voltagedependent . block). 6 It is concluded that in guinea-pig papillary muscles, prazosin inhibited the V,,,, 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 al-adrenoceptors.

Influence of alpha- and beta-adrenoceptor antagonists on ventricular fibrillation in ischemic rat hearts

“…An importance of these effects can be clearly ruled out for this study, since the model uses isolated buffer perfused hearts and therefore avoids humoral or systemic interferences. Furthermore, it has been suggested that direct membrane stabilizing actions similar to those of class I antiarrhythmic agents account for the antifibrillatory effect of phentolamine (Rosen et al 1971), a non-specific effect, which has also been demonstrated for prazosin (Northover 1983;Perez et al 1994). As this argument cannot be clearly ruled out in our investigation, we evaluated further alpha-adrenoceptor antagonists, such as WB 4101.…”

“…The alphaadrenoceptor antagonist prazosin, however, failed to alter ischemia-induced arrhythmias in anesthetized open-chest canine preparations (Bolli et al 1984). These equivocal results may be due to ancillary properties of adrenoceptor antagonists such as class I and III actions (Perez et al 1994), and to the use of different models in which indirect actions of the compounds such as central-neuronal, humoral, and systemic vascular effects were of varying importance.…”

Electrophysiological effects of CI‐980, a tubulin binding agent, on guinea‐pig papillary muscles

“…The relationship between V max and the resting membrane potential from which the action potential was elicited was studied in papillary muscles driven at 0.05 Hz. The resting membrane potential was depolarized by increasing in a step‐wise manner the extracellular K + concentration, [K + ] o , from 2 to 16 mM (Pérez et al , 1994) and the V max was measured after the resting membrane potential had reached a steady‐state at each [K + ] o .…”

“…Under these conditions, the fast inward Na + current was voltage‐inactivated and excitability, i.e. slow action potentials, was restored in depolarized muscles driven at 0.1 Hz by adding isoprenaline(10 −6 m) to the perfusate (Pérez et al , 1994). After control values for each parameter had been obtained, incremental concentrations of each drug were added to the bath to obtain a complete concentration‐response curve.…”

Microdialysis technique for in-vivo monitoring of •OH generation on myocardial injury in the rat

“…Prazosin has been demonstrated to exibit a protective effect on myocardial ischaemic injury [82]. It is known that prazosin has a Na + channel blocking action as well as an α I -adrenoceptor blocking action [83]. Reactive oxygen causes excessive Na + entry through the fast Ca 2+ channel, leading to intracellular Ca 2+ overload through the Na + -Ca 2+ exchange system, and hence myocardial damage [84].…”