Electrophysiological effects of propafenone in untreated and propafenone‐pretreated guinea‐pig atrial and ventricular muscle fibres

Abstract

1 The electrophysiological effects of propafenone (10-7 to 10-4M) were studied on guinea-pig isolated atrial and ventricular muscle fibres obtained from untreated animals and animals pretreated with propafenone, 3 and 1Omg kg-', for 28 days. 2 In untreated atria propafenone produced a dose-dependent decrease in the rate and maximum following frequency, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline. 3 In untreated atrial and ventricular muscle fibres propafenone depressed action potential amplitude and V,"ax, reduced the resting membrane potential and prolonged the action potential duration (APD) and the effective refractory period, lengthening the effective refractory period relative to APD.4 Propafenone depressed the amplitude and V,,.x. and shortened the duration of the slow action potentials induced by isoprenaline and caffeine in K-depolarized papillary muscles. 5 Pretreatment with propafenone reduced atrial rate, but did not modify the action potential characteristics compared to the values obtained in untreated atria. Further addition of propafenone produced similar but more marked changes in untreated atria. 6 In ventricular muscle fibres pretreated with 3 mg kg-, action potential characteristics before and after further addition of propafenone were similar to those obtained in untreated fibres. However, muscles pretreated with 10 mg kg-' exhibited a significant prolongation of the APD compared to that in untreated muscles or those pretreated with 3 mg kg-'; further addition ofpropafenone shortened the APD even when this parameter was of similar value to those observed in the other two series of experiments. 7 It is concluded that even though the effects of propafenone are similar to those of quinidine (class I antiarrhythmic), it also exhibited class II and class IV actions. In pretreated animals a prolongation of the APD (class III action) could also be involved in the antiarrhythmic effects of the drug.

Effects of propafenone on 45Ca movements and contractile responses in vascular smooth muscle

“…In isolated cardiac ventricular muscle propafenone exhibited a high affinity for the inactivated and activated states of the Na channel and dissociated very slowly from the Na channel receptor site (Kohlhardt & Seifert, 1983;Kohlhardt, 1984;Valenzuela et al, 1989). Moreover, propafenone also inhibited the slow contractions and action potentials elicited by isoprenaline or histamine in ventricular muscle fibres partially depolarized with high K (Ledda et al, 1981;Dukes & Vaughan Williams, 1984;Delgado et al, 1985). These results suggest that propafenone may also inhibit the slow inward Ca current in cardiac tissues.…”

“…It has been reported that propafenone inhibited Ca entry through VSCs in cardiac muscle (Kohlhardt, 1977;Ledda et al, 1981;Satoh & Hashimoto, 1984;Delgado et al, 1985) and in fact in the present experiments propafenone inhibited Ca entry induced both by NA and high K. This lack of specificity is in contrast to what has been described with Ca antagonists, which in vascular smooth muscle fibres inhibited high K-induced contractions to a much greater extent than NA-induced contractions (Cauvin et al, 1983;Tamargo, 1984;Godfraind et al, 1986). However, like Ca antagonists (Cauvin et al, 1983;Godfraind et al, 1986) propafenone had no effect on 45Ca uptake in resting aortic strips, which suggests that Ca entry through passive membrane leak channels seems to be insensitive to the drug.…”

Molecular Site of Action of the Antiarrhythmic Drug Propafenone at the Voltage-Operated Potassium Channel Kv2.1

“…Accordingly, sodium channel blocking effects of PROP were described previously (Kohlhardt, 1984). Also, PROP increased the duration of the action potential (Satoh and Hashimoto, 1984;Delgado et al, 1985) and depressed the transient outward current (I to ) in atrial myocytes of the rabbit and ventricular myocytes of the rat (Duan et al, 1993), the hyperpolarization-activated inward current (I f ) in isolated human atrial myocytes (Hoppe and Beuckelmann, 1998), and the delayed rectifier current (I K ) in sinoatrial node cells and atrial myocytes of rabbits and ventricular myocytes of guinea pigs (Satoh and Hashimoto, 1984;Duan et al, 1993). In in vitro expression studies, Kv1.5 and Kv2.1 currents are sensitive to micromolar PROP concentrations (Franqueza et al, 1998;Zhu et al, 1999;Rolf et al, 2000).…”

Postrepolarization Refractoriness Versus Conduction Slowing Caused by Class I Antiarrhythmic Drugs

“…[1][2][3][4] It has been suggested that the proarrhythmic effect of these drugs is mediated by conduction slowing, which shortens the excitation wavelength or creates unidirectional block, thereby providing conditions for reentry, especially in structurally altered hearts. 5,6 Propafenone is another agent with slowly dissociating, rate-dependent sodium channel block 7,8 that has been shown clinically to have proarrhythmic effects in the treatment of ventricular tachyarrhythmias. 9,10 On the other hand, drugs with sodium channel-blocking activity may delay the time-dependent recovery of excitability, thereby prolonging in a rate-dependent manner refractoriness beyond repolarization of the action potential to its resting state.…”