Doctor-patient communication issues for international medical graduates: research findings from Australia.

INTRODUCTION: Understanding the impact of culture on medical communication is particularly important for international medical graduates (IMGs) who enter health systems from different cultures of origin. This article presents data on IMGs' perception of the impact of cultural factors on IMG doctor-patient communication during their integration into the Australian health system. METHODS: The methodology used was a descriptive qualitative methodology, using iterative, open-ended, in-depth interviews with a sample of 30 IMGs employed at a hospital in Brisbane, Queensland, Australia. RESULTS: According to subjects' comments, understanding patient-centered communication is a major challenge faced by IMGs during integration in the Australian health system. They perceive that this difficulty is associated with the major shift from the culture of their country of origin (described as paternalistic doctor-dominated communication system; standard practice to talk to the family and not the patient) to the very different health care culture of Australia (perceived to be more educated and informed consumers that demand high levels of information and discussion). The findings detail IMGs' experience with learning about patient-centered communication at the point of arrival, during integration and practice. Subjects' perceived the need to provide education on patient-centered communication for IMGs integrating into the Australian health system. CONCLUSION: There is a significant need for IMGs to be educated in cultural issues including doctor-patient communication practices in Australia.

Regulation of cardiac ion channels by transcription factors: Looking for new opportunities of druggable targets for the treatment of arrhythmias.

Cardiac electrical activity is governed by different ion channels that generate action potentials. Acquired or inherited abnormalities in the expression and/or function of ion channels usually result in electrophysiological changes that can cause cardiac arrhythmias. Transcription factors (TFs) control gene transcription by binding to specific DNA sequences adjacent to target genes. Linkage analysis, candidate-gene screening within families, and genome-wide association studies have linked rare and common genetic variants in the genes encoding TFs with genetically-determined cardiac arrhythmias. Besides its critical role in cardiac development, recent data demonstrated that they control cardiac electrical activity through the direct regulation of the expression and function of cardiac ion channels in adult hearts. This narrative review summarizes some studies showing functional data on regulation of the main human atrial and ventricular Na+, Ca2+, and K+ channels by cardiac TFs such as Pitx2c, Tbx20, Tbx5, Zfhx3, among others. The results have improved our understanding of the mechanisms regulating cardiac electrical activity and may open new avenues for therapeutic interventions in cardiac acquired or inherited arrhythmias through the identification of TFs as potential drug targets. Even though TFs have for a long time been considered as 'undruggable' targets, advances in structural biology have led to the identification of unique pockets in TFs amenable to be targeted with small-molecule drugs or peptides that are emerging as novel therapeutic drugs.

Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels.

BACKGROUND AND PURPOSE: The human cardiac transient outward potassium current (Ito) is believed to be composed of the pore-forming Kv4.3 alpha-subunit, coassembled with modulatory beta-subunits as KChIP2, MiRP1 and DPP6 proteins. beta-Subunits can alter the pharmacological response of Ito; therefore, we analysed the effects of flecainide on Kv4.3/KChIP2 channels coassembled with MiRP1 and/or DPP6 beta-subunits. EXPERIMENTAL APPROACH: Currents were recorded in Chinese hamster ovary cells stably expressing K(V)4.3/KChIP2 channels, and transiently transfected with either MiRP1, DPP6 or both, using the whole-cell patch-clamp technique. KEY RESULTS: In control conditions, Kv4.3/KChIP2/MiRP1 channels exhibited the slowest activation and inactivation kinetics and showed an 'overshoot' in the time course of recovery from inactivation. The midpoint values (Vh) of the activation and inactivation curves for Kv4.3/KChIP2/DPP6 and Kv4.3/KChIP2/MiRP1/DPP6 channels were approximately 10 mV more negative than Vh values for Kv4.3/KChIP2 and Kv4.3/KChIP2/MiRP1 channels. Flecainide (0.1-100 microM) produced a similar concentration-dependent blockade of total integrated current flow (IC50 approximately 10 microM) in all the channel complexes. However, the IC50 values for peak current amplitude and inactivated channel block were significantly different. Flecainide shifted the Vh values of both the activation and inactivation curves to more negative potentials and apparently accelerated inactivation kinetics in all channels. Moreover, flecainide slowed recovery from inactivation in all the channel complexes and suppressed the 'overshoot' in Kv4.3/KChIP2/MiRP1 channels. CONCLUSIONS AND IMPLICATIONS: Flecainide directly binds to the Kv4.3 alpha-subunit when the channels are in the open and inactivated state and the presence of the beta-subunits modulates the blockade by altering the gating function.

[New calcium channel blockers for the treatment of hypertension]. / Nuevos bloqueadores de los canales de calcio en el tratamiento de la hipertensión arterial.

L-type voltage-gated calcium channels play a key role in the regulation of arterial vascular smooth muscle tone and blood pressure levels and L-type calcium channel blockers (CCBs) are widely used antihypertensive drugs. Additionally, T-type channels regulate vascular tone in small-resistance vessels and renin and aldosterone secretion, and N-type channels, expressed in sympathetic nerve terminals, regulate the release of neurotransmitters. As compared with L-type CCBs, L/N-and L/T-type CCBs decreased intraglomerular pressure, improved renal hemodynamics and provided a greater decrease in proteinuria even in patients already treated with renin-angiotensin-aldosterone inhibitors. Thus, dual L/N-and L/T-type CCBs may exhibit therapeutic advantages over L-type blockers in hypertensive patients with chronic kidney disease. However, further large-scale, long-term comparative trials are needed to confirm that these differences translate into an improvement in clinical outcomes. © 2017 SEHLELHA. Published by Elsevier España, S.L.U. All rights reserved.

Gender differences in the effects of cardiovascular drugs.

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

Investigational calcium channel blockers for the treatment of hypertension.

INTRODUCTION: Voltage-gated Ca2+ channels are the primary route of Ca2+ entry in vascular smooth muscle cells, playing a key role in the regulation of arterial tone and blood pressure. Since the 60´s, L-type Ca2+ channel blockers (CCBs) have been widely used for the treatment of hypertension. Areas covered: T-type Ca2+ channels regulate vascular tone in small-resistance vessels and aldosterone secretion, and N-type channels expressed in sympathetic nerve terminals regulate the release of neurotransmitters. We performed a literature search in MEDLINE, PubMed and ClinicalTrials.gov to identify eligible studies published between January 2001 and March 2016 and reviewed the antihypertensive and renoprotective effects of four CCBs with different pharmacological profiles: azelnidipine (L-type), cilnidipine (L-/N-type) and benidipine and efonidipine (L-/T-type CCBs). Despite similar blood pressure lowering effects, L/N- and L/T-type CCBs, compared with L-type CCBs, decreased intraglomerular pressure, improved renal hemodynamics and provided a greater decrease in proteinuria even in patients already treated with renin-angiotensin-aldosterone inhibitors. Expert opinion: Dual L/N- and L/T-type CCBs may exhibit therapeutic advantages over L-type blockers in hypertensive patients with chronic kidney disease. Because clinical trials supporting these advantages present important biases, further large-scale, long-term comparative trials are needed to confirm that these differences translate into improved clinical outcomes.

An update on atrial fibrillation in 2014: From pathophysiology to treatment.

Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. The trigger for initiation of AF is generally an enhanced vulnerability of pulmonary vein cardiomyocyte sleeves to either focal or re-entrant activity. The maintenance of AF is based on a "driver" mechanism in a vulnerable substrate. Cardiac mapping technology is providing further insight into these extremely dynamic processes. AF can lead to electrophysiological and structural remodelling, thereby promoting the condition. The management includes prevention of stroke by oral anticoagulation or left atrial appendage (LAA) occlusion, upstream therapy of concomitant conditions, and symptomatic improvement using rate control and/or rhythm control. Nonpharmacological strategies include electrical cardioversion and catheter ablation. There are substantial geographical variations in the management of AF, though European data indicate that 80% of patients receive adequate anticoagulation and 79% adequate rate control. High rates of morbidity and mortality weigh against perceived difficulties in management. Clinical research and growing experience are helping refine clinical indications and provide better technical approaches. Active research in cardiac electrophysiology is producing new antiarrhythmic agents that are reaching the experimental clinical arena, inhibiting novel ion channels. Future research should give better understanding of the underlying aetiology of AF and identification of drug targets, to help the move toward patient-specific therapy.

Losartan and its metabolite E3174 modify cardiac delayed rectifier K(+) currents.

BACKGROUND: The effects of type 1 angiotensin II receptor antagonist losartan and its metabolite E3174 on transmembrane action potentials, hKv1.5, HERG, and I(Ks) currents were analyzed. METHODS AND RESULTS: Guinea pig ventricular action potentials were recorded with microelectrode techniques and hKv1.5 and HERG currents with the whole-cell patch-clamp technique. I(Ks) was recorded in guinea pig ventricular myocytes with the perforated-nystatin-patch configuration. Losartan and E3174 transiently increased the hKv1.5 current by 8.0+/-1.4% and 7.4+/-1.6%, respectively. Thereafter, they produced a voltage-dependent block, E3174 being more potent than losartan (P<0.05) for this effect. Losartan decreased HERG currents elicited at 0 mV (23.3+/-4.8%), whereas E3174 increased the current (30.5+/-6.2%). Both drugs shifted the midpoint of the activation curve of HERG channels to more negative potentials. In ventricular myocytes, losartan and E3174 inhibited the I(Ks) (18.4+/-3.2% and 6. 5+/-0.7%, respectively). Losartan-induced block was voltage-independent, whereas E3174 shifted the midpoint of the activation curve to more negative potentials. Losartan lengthened the duration of the action potentials at both 50% and 90% of repolarization, whereas E3174 slowed only the final phase of the repolarization process. CONCLUSIONS: These results demonstrated that at therapeutic concentrations, both losartan and E3174 modified the cardiac delayed rectifier hKv1.5, HERG, and Ks currents.

Block of human cardiac Kv1.5 channels by loratadine: voltage-, time- and use-dependent block at concentrations above therapeutic levels.

OBJECTIVE: The aim of this study was to analyze the effects of loratadine on a human cardiac K+ channel (hKv1.5) cloned from human ventricle and stably expressed in a mouse cell line. METHODS: Currents were studied using the whole-cell configuration of the patch-clamp technique in Ltk- cells transfected with the gene encoding hKv1.5 channels. RESULTS: Loratadine inhibited in a concentration-dependent manner the hKv1.5 current, the apparent affinity being 1.2 +/- 0.2 microM. The blockade increased steeply between -30 and 0 mV which corresponded with the voltage range for channel opening, thus suggesting that the drug binds preferentially to the open state of the channel. The apparent association and dissociation rate constants were (3.6 +/- 0.5) x 10(6).M-1.s-1 and 3.7 +/- 1.6.s-1, respectively. Loratadine, 1 microM, increased the time constant of deactivation of tail currents elicited on return to -40 mV after 500 ms depolarizing pulses to +60 mV from 36.2 +/- 3.4 to 64.9 +/- 3.6 ms (n = 6, P < 0.01), thus inducing a 'crossover' phenomenon. Application of trains of pulses at 1 Hz lead to a progressive increase in the blockade reaching a final value of 48.6 +/- 4.3%. Recovery from loratadine-induced block at -80 mV exhibited a time constant of 743.0 +/- 78.0 ms. Finally, the results of a mathematical stimulation of the effects of loratadine, based on an open-channel block model, reproduced fairly well the main effects of the drug. CONCLUSIONS: The present results demonstrated that loratadine blocked hKv1.5 channels in a concentration-, voltage-, time- and use-dependent manner but only at concentrations much higher than therapeutic plasma levels in man.

Benzocaine enhances and inhibits the K+ current through a human cardiac cloned channel (Kv1.5).

OBJECTIVE: The aim of this study was to analyze the effects of a neutral local anaesthetic, benzocaine, on a cardiac K+ channel cloned from human ventricle. METHODS: Experiments were performed on hKv1.5 channels stably expressed on mouse cells using the whole-cell configuration of the patch clamp technique. RESULTS: At 10 nM, benzocaine increased the current amplitude ("agonist effect") by shifting the activation curve 8.4 +/- 2.7 mV in the negative direction, and slowed the time course of tail current decline. In contrast, benzocaine (100-700 microM) inhibited hKv1.5 currents (KD = 901 +/- 81 microM), modified the voltage-dependence of channel activation, which became biphasic, and accelerated the channel deactivation. Extracellular K+ concentration ([K+]o) also affected the channel gating. At 140 mM [K+]o, the time course of tail currents deactivation was significantly accelerated, whereas at 0 mM [K+]o, it was slowed. At both [K+]o the activation curve became biphasic. Benzocaine accelerated the tail current decay at 0 mM but not at 140 mM [K+]o. The reduction in the permeation of K+ through the pore did not modify the blocking effects of micromolar concentrations of benzocaine, but suppressed the agonist effect observed at nanomolar concentrations. CONCLUSIONS: All these results suggest that benzocaine blocks and modifies the voltage- and time-dependent properties of hKv1.5 channels, binding to an extracellular and to an intracellular site at the channel level. Moreover, both sites are related to each other and can also interact with K+.

Functional expression of an inactivating potassium channel (Kv4.3) in a mammalian cell line.

OBJECTIVE: The goal of this study was to characterize the electrophysiological properties of the Kv4.3 channels expressed in a mammalian cell line. METHODS: Currents were recorded using the whole-cell voltage clamp technique. RESULTS: The threshold for activation of the expressed Kv4.3 current was approximately -30 mV. The dominant time constant for activation was 1.71 +/- 0.16 ms (n = 10) at +60 mV. The current inactivated, this process being incomplete, resulting in a sustained level which contributed 15 +/- 2% (n = 25) of the total current. The time course of inactivation was fit by a biexponential function, the fast component contributing 74 +/- 5% (n = 9) to the overall inactivation. The fast time constant was voltage-dependent [27.6 +/- 2.0 ms at +60 mV (n = 10) versus 64.0 +/- 3.6 ms at 0 mV (n = 10); P < 0.01], whereas the slow was voltage-independent [142 +/- 15 ms at +60 mV (n = 10) versus 129 +/- 33 ms at 0 mV (n = 6) P > 0.05]. The voltage-dependence of inactivation exhibited midpoint and slope values of -26.9 +/- 1.5 mV and 5.9 +/- 0.3 mV (n = 21). Recovery from inactivation was faster at more negative membrane potentials [203 +/- 17 ms (n = 13) and 170 +/- 19 ms (n = 4), at -90 and -100 mV]. Bupivacaine block of Kv4.3 channels was not stereoselective (KD approximately 31 microM). CONCLUSIONS: The functional profile of Kv4.3 channels expressed in Ltk- cells corresponds closely to rat ITO, although differences in recovery do not rule out association with accessory subunits. Nevertheless, the sustained component needs to be considered with respect to native ITO.

New antihypertensive drugs under development.

Hypertension is the most common cardiovascular disease and remains the most prevalent risk factor for cardiovascular diseases and a major cause of death worldwide. Despite the large number of antihypertensive drugs available, in the majority of patients blood pressure still remains not optimally controlled and persists at high risk of cardiovascular complications. The limitations of current therapies have stimulated the research and development of new classes of antihypertensive agents, with different mechanisms of action, that provide a better blood pressure control, greater protection against organ damage, better tolerability and more effective prevention of cardiovascular diseases. However, essential hypertension is a multifactorial and multigenic disorder, which means that various mechanisms contribute to a greater or lesser extent to increase BP. Recent advances in the understanding of the multiple and complex cellular signalling pathways that modulate vascular smooth muscle cell contraction and growth involved in the regulation of vascular tone and in hypertension-induced end-organ damage have provided valuable insight in identifying new therapeutic targets. This article reviews new antihypertensive drugs under development, focusing on their mechanisms of action and possible advantages compared with traditional drugs.

Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat.

Fructose feeding induces a moderate increase in blood pressure levels in normal rats that is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. The sympathetic nervous system seems to participate in the alterations of this model. To further explore the mechanisms underlying fructose-induced hypertension, the effects of the AT1 receptor antagonist losartan on blood pressure, insulin resistance, renal function, and vascular reactivity in mesenteric vascular beds were studied. Sprague-Dawley rats were fed for 4 weeks with diets containing 60% fructose or 60% starch (control), and half of each group received losartan (1 mg/kg per day) in the drinking water. Fructose-fed rats showed higher (P < .05) blood pressure levels and plasma concentrations of triglycerides and insulin than those of controls. Losartan treatment prevented both blood pressure elevation and hyperinsulinemia in fructose-fed rats but not elevation of plasma triglycerides. Plasma glucose and insulin levels in response to an oral glucose load were higher (P < .05) in fructose-fed rats than in controls. These exaggerated responses were prevented by losartan treatment. No differences in the constrictor responses of mesenteric vascular beds to KCl (60 mumol), angiotensin II (1 nmol), phenylephrine (10(-5) mol/L), or endothelin-1 (10 pmol) were found between the two groups. Relaxing responses to acetylcholine or sodium nitroprusside in phenylephrine-precontracted mesenteric vascular beds and constrictor response to the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (100 nmol) were comparable in both groups. Losartan blunted angiotensin II constriction and reduced (P < .05) responses to phenylephrine in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of oxytocin on contractile responses and 45Ca movements in rat isolated aortic strips.

The effects of oxytocin (Oxt) on contractile responses and transmembrane Ca fluxes were studied in rat isolated aortic strips. Oxt (50-1000 mu ml-1) induced a dose-dependent contractile response and spontaneous myogenic activity. The Oxt-induced contractile response was not inhibited by pretreatment of aortic strips with phentolamine plus practolol, atropine, diphenhydramine plus cimetidine or indomethacin, but was significantly reduced by verapamil or deamino-ethyl-Oxt. The dose-response curve for Oxt was shifted upwards and to the left by increasing the Ca concentration of the medium from 1.8 to 4 mM. Oxt also shifted upwards the dose-response curve to Ca (1 to 5 mM) in aortic strips incubated in K depolarizing Ca-free media. Oxt increased the La3+-resistant 45Ca content without altering 45Ca efflux. The present results suggest that in rat isolated aortic strips Oxt produces a contractile response which, as previously found with other neurotransmitters, can be partly attributed to an increase of Ca influx through receptor-operated channels and to the release of Ca from intracellular stores.

Effect of somatostatin on 45Ca fluxes in guinea-pig isolated atria.

The effect of somatostatin (SS, 10(-6) M and 5 X 10(-6) M) was studied on 45Ca fluxes in guinea-pig isolated atria. SS produced a dose-dependent decrease in 45Ca uptake, this effect being dependent on the stimulation rate and Ca concentration in the bathing media. The decrease in 45Ca uptake was more evident at faster (60 and 180 beats min-1) than at slower frequencies (15 beats min-1) and was less evident in high Ca (5.4 mM). SS had no effect on 45Ca efflux. These results suggest that SS inhibits the slow inward Ca current in guinea-pig atrial fibres.

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

1. The inhibitory effects of oxodipine, a new dihydropyridine, were compared with those of nifedipine on contractile responses in rat isolated aortic strips and on spontaneous mechanical activity in portal vein segments. 2. In rat isolated aorta oxodipine (IC50 = 7.8 +/- 1.8 x 10(-9)M) and nifedipine (IC50 = 8.5 +/- 2.5 x 10(-9)M) dose-dependently inhibited the contractile responses induced by high K (80 mM), whereas responses to noradrenaline (NA, 10(-6)M) were only slightly affected (IC50 greater than 10(-7)M). These inhibitory actions were observed with both drugs added either before or after the induced contractions. 3. Contractile responses induced by addition of Ca to 0Ca high-K solution were also dose-dependently inhibited by oxodipine (IC50 = 4.5 +/- 2.5 x 10(-9)M). However, oxodipine up to 10(-6)M did not modify the contractile responses obtained in strips incubated in 0Ca when Ca was added in the presence of NA. 4. Oxodipine and nifedipine also inhibited the development of spontaneous mechanical activity in portal vein segments. 5. Oxodipine inhibited 45Ca uptake stimulated by high K (I50 = 8.7 +/- 2.5 x 10(-9)M) or by NA (I50 greater than 10(-7)M). However, it did not modify 45Ca uptake and 45Ca efflux in resting strips or 45Ca efflux stimulated by NA. 6. These results indicate that the effects of oxodipine on vascular smooth muscle may be due to the blockade of Ca entry through potential- and receptor-operated channels; it was at least 10 times more selective for potential-operated channels. Oxodipine did not modify Ca entry through passive leak channels and NA-induced intracellular Ca release.

Electrophysiological effects of imipramine on bovine ventricular muscle and Purkinje fibres.

1 The effect of imipramine in concentrations between 0.01 microM and 50 microM has been studied on bovine Purkinje fibres and ventricular muscle transmembrane potentials. 2 In electrically stimulated fibres, imipramine had no effect on the resting membrane potential, but decreased the action potential amplitude, overshoot and maximum rate of depolarization (Vmax). 3 In Purkinje fibres, imipramine also decreased the conduction velocity and shifted the membrane responsiveness and recovery time curves downward and to the right. 4 In both Purkinje fibres and ventricular muscle, imipramine decreased the amplitude of phase 2 and prolonged phase 3. In Purkinje fibres, imipramine did not alter the action potential duration (APD) but prolonged the effective refractory period (ERP). In ventricular muscle, at concentrations higher than 1 microM imipramine shortened both the APD and the ERP and made the ERP long as compared to APD. 5 Imipramine decreased the slope of phase 4 diastolic depolarization in spontaneously beating Purkinje fibres. 6 These properties of imipramine are quite similar to those of quinidine or procainamide (class 1 antiarrhythmics). The mechanisms responsible for the cardiac effect of imipramine are discussed.

Electrophysiological effects of imipramine in nontreated and in imipramine-pretreated rat atrial fibres.

1 The effect of imipramine (Imip) in concentrations between 10(-7)M and 5 X 10(-5)M has been studied on rat atrial transmembrane potentials. In another group of experiments the effect of Imip was studied in atrial fibres from rats pretreated for 24 days with twice daily intraperitoneal injections of Imip 7.5 mg/kg or saline. 2 In non-treated atria Imip depressed action potential amplitude and Vmax, reduced th e resting membrane potential and shifted the membrane responsiveness and recovery time curves downward and to the right. 3 Imip also prolonged the action potential duration and the effective refractory period, lengthening the effective refractory period relative to action potential duration. 4 Pretreatment with Imip decreased the resting membrane potential, amplitude and Vmax of the action potential and prolonged the effective refractory period. Further addition of Imip produced similar but more marked changes than in non-treated animals. 5 Imip suppressed the spontaneous atrial automaticity as well as the abnormal automaticity induced by BaCl2, aconitine, ouabain or isoprenaline. 6 The drug produced a negative inotropic effect and depressed the amplitude of the slow contractions elicited by isoprenaline in K-depolarized atria. 7 It is concluded that even when the effects of Imip are similar to those of quinidine (group I of antiarrythmics), it also produces a reduction in Ca and K conductances.

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

The electrophysiological effects of propafenone (10(-7) to 10(-4) M) were studied on guinea-pig isolated atrial and ventricular muscle fibres obtained from untreated animals and animals pretreated with propafenone, 3 and 10 mg kg-1, for 28 days. 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. In untreated atrial and ventricular muscle fibres propafenone depressed action potential amplitude and Vmax, 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. Propafenone depressed the amplitude and Vmax and shortened the duration of the slow action potentials induced by isoprenaline and caffeine in K-depolarized papillary muscles. 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. In ventricular muscle fibres pretreated with 3 mg kg-1, 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-1 exhibited a significant prolongation of the APD compared to that in untreated muscles or those pretreated with 3 mg kg-1; further addition of propafenone shortened the APD even when this parameter was of similar value to those observed in the other two series of experiments. 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.