[Epidemiology of Haemophilus influenzae strains collected in 2004 in France and in vitro assessment of their susceptibility to antibiotics]. / Epidémiologie et évaluation de la sensibilité aux antibiotiques de souches d'Haemophilus influenzae isolées en 2004 en France.

OBJECTIVES: The aim of this study was to describe the epidemiology of H. influenzae strains collected in 2004 at the National Reference Center and to evaluate their susceptibility to various antibiotics. METHODS: Demographic and clinical characteristics, capsular serotyping by slide agglutination with specific antisera, beta-lactamase by a chromogenic cephalosporin test (Nitrocefin) and MICs of amoxicillin, co-amoxiclav, cefpodoxime, cefaclor, cefuroxime, cefotaxime, erythromycin, pristinamycin and telithromycin by agar dilution method on Haemophilus Test Medium were determined for each strain. RESULTS: 807 strains of H. influenzae were identified: 41.8% from bronchial secretions (BS), 16.2% from conjunctivitis, 6.6% from otitis media (OM), 4.2% from CSF and 8.6% from blood cultures. 95.6% of strains was not capsulated and 4.4% was of serotype b, e, or f. 26.3% of strains was beta-lactamase producing (TEM type). 185 isolates (22.8% of total strains) had reduced susceptibility to beta-lactams due to modification of the target associated or not with beta-lactamase production. When beta-lactamase was produced, the MICs of amoxicillin increased, but the activity of the other antibiotics was unchanged. Low BLNAR strains showed an increase in the MICs of all beta-lactams. This increase was weak and variable according to beta-lactams. Pristinamycin and telithromycin activities were unchanged against these strains. Two strains were resistant to erythromycin. CONCLUSIONS: Theses results show that both beta-lactamase and modifications of the target are widespread among H. influenzae strains isolated in France. Cefpodoxime remains the most active compounds against H. influenzae, whatever the resistance mechanisms, followed by pristinamycin, telithromycin, and co-amoxiclav.

Genotyping of type b Haemophilus influenzae strains, comparison of strains collected before and during vaccine availability.

OBJECTIVE AND METHOD: Five hundred and seventy-eight strains of type b Haemophilus influenzae (521 isolated in children, and 57 in adults) were compared using pulsed-field gel electrophoresis (PFGE) to assess strain evolution and to study the impact of the generalization of anti-Haemophilus b (anti-Hib) vaccination in France. Among these strains, 398 (including 342 from meningitis) were isolated in 1985-1992 (pre-vaccination era), 39 (including 31 from meningitis) in 1993 (year of the generalization of anti-Hib vaccination), and 141 (including 50 from CSF) in 1994-2001 (vaccination era). RESULTS: A total of 102 PFGE patterns (patterns for 1-101 isolates) were obtained after SmaI restriction of the 578 strains. The strains isolated in children were distributed in 96 patterns, and those isolated in the adult in 34 patterns. The strains isolated during the pre-vaccination era presented 94 patterns. During the vaccination era, 50% of the patterns disappeared and 12 new patterns (11.7%) including 15 strains were observed. The strains belonging to the new patterns (including the two observed in 1993) were isolated in adults (n=7) from blood culture and bronchial secretions, and children (n=9) from CSF, blood culture, and bronchial secretions. In children, among the strains associated to vaccination failure, two presented with a new pulsotype. CONCLUSION: There is no evidence that the vaccination program brought about any drastic modifications in the type b strains causing meningitis or in the other type b strains in circulation whether in adults or children.

Protection against ventricular and atrial fibrillation by sotalol.

Sotalol is not only a beta blocker but a class III antiarrhythmic drug. Its possible antifibrillatory activity was therefore investigated in both the ventricles and atria of dog heart in situ, since vulnerability to fibrillation is not the same in both these parts of the myocardium. Fibrillation threshold was measured concurrently with the duration and amplitude of monophasic action potential, the effective refractory period, the conduction time in the contractile fibres, and after fibrillation had been triggered the fibrillation rate. Variables were measured at 5 and 10 min after sotalol had been given intravenously in closed chest dogs in three doses (1, 1, and 2 mg X kg-1) at 15 min interval. Sotalol produced a rise in fibrillation threshold that occurred simultaneously with a prolongation in monophasic action potential duration and effective refractory period of the contractile fibres and a slowing in fibrillation rate, whereas conduction time was not affected. The changes appeared, however, to be less pronounced in the ventricles than in the atria, in which vulnerability to fibrillation, normally increased by vagal tone, had been previously enhanced by acetylcholine. Sotalol antagonised the changes due to acetylcholine. In both the atria and the ventricles the first dose (1 mg X kg-1), which produced plasma concentrations of approximately 2 micrograms X ml-1 10 min after injection, produced a submaximal effect. Nevertheless, subsequent administrations increased the beneficial effects but not in proportion to the dose and plasma concentrations.

Cardiac beta-adrenoreceptor activation and ventricular fibrillation under normal and ischemic conditions.

OBJECTIVES: To investigate the role of ventricular and atrial beta-adrenoceptor activation by isoprenaline in the genesis of rhythm disorders and risk of fibrillation in the healthy or ischaemic heart. METHODS: The study was performed in anaesthetized, open-chest pigs. Electrical fibrillation threshold (EFT) of the ventricles was measured with trains of diastolic stimuli of 100 ms duration synchronized with respect to the R-waves and delivered to the myocardium by a subepicardial electrode introduced into the area which could be subjected to ischaemia. Monophasic action potential (MAP) and effective refractory period (ERP) were recorded in the same area. Ischaemia was obtained by complete occlusion of the left anterior descending coronary artery near its origin during increasing periods (30, 60, 90, 120, 150, 180, 240 s). RESULTS: At a rate varying according to the action exerted by isoprenaline on the sinus rate, EFT decreased by about 30% in the healthy heart during the infusion of 0.5 micrograms/kg/min isoprenaline under the influence of the acceleration of cardiac beats. In the ischaemic heart, sinus tachycardia accelerated the fall in EFT and the reduction in MAP duration and resulted sooner in spontaneous ventricular fibrillation. During ventricular pacing at a constant rate of 200 beats/min, isoprenaline raised EFT by nearly 80% in the absence of ischaemia, but this rise was abolished by ischaemia, at least of no-flow type. CONCLUSION: Tachycardia produced by activation of atrial adrenoceptors decreases EFT in the healthy heart and aggravates its fall in the ischaemic heart. Ventricular adrenoceptor activation counteracts the EFT fall related to tachycardia in the healthy heart, but not in the ischaemic heart. Therefore, the protection against ischaemic fibrillation due to beta-blockers would be essentially attributable to their action on the sinus nodes.

Efficacy of a beta-adrenergic receptor antagonist, propranolol, in preventing ischaemic ventricular fibrillation: dependence on heart rate and ischaemia duration.

OBJECTIVES: To investigate the prevention of ventricular fibrillation with a beta-adrenergic receptor (beta-AR) antagonist in anaesthetized, open-chest pigs in a model of ischaemia, intended to reproduce what happens either in anginal attack or in the first hour of infarction. METHODS: Ventricular fibrillation threshold (VFT) was determined with trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode inserted in the area subjected to ischaemia. Ischaemia was obtained by the complete occlusion of the left anterior descending coronary artery, either near its origin during brief but increasing periods (30, 60, 90, 120, 150, 180, 240, 300 s), or half-way from its origin for a much longer time (more than 60 min). RESULTS: During transient proximal occlusion and isoprenaline infusion (0.25 microgram/kg/min), propranolol (50 micrograms/kg plus 2 micrograms/kg/min) attenuated both tachycardia and the fall in VFT to 0 mA. The shortening of MAP duration accompanying depolarization of the fibres was concurrently slowed down, and time to fibrillation prolonged (122 +/- 15 to 262 +/- 14 s, p < 0.001). In the absence of isoprenaline infusion, propranolol exerted similar effects, but to a lesser degree, in proportion to heart rate dependent on sympathetic activity. In contrast, it became unable to raise VFT before and during ischaemia, when heart rate was kept constant by pacing. After persistent midportion occlusion, significant differences in VFT were found only at the 5th min, depending on whether heart rate was accelerated by isoprenaline (0.8 +/- 0.2 mA), left normal (1.8 +/- 0.3 mA) or slowed down by propranolol (1.6 +/- 0.3 mA). Later on, especially after 15 and 25 min of ischaemia, VFT, which was below 1.0 mA, did not appear to be influenced by the activation or blockade of beta-ARs: spontaneous fibrillations were observed in the same number in this period with or without the administration of propranolol. Beyond 30 min after occlusion, the rise in VFT, subsequent to the first irreversible cell damage, also occurred in the same way. CONCLUSIONS: The prevention of ischaemic ventricular fibrillation by a beta-AR antagonist, judged from VFT, is easily checked experimentally when ischaemia is only transitory, especially if sympathetic activity is high. The maintenance of VFT at a relatively high level is essentially related to the depressant effect on the sinus rate. The same animal model does not give support to an effective protection in the first hour of infarction. However, the control of heart rate may also be beneficial in these circumstances by attenuating systemic haemodynamic disorders.

Relationship between lactate arteriovenous gradient and tissue lactate content in subendocardial and subepicardial layers of the ischaemic in situ heart.

Myocardial lactate content and simultaneous evolution of a lactate arteriovenous gradient associated with incomplete obstruction of the left coronary bed were studied in dog hearts. Samples of blood were taken from a peripheral artery and the coronary sinus; transmural samples of myocardial tissue were obtained from the left ventricular wall by drill biopsy in animals under total cardiopulmonary by-pass. Lactate content was assessed in subendocardial and subepicardial layers separately. A 40 to 70% reduction in coronary flow induced a quick reduction and even an inversion of the positive lactate gradient while the tissue content, which was similar to the arterial content, rose considerably, chiefly in the subendocardial layer. Lactate accumulating in tissue was released into the blood approximately in proportion to the tissue concentration. The value of employing the lactate concentration difference between arterial blood and coronary sinus blood as an index of the severity and duration of myocardial ischaemia is discussed.

Blockade by verapamil of cholinergic effects on atrial specialised tissue in the anaesthetised dog.

The effects of verapamil were studied in anaesthetised dogs administered dextromoramide intrathecally to provide background vagal tone. Measurements were made of spontaneous heart rate, and, in paced hearts, of conduction times in atrial muscle, the atrioventricular node (A-V node) and His-Purkinje system by means of His bundle potential recording. The effective refractory period (ERP) of A-V node was measured by the extrastimulus method. In atropinised and vagotomised animals, verapamil reduced sinus rate and increased A-V nodal conduction time. In dogs high vagal tone after dextromoramide, however, verapamil increased sinus rate and reduced A-V nodal ERP. After dextromoramide alone, A-V block was observed at an atrial pacing rate of 150 beats X min-1, but after verapamil 1:1 A-V conduction was restored. The decrease in conduction velocity in the A-V node due to ACh was neither attenuated nor enhanced by verapamil.

Ischaemia-induced loss or reversal of the effects of the class I antiarrhythmic drugs on vulnerability to fibrillation.

1. In the last decade, a number of clinical observations have questioned the efficacy of certain class I antiarrhythmic drugs against ischaemia-induced ventricular fibrillation. The effects of three drugs of this class, disopyramide (Ia), lignocaine (Ib) and flecainide (Ic) on the vulnerability to fibrillation during experimental ischaemia were investigated. 2. The study was carried out in anaesthetized, open-chest pigs (n = 8 for each of the drugs, in addition to the control group, n = 6). Vulnerability to fibrillation was evaluated by measuring electrical fibrillation threshold (EFT) by means of stepwise increased intensity of wide (100 ms) diastolic impulses applied to the ischaemic tissue at a 180 beats min-1 rate. Monophasic action potential (MAP) duration and conduction time in the ischaemic region were also measured. 3. EFT determinations were performed before and during periods of ischaemia induced by complete occlusion of the left anterior descending coronary artery near its origin. Ischaemic periods of increasing duration (30, 60, 90, 120, 150 s) were induced to determine the electrophysiological changes, of EFT especially, leading to fibrillation. 4. In the absence of ischaemia, all three drugs, administered by intravenous route (1 mg kg-1 plus 0.04 mg kg-1 min-1) increased EFT to a similar extent (from approximately 7 to 10 mA), despite a 25% prolongation of conduction time. 5. During ischaemia, none of the drugs prevented the fall in EFT towards 0 mA, resulting in spontaneous fibrillation. After 30 s of ischaemia, they no longer had any capacity for raising EFT and, after 60, 90 and 120 s of ischaemia, the decrease in EFT was exacerbated. This accelerated reduction in EFT shortened the time to onset of fibrillation (after 120 s of ischaemia, 62.5% of fibrillations with flecainide instead of 12.5 under control conditions, 75% instead of 25 with lignocaine and 50% instead of 25 with disopyramide). The reduction in MAP duration due to ischaemia was also significantly accelerated (at 60 s, 178 +/- 5 ms instead of 192 +/- 4 with flecainide, 175 +/- 3 ms instead of 194 +/- 5 with lignocaine and 180 +/- 5 ms instead of 196 +/- 3 with disopyramide) and the slowing of conduction was made worse (prolongation of conduction time by 70% instead of 50). 6. In conclusion, the antifibrillatory properties normally manifested by these drugs are first suppressed, then inverted by ischaemia, depending on oxygen debt varying with severity and duration of ischaemia.

Relationship between atrial and ventricular rates of fibrillation and cardiac contractile tissue effective refractory periods in the dog.

1 During total cardiopulmonary bypass, acetylcholine-, isoprenaline-, ouabain- and quinidine-induced variations in the atrial and ventricular rates of fibrillation were studied and compared with the variations in effective refractory periods (ERP) of atrial and ventricular contractile tissue obtained under the same experimental conditions. 2 Acetylcholine significantly shortened the ERP and accelerated the rate of fibrillation in the atrium but did not provoke any change in ventricular tissue. A parallel decrease in atrial and ventricular ERP and a parallel increase in atrial and ventricular rates of fibrillation were observed with isoprenaline. 3 Ouabain exerted a biphasic effect on the atrium, with an initial decrease in the ERP and an initial acceleration of the rate of fibrillation. It produced only a slight decrease in the ventricular ERP and no significant variation in the ventricular rate of fibrillation. 4 Quinidine induced a greater increase in the ERP and a greater slowing of the rate of fibrillation in the atrium than in the ventricle. 5 The variations in percentage change of refractoriness and rate of fibrillation were strictly correlated: r = 0.89 (P less than 0.001); the equation of the regression line was y = --0.86 x --2.98.

Doxorubicin concentration time course in the myocardium after single administration to the dog. Possible role in the cardiac effects.

Three hours after i.v. administration of doxorubicin, concentrations of the drug in the myocardium are much higher (about 50 times) and decrease much more slowly (drug still detected 21 days later) than those in the plasma, so that storage results from too early readministration, with possible toxic signs.

Centrally mediated cardiovascular effects of nicergoline in the dog compared to those of clonidine.

The intracisternal administration of nicergoline (5 micrograms/kg) or clonidine (4 micrograms/kg) in chloralose-anesthetized dogs induced significant decreases in blood pressure and heart rate. The same dose of nicergoline induced similar effects on atropine-pretreated dogs. Guanethidine pretreatment (30 mg/kg i.v. the day before) prevented the hypotension but not the bradycardia induced by clonidine. Guanethidine prevented both the hypotension and the bradycardia induced by nicergoline. Thus, nicergoline, unlike clonidine, does not increase cardiac parasympathetic activity. When administered by the same route at the same doses, nicergoline did not change the slope and reduced the amplitude whereas clonidine increased both the slope and the amplitude of the heart period vs. blood pressure curve obtained by intravenous administration of phenylephrine. Taken together, these results suggest that nicergoline and clonidine probably act on different structures within the central nervous system.

Biphasic effect of a gradual rise in plasma calcium concentration on vulnerability to fibrillation.

The possible potentiation by a rise in plasma calcium concentration of the effects of acetylcholine (ACh) on the atrial myocardium was investigated, mainly with a view to define the increase in vulnerability to fibrillation by hypercalcaemia. The effective refractory period (ERP) of the atrial myocardium, the atrial fibrillation threshold (AFT) and the atrial fibrillation rate (AFR) were measured repeatedly before and during the intravenous infusion of calcium at the rates of 0.025, 0.050 and 0.100 mmol . kg-1 . min-1 in dogs whose heart was, in addition, submitted to a cholinergic influence. 1. As long as the rise in plasma calcium concentration did not reach 100% approximately, this influence was enhanced considerably: in particular, ACh shortened ERP and raised AFR to a much larger extent, so that it resulted in fibrillation with a minor electrical stimulation. 2. When the rise in plasma calcium concentration exceeded 100%, hypercalcaemia became inhibitory of the effects of ACh, with a reversal in the modification of all the parameters, AFT especially, and, finally, prevention or even conversion to sinus rhythm of fibrillation.

Enhancement by Ca2+ ions of cholinergic effects on the canine heart in situ.

The effects of Ca2+ ions were studied on the canine heart in situ, submitted to vagal influence or not. In addition to heart rate, conduction time was determined separately in atrial muscle, atrioventricular node and His-Purkinje system by means of His bundle potential recording and the effective refractory period (ERP) measured in atrioventricular node, atrial and ventricular muscle according to the extrastimulus method. In the presence of acetylcholine (ACh) released by vagal endings, an increase in plasma calcium concentration from 2.40 to 4.12 mmol/l, acutely induced by the infusion of calcium chloride, elicits the following alterations: slowing down of sinus rate, lengthening of conduction time in atrioventricular node without change of this time in atrial muscle and His-Purkinje system, prolongation of atrioventricular node ERP, but notable decrease of atrial muscle ERP and slight decrease of ventricular muscle ERP. These effects are similar to those of ACh:Ca2+ ions probably enhance the responsiveness to ACh.

Effects of mild hyperkalemia on conduction velocity and effective refractory period in various parts of the dog heart in situ.

Effects of mild hyperkalemia on conduction velocity, effective refractory periods (ERPs) and sinus rate were studied on 16 anesthetized dogs, using endocavitary His bundle recordings, the extrastimulus method and standard electrocardiogram. Six dogs were placed under acetylcholine infusion (300 micrograms/kg/min) (ACh group), 10 received atropine sulfate 0.2 mg/kg intravenously (atropine group). Intraventricular conduction time, ventricular ERP and QRS duration of the EKG were studied on 7 other open-chested dogs (ventricular group). During a 60 min potassium chloride infusion (0.025 mmol/kg/min, 30 min, then 0.05 mmol/kg/min, 30 min), following observations were made: - In the ACh group, AV node conduction time (A-H interval) decreased by 20% and AV node ERP by 17%, whereas, in the atropine group, the former parameter was not affected and atrial ERP increased by 29%. - At the same time, sinus rate increased in the ACh group and was unaffected in the atropine group. - Conduction times in atrial contractile tissue (S-A interval), His-Purkinje system (H-V interval) and ventricular contractile tissue, like ventricular ERP, exhibited no variation or very slight, occasionally biphasic variations under both conditions. These results can be accounted for by an "anticholinergic" effect of mild hyperkalemia which is discussed.

Effects of hypokalemia on the various parts of the conduction system of the dog heart in situ.

The effects of hypokalemia were studied on the various parts of the conduction system by means of His bundle potential recording in the heart of vagotomized dogs. Plasma potassium concentration was lowered by extracorporeal dialysis, precautions being taken against the simultaneous impairment of other parameters, especially humoral. In order to make sure that the changes in atrioventricular conduction observed were due to hypokalemia, a control series of experiments was carried out, under strictly identical conditions except that the dialysis fluid was not devoid of potassium. The following alterations were observed during the lowering of potassium concentration from 3.2 to 1.6 mmol/l: atrioventricular node conduction time (AH interval) increased steadily up to 250% of control values; conduction time in atrial contractile tissue (SA interval) and His Purkinje system (HV interval) exhibited variations much later and much smaller; conduction time in ventricular contractile tissue was not significantly affected; effective refractory period (ERP) of atrial muscle, initially the longest in ERPs of conduction system in vagotomized animals, was shortened by about 20%. The mechanism of all these alterations is discussed.

Biphasic dose-response relationship observed with Bay k 8644 on atrioventricular nodal conduction inhibited by verapamil.

The effects of a calcium channel blocker, verapamil, on the atrioventricular (AV) node, are antagonized by calcium, intravenously infused, so long as plasma calcium concentration does not reach 5.0 or 5.5 mmol.l-1, as previously shown. Beyond this, the antagonistic effects decrease progressively, so that there is a bell-shaped relationship between dose (or concentration) and response. The purpose of the present experiments has been to investigate a possible similar dose-response curve with a calcium channel activator, Bay k 8644. The study was carried out in anaesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitary electrodes and the AV nodal effective refractory period was measured by the extrastimulus method. Verapamil impaired AV nodal conduction and additional infusion of Bay k 8644 at a rate of 1 microgram.kg-1.min-1 partly antagonized this effect. Increasing the infusion rate of Bay k 8644 to 5 micrograms.kg-1.min-1 did not further increase but reduced the antagonism. In other experiments where infusion of calcium had partly antagonized the effect of verapamil, Bay k 8644 infused after cessation of calcium infusion did not further antagonize the effect of verapamil which even became again increasingly marked. Consequently, in the AV node depressed by a calcium channel blocker, Bay k 8644 gives rise to a bell-shaped dose-response relationship of its verapamil-antagonistic action and the reversal of this action by high doses of Bay k 8644 can be observed after both administration of either calcium or Bay k 8644 in moderate doses.

Attenuation of the ischaemia-induced fall of electrical ventricular fibrillation threshold by a calcium antagonist, diltiazem.

Calcium antagonists have been reported to decrease the incidence of sudden death in postinfarction management and vulnerability to fibrillation secondary to experimental coronary occlusion. In order to confirm such beneficial results regarding ischaemic ventricular fibrillation, the threshold intensity for fibrillation electrically induced with impulses of 100 ms and 180 beats.min-1 was measured during the course of ischaemias obtained by total occlusion of the left anterior descending coronary artery near its origin in open-chest pigs. The variations of electrical fibrillation threshold with ischaemia duration (30, 60, 120, 180, 240, 360 s) were compared under control conditions and after i.v. diltiazem (0.50 mg.kg-1 plus 0.02 mg.kg-1.min-1 over 25 min). Electrical fibrillation threshold was not influenced by diltiazem before, but raised during ischaemia, particularly from the 60th s (1.7 to 4.0 mA), with delay in the triggering of fibrillation which occurs when the fibrillation threshold falls down to the pacing threshold (0.2 to 0.3 mA). In 6 pigs out of 8, fibrillation was even avoided in the longest of the ischaemic periods considered (360 s), for fibrillation threshold ceased falling before reaching the critical level. These experimental results obtained with diltiazem are consistent with the clinical effectiveness of calcium antagonists recently observed in the prevention of postinfarction sudden death, provided that myocardial contractility is not too much adversely affected. But, left ventricular dP/dtmax was not reduced by more than 6.8% in the present experiments.

Ventricular and atrial electrophysiological effects of a IC antiarrhythmic drug, cibenzoline, in the innervated dog heart. Role of sodium and calcium channels.

The effects of cibenzoline, rightly known as a sodium channel inhibitor (class IC antiarrhythmic drug), were investigated in anaesthetized, closed-chest dogs, on conduction in the contractile fibres, ventricular and atrial, the His-Purkinje system and the atrioventricular node. In ventricular muscle, conduction time was measured between base and apex by two endocavitary electrodes. The other conduction times were obtained from the recording of the His bundle potentials. In addition, effective refractory period was determined by the extrastimulus method in ventricular and atrial muscle and in the atrioventricular node, and sinus rate monitored in the intervals of pacing periods. In the absence of vagal tone, cibenzoline in 4 mg.kg-1 dose prolonged conduction times in the ventricular contractile tissue, His-Purkinje system and atrial contractile tissue to a large extent, but decreasingly from the former to the latter. This prolongation was antagonized by hypernatremia (174 mmol.l-1). In contrast, conduction time in the atrioventricular node, effective refractory periods and sinus rate were very little influenced. In the presence of vagal tone, the prolongation of conduction times in the ventricular contractile tissue. His-Purkinje system and atrial contractile tissue did not differ substantially from previously. It was the same for ventricular effective refractory period. But atrial effective refractory period was then considerably lengthened, while conduction time and effective refractory period in the atrioventricular node were greatly shortened and sinus rate notably accelerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Class Ic antiarrhythmic drugs and myocardial ischaemia: study in the pig heart in situ.

The effects of three Ic antiarrhythmic drugs, flecainide, propafenone and cibenzoline, were investigated in anaesthetized, open-chest pigs, in a left ventricular area, during pacing at a constant high rate (180 beats min-1), in the absence and the presence of ischaemia. Ischaemia was produced by transient complete occlusion of the left anterior descending coronary artery 1-1.5 cm from its origin. In addition to surface electrocardiogram, conduction time and monophasic action potential were recorded in the contractile fibres. Measurement of the effective refractory period was added in the absence of ischaemia. In this event, flecainide and propafenone, each in a dose of 2.5 mg kg-1 i.v. and cibenzoline, 2.0 mg kg-1, i.v., considerably lengthened (by 50-90%) conduction time, but did not affect or hardly affected the duration of the monophasic action potential or the effective refractory period. Thus, it seems that these Ic antiarrhythmic drugs enhance the prolongation of conduction time by 60% and do not prevent the 30% shortening of monophasic action potential caused by ischaemia: contrary to expectation, they produced a large reduction (from about 120 to 25 s) in the onset time of fibrillation due to ischaemia. Thus, they manifested profibrillatory properties (more pronounced than those of other class I antiarrhythmic drugs), which might be explained by their potent action on depolarization with almost total absence of action on repolarization.

Potentiation by hypokalemia of the effects of acetylcholine on the canine heart in situ.

In the heart in situ of vagotomized dogs, atrioventricular conduction was studied by the His bundle potential recording, sinus rate continuously registered and the effective refractory period (ERP) of the atrial muscle measured by the extrastimulus method. The modifications induced by the acute lowering of plasma potassium concentration from 3.5 to 2.0 mmol/l obtained by hemodialysis appeared to be similar to those due to parasympathetic stimulation and the effects of hypokalemia and acetylcholine (ACh) on the atrioventricular (A-V) and sinoatrial nodes as well as on the atrial contractile tissue gave rise to potentiation. Intraaortically injected near coronary ostia in a dose lower than liminal dose, ACh enhanced to a large extent all the phenomena elicited by hypokalemia, since the variations respectively observed under the influence of hypokalemia alone and the combination of hypokalemia and ACh were as follows: lengthening of conduction time in the A-V node by 100 and 180%, reduction of sinus rate by 10 and 20%, shortening of the atrial ERP by 20 and 40%.