RESUMEN

It is now accepted that serotonin can either initiate or aggravate myocardial ischaemia through a vasoconstrictor action and platelet activation. It is therefore possible that substances likely to neutralize the effects of serotonin could be used, without any danger, in humans with ischaemic heart disease. This type of action may therefore be exerted by 5-HT2 antagonists, such as naftidrofuryl. A recent double-blind clinical study has in fact shown that administration of naftidrofuryl versus placebo leads to better exercise tolerance, with an increase in the maximum level and delay in ST segment shift (increase in the threshold of onset of ischaemia). The purpose of this study was therefore to evaluate, in an animal model (pig) of acute myocardial ischaemia (occlusion of the proximal section of the left anterior descending coronary artery), the action of serotonin, naftidrofuryl and a combination of both substances on the following parameters: 1) electrophysiological (sinus heart rate, ST segment shift, T-wave amplitude, duration of monophasic action potentials, intraventricular conduction time); 2) haemodynamic (systolic, diastolic and mean blood pressure, first derivative of rate of increase of left ventricular pressure with time: LV dP/dt max); and 3) biochemical (malonedialdehyde concentration as an index, cell peroxidation index, creatine phosphate and adenosine triphosphate). It was found that co-infusion of serotonin aggravated the myocardial ischemia and that naftidrofuryl exerted beneficial effects on the serotonin-mediated aggravation of myocardial ischaemia.

Asunto(s)

RESUMEN

It is known that class I antiarrhythmic drugs lose their antifibrillatory activity with severe ischaemia, whereas class IV antiarrhythmic drugs acquire such activity. Tachycardia, which is also a depolarizing factor, has recently been shown to give rise to an alteration of ion transmembrane exchanges which is particularly marked in the case of calcium. This leads one to wonder if the change in antifibrillatory activity of antiarrhythmic drugs caused by ischaemia depends on the same process. The change in antifibrillatory activity was studied in normal conditions ranging to those of severe ischaemia with a class I antiarrhythmic drug, flecainide (1.00 mg x kg(-1) plus 0.04 mg x kg(-1)x min(-1), a sodium channel blocker, and a class IV antiarrhythmic drug, verapamil (50 microg x kg(-1) plus 2 microg x kg(-1) x min(-1)), a calcium channel blocker. The experiments were performed in anaesthetized, open-chest pigs. The resulting blockade of each of these channels was assessed at the end of ischaemic periods of increasing duration (30, 60, 120, 180, 300, and 420 s) by determining the ventricular fibrillation threshold (VFT). VFT was determined by means of trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode introduced into the myocardium (heart rate 180 beats per min). Ischaemia was induced by completely occluding the left anterior descending coronary artery. The monophasic action potential was recorded concurrently for the measurement of ventricular conduction time (VCT). The monophasic action potential duration (MAPD) varied with membrane polarization of the fibres. The blockade of sodium channels by flecainide, which normally raises VFT (7.0 +/- 0.4 to 13.8 +/- 0.8 mA, p < 0.001) and lengthens VCT (28 +/- 3 to 44 +/- 5 ms, p < 0.001), lost its effects in the course of ischaemia. This resulted in decreased counteraction of the ischaemia-induced fall of VFT and decreased aggravation of the ischaemia-induced lengthening of VCT. The blockade of calcium channels, which normally does not alter VFT (between 7.2 +/- 0.6 and 8.4 +/- 0.7 mA, n.s.) or VCT (between 30 +/- 2 and 34 +/- 3 ms, n.s.), slowed the ischaemia-induced fall of VFT. VFT required more time to reach 0 mA, thus delaying the onset of fibrillation. Membrane depolarization itself was opposed as the shortening of MAPD and the lengthening of VCT were also delayed. Consequently there is a progressive decrease in the role played by sodium channels during ischaemia in the rhythmic systolic depolarization of the ventricular fibres. This reduces or suppresses the ability of sodium channel blockers to act on excitability or conduction, and increases the role of calcium channel blockers in attenuating ischaemia-induced disorders.

Asunto(s)

RESUMEN

The effects of three antiarrhythmic drugs were investigated in anesthetized, open-chest pigs, in a left ventricular area, under pacing at a constant high rate (180 beats/min), in the absence and presence of ischemia. Ischemia was produced by transient complete occlusion of the left anterior descending coronary artery near its origin. In addition to the surface electrocardiogram, conduction time and monophasic action potential were recorded in the contractile fibers. In the absence of ischemia, intravenous flecainide and propafenone 2.5 mg/kg, and intravenous cibenzoline 2.0 mg/kg considerably lengthened conduction time (by 50-90%) but had no significant effect on the monophasic action potential duration. Consequently, the cited antiarrhythmic drugs enhance the prolongation of conduction time by 60% but do not limit the 30% shortening of the monophasic action potential caused by ischemia. Contrary to what was expected, they largely reduced the time to onset of the fibrillation due to ischemia from about 120 to 25 seconds. Thus, they manifested profibrillatory properties (more pronounced than those of other antiarrhythmic drugs of class I), which might be explained by their potent action on depolarization.

Asunto(s)

RESUMEN

Class Ic antiarrhythmic drugs, which are known to slow down conduction in the ventricular muscle, are likely to impair synchrony in activity of the ventricular fibres. Asynchronous activation was first investigated between an ischaemic and a normal area by the simultaneous recording in anaesthetized, open-chest pigs of two left ventricular monophasic action potentials (MAPs) under ventricular pacing at a high rate of 180 beats.min-1. Asynchronous activation was then investigated in the intact myocardium according to the distance separating the recording from the pacing electrode. Furthermore, mechanical effects of left ventricular systole were observed by recording dP/dt(max) and mean arterial blood pressure during the pacing periods. Ischaemia was produced by transient complete occlusion of the left anterior descending coronary artery near its origin; as a result, activation time reached 85 ms in the ischaemic area under flecainide administered iv in a 2.5 mg.kg-1 dose instead of approximately 60 ms in the normal area for fibres equi-distant from the pacing electrode. Similar delays in activation were observed in the intact myocardium, depending on whether the explored region was close to or far from the pacing electrode. In the latter case, the difference in activation time may become markedly greater if the distance or the dose of flecainide are increased. This difference, which possibly exceeds one-third of the MAP duration (practically unchanged by flecainide), may account for the occurrence of fibrillation or the sudden loss of systole mechanical efficacy.

Asunto(s)

RESUMEN

The effects of the calcium channel modulators, Bay k 8644, infused i.v. at a rate of 2.5 micrograms/kg/min, and diltiazem, injected i.v. in a dose of 0.5 mg/kg, on the susceptibility to fibrillation induced by ischaemia, were investigated in anaesthetized, open-chest pigs. Ischaemia was produced, under ventricular pacing at constant high rate (180 beats/min), by transient complete occlusion of the left anterior descending coronary artery, near its origin. It was maintained till the triggering of fibrillation. The propensity to fibrillation was judged from the time elapsing between the onset of occlusion and the onset of fibrillation (time to fibrillation). In addition to the surface electrocardiogram, conduction time and monophasic action potential were recorded in the ventricular contractile fibres, as were dP/dtmax in the left ventricle and blood pressure in the carotid artery. At the end of a 10 min infusion, Bay k 8644 lowered to a large extent (about 40%) the time to fibrillation, which returned to its control values within the following 20 min. Conversely, diltiazem increased the time to fibrillation by a factor 4 or 5 at 5 min after its administration. This time to fibrillation remained substantially increased 25 min later. These changes were not associated with alterations in conduction time or monophasic action potential duration in the absence of ischaemia, but with significant alterations in myocardial contractility and blood pressure: in the direction of an increase with Bay k 8644 and of a decrease with diltiazem. These results are in agreement with the enhancement by Bay k 8644 and the prevention by diltiazem of cell calcium overload which is at present recognized as being the essential determinant of the fibrillatory process.

Asunto(s)

RESUMEN

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.

Asunto(s)

Asunto(s)