Éva Udvary

Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction.

1 The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium‐sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham‐operated dogs with essentially normal cardiac function. 2 Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean−1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing‐induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham‐operated dogs (group 2) served as controls. 3 In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing. Thus, there was a marked reduction in LVSP (15%), + dP/dtmax (35%), ‐dP/dtmax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 ± 1.4 to 20.0 ± 2.2 mmHg). A marked elevation occurred in endocardial ST‐segment (138%), lasting for 20 min. 4 Levosimendan was administered intravenously in doses of 0.005, 0.01 and 0.03 μmol kg−1 to 2 groups of conscious dogs. In the sham‐operated dogs (group 2), only the higher dose (0.03 μmol kg−1) produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 μmol kg−1 levosimendan resulted in an improvement in + dP/dtmax (26%, 38% and 49%), ‐dP/dtmax (20%, 25% and 38%) and in dP/dt/P (19%, 34% and 50%) and reduction in the elevated LVEDP (from 20 ± 2.2 mmHg to 16 ±1.0, 10 ± 1.3 and 9± 1.0 mmHg, respectively). 5 Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.

7-oxo-PgI2 induced late appearing and long-lasting electrophysiological changes in the heart in situ of the rabbit, guinea-pig, dog and cat.

We have previously observed a long-lasting antiischemic and antiarrhythmic effect induced by prostacyclin (PgI2) or its stable analogue, 7-oxo-PgI2-ephedrine salt in dogs subject to local myocardial ischemia. This protection appeared when the vasodilating and platelet aggregation inhibiting effect of PgI2 or its analogue was over and persisted even 72 h after treatment. We have also found that short incubation with 7-oxo-PgI2 may induce a long-lasting prolongation of the action potential duration and of the effective refractory period in the isolated rabbit papillary muscle preparation without affecting the membrane potential or the rate of rise of the action potential. Our present experiments have shown a 7-oxo-PgI2 induced, dose-dependent prolongation of the ventricular functional refractory period in conscious rabbits and anesthetized dogs, as well as an increase of the QT interval in the ECG in both species and also in conscious guinea-pigs. In all three species 50 micrograms/kg i.m. dose proved to be optimal, evoking maximal effect 48 h after treatment. In conscious rabbits this pre-treatment prevented the train of non-stimulated extra beats induced by premature stimuli. Furthermore it also prevented widening of the QRS complex appearing in non-treated controls after programmed stimulation. Pre-treatment significantly increased electrical fibrillo-flutter thresholds in the auricles and ventricles of anesthetized cats. These electrophysiological changes seem to be closely related to the 7-oxo-PgI2 induced, late appearing and long-lasting protection from ischemic and reperfusion arrhythmias.

Effect of the blood supply to the normal noninfarcted myocardium on the incidence and severity of early postocclusion arrhythmias in dogs

SummaryThis work was initiated by the discrepancy existing between the traditional experimental infarction model with occlusion of one single major coronary artery in the otherwise healthy myocardium and the clinical situation in which two or more major coronary arteries are stenosed at the same time. A model mimicking this latter clinical situation was elaborated as follows:In anaesthetized, open-chest dogs the haemodynamic, electrophysiological and blood flow changes due to 5 min occlusion of the left anterior descending coronary artery (LAD) were studied in the absence and presence of a critical constriction of the left circumflex coronary artery (LCX). Control LAD occlusion resulted in enhanced ST-segment elevation and inhomogeneity of electrical activation, depressed left ventricular contractility (LVdP/dt) and local myocardial contractility, as well as in a decline of myocardial blood flow (MBF) in the ischaemic area supplied by LAD. These changes were accompanied by no or slight extrasystolic activity.In the presence of critical stenosis of LCX, occlusion of the LAD aggravated myocardial ischaemia, i.e. ST-segment elevation and diminution of MBF were more marked, mainly in the subepicardium of the ischaemic area. The incidence and severity of arrhythmias significantly increased. Even ventricular fibrillation occurred in one third of the animals, both during LAD occlusion and after its release.Thus, acute LAD occlusion in the presence of a stenosed LCX produced a more severe myocardial ischaemia associated with more severe arrhythmias than occlusion of LAD alone. This model is more relevant to the clinical situation in which multivessel coronary artery disease is common.

Importance of myocardial blood flow changes in the protective action of diltiazem in a new model of myocardial ischaemia

1 The effect of diltiazem was studied in a new model of myocardial ischaemia in which in addition to a critical constriction of the left circumflex branch (LCX), the left anterior descending coronary artery (LAD) was suddenly occluded. This model is probably more relevant to the clinical situation in which multivessel coronary artery disease is common. 2 In this model diltiazem exerted a beneficial effect, manifested by an increase in myocardial blood flow (MBF) within the stenosed area of the LCX; by a marked reduction of the enhanced preload (LVEDP); by a diminution of the inhomogeneity of electrical activation and by a decrease in ST‐segment elevation. Diltiazem also caused a significant reduction both in the number of extrasystoles and in the incidence of ventricular fibrillation. 3 Increased MBF within the stenosed area was associated with enhanced blood flow to the ischaemic myocardium, i.e. diltiazem directed flow to the ischaemic zone by improvement of the collateral circulation. 4 The beneficial electrophysiological changes caused by diltiazem are probably at least partly due to the drug‐induced improvement of myocardial blood supply to the ischaemic area.

Comparison of two calcium antagonists, verapamil and fendiline, in an experimental model of myocardial ischaemia mimicking classical angina on effort.

1 The effects of verapamil (0.15/kg) and fendiline (3 mg/kg) were studied in anaesthetized, thoracotomised dogs with a critical constriction of the left anterior descending coronary artery, paced in excess of the initial rate by 60–70 beats/min. Epicardial ST‐segment elevation and changes in lactate uptake were used to assess the severity of myocardial ischaemia. 2 Both drugs prevented the ST‐segment elevation and the reduced lactate uptake that resulted from atrial pacing. 3 The anti‐ischaemic effect of fendiline is mainly due to its negative chronotropic action, whereas that of verapamil is due in part to bradycardia and in part to the reduced preload and afterload. In addition, both agents increase coronary flow to the ischaemic area and thus improve the myocardial oxygen supply/oxygen requirement ratio.

Sympathetic neural mechanisms in cardiac arrhythmias

In the present experiments the dominant role in the genesis of arrhythmias of stimulation of beta adrenoceptors over that of alpha adrenoceptors has been demonstrated by: (i) infusion of catecholamines in the isolated right ventricular Purkinje fiber preparation of rabbits; and (ii) by subepicardial microinfusion of these substances to anesthetized thoracotomized dogs. Activation of the latent pacemaker areas by local myocardial ischemia was shown. Catecholamine-induced arrhythmias also resulted from premature excitation of the working myocardium as a consequence of an interaction of Purkinje firing and excitation originating from higher pacemaker areas.

Haemodynamic factors influencing myocardial ischaemia in a canine model of coronary artery stenosis: the effects of nitroglycerine.

1 At a critical degree of coronary stenosis (allowing a just adequate blood supply to the poststenotic area only at the expense of maximal hypoxic coronary vasodilatation), an additional loading of the heart induced marked local myocardial ischaemia, as indicated by appropriate biochemical, electrophysiological and haemodynamic changes. 2 In this model myocardial oxygen demand was increased in three different ways: (i) increasing heart rate by atrial pacing; (ii) increasing afterload by aortic occlusion and (iii) increasing preload by blood infusion. These procedures were compared in their ability to produce local myocardial ischaemia and characterized by ST‐segment elevation recorded from the endocardium and epicardium. 3 Increasing afterload evoked the mildest degree of ischaemia since the resulting increase in coronary perfusion pressure and coronary flow almost met the augmented myocardial oxygen demand evoked by the elevated peripheral resistance and by the simultaneously increased preload. A rather more pronounced ischaemia was produced by increasing the preload. The most serious ischaemia of all was induced by atrial pacing. This reduced coronary flow and perfusion pressure and increased left ventricular end diastolic pressure (LVEDP). 4 Nitroglycerine transiently reduced blood pressure and coronary blood flow and increased epicardial and endocardial ST‐segment elevation; the changes had disappeared 10 min after terminating the infusion. However, at this time a prolonged protective action against pacing‐induced ST‐segment elevation was observed. This protection was also seen after intracoronary injections of nitroglycerine. This indicated that part of the beneficial effect of nitroglycerine in ischaemia is due to direct coronary and/or myocardial actions.

Nifedipine effects in severe myocardial ischaemia in the dog due to left anterior descending coronary occlusion with left circumflex coronary artery constriction

1 The effects of nifedipine were studied in a model of local myocardial ischaemia, comprising anaesthetized thoracotomized dogs in which a critical constriction of the left circumflex coronary artery (LCX) was combined with sudden occlusion of the left anterior descending coronary artery (LAD). Since more than one coronary artery is involved in ischaemic heart disease, the model seems to reflect the clinical situation very closely. 2 In this model, infusion of 1 μg kg−1 min−1 nifedipine increased myocardial blood flow within the stenosed area served by the LCX as well as in the myocardial region supplied by the LAD, mainly in the subepicardium. Accordingly, the drug reduced ischaemic ST‐segment elevation only in the epicardium. 3 It is suggested that nifedipine directed flow to the sub‐epicardium of the ischaemic area by improving the collateral circulation. This redistribution of flow resulted in a decrease in the endo/epicardial flow ratio. 4 Nifedipine did not change the inhomogeneity of electrical activation indicating that it has no effect on the ischaemia‐induced conduction delay. At the same time nifedipine was not able to reduce either the number of extrasystoles appearing in the early postocclusion and reperfusion phase or the incidence of ventricular fibrillation occuring mainly during reperfusion.

Antiarrhythmic Action of Calcium Antagonists

The marked coronary dilating and negative inotropic effect of prenylamine /1/ as well as that of verapamil /2/ was described in the early sixties, however Fleckenstein et al. /3/ were the first to show that these agents are capable of depressing cardiac contractility in concentrations not yet affecting the action potential. Thus they inhibit the electromechanical coupling. The authors attributed this effect to a drug induced depression of the transmembrane inward Ca2+ current hence the name: calcium antagonists /Ca-s/. Later Grun and Fleckenstein /4/ have shown electromechanical uncoupling effect of CA-s in the smooth muscle too. The steadily growing interest has initiated a number of experimental and clinical studies showing that in addition to its scientific importance introduction of this new group of drugs into clinical therapy represents a major breakthrough.

Verapamil in a new model of severe local myocardial ischaemia due to combined coronary occlusion and stenosis

The effect of verapamil was studied in a new canine model of local myocardial ischaemia. In this model in addition to the critical construction of the left circumflex coronary artery, the left anterior descending branch was suddenly occluded. Experiments were performed in the anaesthetized, thoracotomized and artificially respired dog. The model represents a severe form of myocardial ischaemia and mimics the clinical situation in which usually more than one coronary artery is involved in the stenotic process. Verapamil (0.15 mg kg -1 i.v.) moderated the extent of the ischaemic changes (indicated by the ST segment elevation in the epicardial and endocardial ECG) as well as their consequences e.g. the incidence and severity of early postocclusion and reperfusion arrhythmias. This beneficial effect was probably due to the drug-induced favourable haemodynamic action (reduction of left ventricular end-diastolic pressure and slight increase in left ventricular dP/dtmax) and to the electrophysiological effects (e.g. decreased inhomogeneity of electrical activation, diminution of extrasystolic activity) and blood flow changes (enhanced blood supply to the ischaemic subepicardium).