The mechanism of the proarrhythmic action of the Na+ and Ca++ channel blocking agent lidoflazine (Clinium) in animal experiments was analysed. Lidoflazine pretreatment was found to increase the electrically induced atrial fibrillatory threshold in the intact cat, but to decrease this parameter in the ventricular heart muscle. The changes induced by lidoflazine in the ventricular repolarization of the normoxic dog heart (T wave flattening, appearance of prominent U waves, T-U fusion, QT/QTU prolongation) are considered to be proarrhythmic ECG signs.

Animals↗

PubMed1989

Cyclosporin for dystrophic epidermolysis bullosa.

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Aged↗

PubMed1989

[Epidural administration of a morphine-adrenaline-bupivacaine mixture in obstetric anesthesia].

Pain relieving effect of epidurally given epinephrine-morphine-bupivacaine drug combination was studied in 50 primiparous women during labour. The double-blind, randomised clinical evaluation showed that the components of our drug combination act synergistically. The total dose and the mg min-1 dose of bupivacaine was significantly less following epinephrine-morphine pretreatment than the dose required when only bupivacaine was used for pain relief. The duration of analgesic effect of separate top-up doses was also significantly prolonged when the drug combination was used. It was established that this method of obstetric pain relief uses about 30% less bupivacaine than the classical method. This means decreased drug exposure of mother and fetus alike. In addition to this the use of this drug combination provides also a long-lasting postpartum analgesia.

Anesthesia, Obstetrical↗

PubMed1989

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.

Action Potentials↗

PubMed1989

Possible involvement of platelet activating factor in anaphylaxis of passively sensitised, isolated guinea pig hearts.

There is evidence that cardiac tissue may be a target for antigen/antibody reactions. Platelet activating factor (PAF) is released during anaphylaxis and could mediate cardiac damage. To investigate this, guinea pigs were passively sensitised by anti-ovalbumin rabbit serum (6 mg.kg-1 intravenously) and 24 h later their hearts were excised and isolated according to a working heart preparation technique. After a 20 min equilibration period, anaphylactic challenge was induced by a bolus injection of ovalbumin (2 mg in 0.2 ml buffer) via the side arm of the aortic cannula. Heart rate, coronary flow, aortic flow, left ventricular developed pressure (LVDP), its first derivative (LVdp/dtmax) and left ventricular end diastolic pressure (LVEDP) were recorded. After ovalbumin challenge, heart rate and LVEDP were markedly increased, while coronary flow, aortic flow, LVDP, and LVdp/dtmax were profoundly decreased. All these alterations were over within 5 min, and the measured variables returned to approximately the pre-challenge values. BN 52021, a specific PAF receptor antagonist, was dissolved in the perfusion buffer and given in doses of 15, 30 and 60 mumol.litre-1 10 min prior to the induction of anaphylactic challenge until the end of the observation period. BN 52021 inhibited the increase in heart rate and LVEDP and the decrease in coronary and aortic flow, LVDP and LVdp/dtmax in a dose dependent manner. The changes produced by 30 and 60 mumol.litre-1 were statistically significant at the levels of p less than 0.01 and p less than 0.001 when compared to the control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylaxis↗

PubMed1989

On the 7-oxo-PGI2 induced late appearing long-lasting cytoprotective effect.

Our results indicate that 7-oxo-PgI2 pretreatment may induce a long lasting cytoprotective effect by preventing ischemia induced intracellular potassium loss and sodium accumulation in myocardial cells of guinea pigs furthermore by protecting from ischemic ultrastructural changes as sarcomere shortening, mitochondrial swelling and irregularity of I, A and Z bands in the rabbit myocardium.

Animals↗

PubMed1989

Effects of the lipolysis inhibiting agent beta-pyridylcarbinol (Ronicol) in acute myocardial ischaemia.

The antilipolytic, nicotinic acid analogue beta-pyridylcarbinol (Ronicol) has previously been reported to decrease the free fatty acid (FFA) concentration of the arteria-blood, and to moderate the FFA-uptake and O2-consumption of the myocardium; on this basis, the drug may be expected to exert a cardioprotective action. The cardiac effects of Ronicol were therefore studied on a self-control, 'single-vessel' coronary artery ligature dog model. The left anterior descending coronary artery (LAD) was prepared in the in situ heart of anaesthetized, thoracotomized animals. Following the control ligation, a stabilization period and Ronicol infusion (1 mg/kg iv. during 10 minutes), the LAD was repeatedly ligated. The duration of the individual occlusions was 10 minutes. Ronicol significantly decreased the arterial FFA concentration and the epicardial ST segment elevation; its antilipolytic and anti-ischaemic effects were protracted and were still observed 120 minutes after pretreatment. The drug did not decrease the inhomogeneity of ventricular depolarization in the ischaemic myocardium and in the dose applied it had no influence on the heart rate, arterial blood pressure, left ventricular end-diastolic pressure and left ventricular contractility (LV dP/dtmax). In the canine myocardial infarction model employed it was observed that the duration of the anti-ischaemic effect of Ronicol (1 mg/kg iv.) is about 120 minutes. It has the advantage that it does not possess the unwanted cardiovascular side-effects displayed by nicotinic acid observed by us too in this model earlier (Cardiol. Hung. 13, 33-41, 1984).

Animals↗

PubMed1988

Pacing and reperfusion induced arrhythmias: protection by slow heart rate in the rat heart.

Using the isolated perfused rat heart with transient (10 min) regional ischaemia induced by coronary artery ligation, we have shown that slow heart rate can dramatically reduce the vulnerability of the myocardium to reperfusion induced ventricular fibrillation and ventricular tachycardia. In the heart rate range of 200-400 beats.min-1, slower heart rates exerted a frequency dependent protective effect against reperfusion induced arrhythmias. At the optimal rate of 200 beats.min-1, the incidence of total ventricular fibrillation (irreversible plus reversible) and ventricular tachycardia fell to 33% and 50% of their control values (100%). The anti-arrhythmic effect was achieved with only a minor (less than 20%) effect on coronary flow. To ascertain whether or not slow heart rate achieved an absolute reduction in vulnerability to arrhythmias irrespective of the duration of ischaemia, hearts were also subjected to 5, 10, 20, 30 or 40 min of ischaemia followed by 30 min of reperfusion with and without pacing at 200 beats.min-1. A bellshaped time-response profile was obtained in both groups. In unpaced controls (n = 12) this gave a maximal vulnerability to arrhythmias after 10 min of ischaemia. In the paced hearts (n = 12) the curve was shifted to the right, with a peak vulnerability at 20 min. These results show that the action of pacing is to exert a delaying effect which extends the duration of ischaemia that can be tolerated before the heart becomes vulnerable to reperfusion induced arrhythmias. Heart rate can have a substantial effect on reperfusion induced arrhythmias and should be considered when making therapeutic interventions and risk assessments in this setting.

Animals↗

PubMed1988

Electrophysiological effects of GYKI-23 107, a new antiarrhythmic compound, in isolated rabbit and canine cardiac preparations.

The cellular cardiac electrophysiological effects of GYKI-23 107 (1-/2,6-dimethylamino/-2-dimethylaminopropane dihydrochloride), a new investigational antiarrhythmic drug, were studied in rabbit and canine ventricular muscle and Purkinje fibers. For comparison, mexiletine was used. GYKI-23 107, like mexiletine, did not affect the resting membrane potential and slightly reduced the action potential amplitude in both fiber types. The time for repolarization was shortened, but the ratio of effective refractory period to action potential duration was increased by both drugs. The maximum rate of depolarization (Vmax) was depressed by the drugs in a frequency-dependent ("use-dependent") manner. GYKI-23 107 slowed the recovery kinetics of Vmax in the canine ventricular muscle (Tc = 229.9 +/- 5.6 ms; n = 7) and Purkinje fiber (Tc = 149.6 +/- 33.8 ms; n = 7) in the same way as mexiletine. The kinetics of restitution of action potential duration during premature and postmature stimulation were slowed to similar degrees in the presence of both GYKI-23 107 and mexiletine in canine Purkinje fibers. It is concluded that, on the basis of its cardiac cellular electrophysiological effects, GYKI-23 107 can be categorized as a class Ib antiarrhythmic agent.

Animals↗

PubMed1988

Protective effect of lidocaine against ischemia and reperfusion-induced arrhythmias and shifts of myocardial sodium, potassium, and calcium content.

Isolated guinea pig hearts subjected to global ischemia, were used to investigate whether lidocaine exerts an antiarrhythmic action against reperfusion-induced arrhythmias, and the effects of this drug upon myocardial ion contents during ischemia and reperfusion were studied. In the first series of experiments, the drug was administered 5 min prior to the induction of global ischemia and maintained during reperfusion. With 3.6 X 10(-6), 7.2 X 10(-6), 14.7 X 10(-6), and 29.5 X 10(-6) mol/L lidocaine, reperfusion-induced ventricular fibrillation and tachycardia were reduced from their control incidence of 83% and 100% to 41% and 58%, 33% (p less than 0.05) and 25% (p less than 0.001), 8% (p less than 0.01) and 8% (p less than 0.001), 0% (p less than 0.001) and 0% (p less than 0.001), respectively. The ion contents of myocardium were determined by atomic absorption spectrophotometer after washout of the ions from vasculature. Ischemia induced a marked accumulation of sodium and loss of potassium in the myocardial tissue. Both ischemia-induced sodium gain and potassium loss were significantly inhibited by lidocaine treatment. During reperfusion, sodium was further increased in the control group and this value was significantly lower in the lidocaine-treated group after 1 min of reperfusion. Sodium content remained at nearly constant level for the rest of reperfusion period. Potassium was suddenly increased during the first 5 min of reperfusion then continuously decreased until the end of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

On the 7-oxo-PgI2 induced lasting protection against ouabain arrhythmias in anesthetized guinea pigs.

In our earlier experiments prolonged administration of the stable PgI2 analogue: 7-oxo-PgI2 ephedrine salt to dogs afforded a long-lasting protection against coronary occlusion induced ischemia as well as against postocclusion and reperfusion arrhythmias. In the present experiments we wanted to clear, whether this prolonged protective action is present in other types of arrhythmia, which are not due to ischemia. The ouabain-arrhythmia seemed to be suitable for elucidation of this question. Therefore guinea pigs were pretreated with 50 micrograms/kg i.p. 7-oxo-PgI2 and 24, 48, 72 and 96 hrs after treatment anesthetized with 35 mg/kg sodium pentobarbitone. To prevent ouabain bradycardia, 0.4 mg/kg atropine was administered i.p. Ouabain was applied by intermittent infusion technique i.e. an initial infusion for 5 minutes of a total dose of 60 micrograms/kg into the right jugular vein was followed after a 25 minutes interval by infusions of 30 micrograms/kg for 2.5 minutes every 10 minutes until cardiac arrest. The ouabain induced rhythm disturbances appeared in the following order: Anomalies in T wave morphology, ventricular or nodal extrasystoles, atrio-ventricular and intraventricular conduction disturbances, ventricular tachycardia, ventricular fibrillation and finally cardiac arrest. If 50 micrograms/kg i.p. 7-oxo-PgI2 was given to ouabain-intoxicated animals at the appearance of the first extrasystole a transient aggravation of this arrhythmia developed. In 7-oxo-PgI2 pretreated animals the total amount of ouabain necessary to induced rhythm disturbances was markedly elevated, the appearance of the various arrhythmias significantly delayed. Maximal protective effects were seen 48 hrs after the administration of 50 micrograms/kg 7-oxo-PgI2.

Animals↗

PubMed1988

7-oxo-PGI2 induced late appearing and long lasting antiischaemic and antiarrhythmic action in dogs.

In our earlier experiments administration of the stable PGI2 analogue: 7-oxo-PGI2-ephedrine salt to dogs resulted in a late-appearing and long-lasting protection from coronary ligation induced ischaemia as well as from postocclusion and reperfusion arrhythmias. Objective of the present study was to evaluate the extent and duration of antiischaemic and antiarrhythmic action induced by a single dose 50 ug/kg i.m. 7-oxo-PGI2 in dogs subjected to myocardial ischaemia evoked by left anterior descending coronary artery (LAD) ligation at different intervals (2, 6, 24, 48, 72 hours and 2 weeks) after treatment. After anaesthesia and thoracotomy the electrophysiological parameters - sinus cycle length (SCL), corrected sinus node recovery time (CSNRT), atrial and ventricular functional refractory period (AFRP, VFRP), and atrio-ventricular effective refractory period (A-V ERP) - were determined by means of computer controlled programmed electrical stimulation. Then the animals were subjected to LAD occlusion for 25 minutes and subsequent reperfusion. 7-oxo-PGI2 pretreatment considerably protected against myocardial ischaemia i.e. there was significant reduction in ST-segment elevation, the number of extrasystoles (ES) and the incidence of ventricular fibrillation (VF). The antiischaemic action started 2 or 6 hours after the drug administration, however, the maximal protection - indicated by the diminution of ischaemic epicardial ST-segment elevation - as well as the most striking reduction in postocclusion and reperfusion arrhythmias could be observed 48 hours after the single dose of 7-oxo-PGI2 and in case of two weeks treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

On the nature and molecular basis of prostacyclin induced late cardiac changes.

The late appearing and long-lasting cardiac effects induced by PgI2 or its stable analogue 7-oxo-PgI2 described by us first in 1983 include: 1.) antiischemic, 2.) antiarrhythmic, 3.) selective electrophysiological and 4.) cardiac cytoprotective changes. Evidence for 1.: Protection from myocardial ischemia due to coronary occlusion in dogs furthermore a significant diminution of ischemic loss of the myocardial ATP and CP content and of the myocardial lactate accumulation in excised rat heart exposed to global ischemia. 2: Protection from postocclusion and reperfusion arrhythmias in dogs. 3: A selective prolongation of the ventricular refractory period (VERP) as well as of the action potential duration (APD90) in the isolated rabbit papillary muscle furthermore prolongation of QT distance and VERP in the rabbit and the guinea pig heart "in situ". 4.: The cardiac cytoprotective effect, i.e. ischemic loss of intracellular K+ and ischemic gain of intracellular Na+ in isolated hearts of 7-oxo-PgI2 treated guinea pigs subjected to 25 min global ischemia was significantly moderated. These protective actions proved to be dose and time dependent - maximal effects appeared 48 hrs after administration of a single dose of 50 micrograms/kg i.m. 7-oxo-PgI2. These effects are certainly not due to 7-oxo-PgI2 itself but this latter seems to be indispensable for induction of a long acting principle, which can probably be extracted from hearts of pretreated animals and this substance of lipoid character exerts electrophysiological effects similar to those observed after 7-oxo-PgI2 pretreatment. Pretreatment may also reduce isoproterenol induced heart rate increase and prolong bleeding time in conscious rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1988

Effect of chloroquine in experimental myocardial ischaemia.

The cardiac effects of the phospholipase A2 inhibiting agent chloroquine were studied in dogs, rats and cats. During left anterior descending coronary artery occlusion produced in anaesthetized mongrel dog, chloroquine pretreatment considerably reduced the epicardial ST-segment elevation in the ischaemic area, as well as the number of premature ventricular contractions. In conscious male Sprague-Dawley CFY rats it diminished the duration and prolonged the latency of appearance of the early post-infarction arrhythmias and increased the survival rate following coronary artery ligation. Chloroquine failed to affect the ventricular fibrillation threshold in the normoxic cat heart. The cardioprotective action of chloroquine could be explained at least partly by its antiphospholipase activity.

Animals↗