L. Szekeres

Effect of adenosine on sinoatrial and ventricular automaticity of the guinea pig

SummaryIn isolated spontaneously beating right ventricular strips and right atrial preparations of guinea pigs adenosine was found to exert a concentration-dependent suppressing effect on the pacemaker activity. Responsiveness to adenosine was approximately 30-fold higher in ventricular than in atrial preparations. A decrease in the rate of slow diastolic (phase 4) depolarization of Purkinje and sinoatrial nodal fibers proved to be a major determinant of the adenosine-induced alteration in pacemaker activity. It is suggested that adenosine might exert its depressant effect on ventricular automaticity via direct excitation of purine receptors located in the specialized pacemaker fibres of the ventricular tissue.

Naloxone inhibits early arrhythmias resulting from acute coronary ligation

The intravenous administration of naloxone 15 min before acute coronary artery ligation in both anaesthetized and conscious male rats markedly reduced the incidence and severity of the ventricular arrhythmias that occur within 30 min of the onset of myocardial ischaemia. The incidence of ventricular fibrillation was especially reduced and, in conscious rats, the survival 16 h after ligation was increased from 27% (in the controls) to 58 and 73% after 2 and 4 mg/kg naloxone respectively. One possible explanation of these results implies a detrimental effect of released endorphin in the early stages of myocardial ischaemia.

Delayed protection of the heart against ischaemia

Ischaemic preconditioning is the protective adaptive mechanism produced by short periods of ischaemic stress that results in a marked resistance of the myocardium to prolonged periods of the same stress; however, this protection is transient. There is now evidence that protection resulting from preconditioning returns several hours later, and here James Parratt and Laszlo Szekeres highlight the possible importance of this concept, which may lead to novel approaches to the long-term protection of the heart against ischaemic injury.

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

Summary: 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 l0−6x14.7 x 10−6 and 29.5 x 10−6mol/L lidocaine. reperfusion-induced ventricular fibrillation and tachycardia were reduced from their control incidence of 83% and 100% to 41% and 58%. 33% (p < 0.05) and 25% (p < 0.001). 8% (p < 0.01) and 8% (p < 0.001). 0% (p < 0.001) and 0% (p < 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 I 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. Lidocaine (14.7 x 10 6 mol/L) significantly reduced the sudden increase of potassium in the first few minutes of reperfusion as well as its decline in the further course of reperfusion. Ischemia induced a moderate accumulation of tissue calcium only followed by a steep increase in calcium from the seventh minute of reperfusion. These changes were not influenced by lidocaine. The results obtained describe time-dependent changes of myocardial ion contents in the course of ischemia and reperfusion. and indicate that the protective effect of lidocaine against ischemia-, and reperfusion-induced arrhythmias may be due to the effect of this drug preventing ion movements induced by the above pathologic changes.

Actinomycin D suppresses the protective effect of dexamethasone in rats affected by global cerebral ischemia.

Simultaneous occlusion of both common carotid arteries in female Sprague-Dawley CFY rats produced characteristic symptoms of global cerebral ischemia, such as staggering, circling, convulsions, followed by coma and death. A close correlation existed among these symptoms and the elevation of water and Na+ content, appearing at the stage of staggering; Evans blue extravasation and diminution of K+ content, detected at circling; and the increase in Ca2+ content in the total brain tissue, manifesting itself at the phase of convulsions, indicating the development of cerebral edema due to ischemia. Dexamethasone given subcutaneously in a single 2.0 mg kg-1 dose 5 hours prior to the induction of global cerebral ischemia reduced considerably the morbidity and mortality, the alterations in water and electrolyte content, and albumin leakage in the brain tissue. Actinomycin D, in a dose of 0.5 mg kg-1 injected intravenously 1 hour before steroid treatment, abolished the beneficial effect. This finding suggests that de novo protein synthesis is involved in the cerebroprotective effect of dexamethasone.

Antiarrhythmic actions of meptazinol, a partial agonist at opiate receptors, in acute myocardial ischaemia.

1 The intravenous administration, to anaesthetized rats, of meptazinol (1 and 2 mg kg−1), a partial agonist at opiate receptors, greatly reduced the incidence of ventricular extrasystoles that resulted from acute coronary artery occlusion. The incidence of ventricular fibrillation (VF) was reduced from 50% (in the controls) to 10% and the mortality from 30% to zero. 2 In similar doses, pretreatment with meptazinol also reduced ventricular arrhythmias, including fibrillation, in conscious rats subjected to coronary artery occlusion. In this model, survival at 16 h was increased from 27% in the controls to 50% and 83% respectively in rats pre treated with 1 and 2 mg kg−1 of the drug. 3 In antiarrhythmic doses, meptazinol had little effect on either heart rate or systemic arterial blood pressure. 4 Intracellular action potential recordings from papillary muscle removed from rats given meptazinol (2 mg kg−1) 15 min previously showed an increase in APD50 and APD90 of more than 40%. There was no effect on dV/dtmax. When superfused with meptazinol in vitro normal rat papillary muscle stimulated at 1 or 3 Hz showed an increase in APD90 and a decrease in dV/dtmax. 5 The antiarrhythmic effect of meptazinol in these models can probably be explained by direct actions on the cardiac muscle action potential (increase in APD) although effects on opiate receptors cannot be ruled out. It is suggested that meptazinol might be useful in relieving pain, and in reducing the severity of arrhythmias in the early stages of acute myocardial infarction.

Effect of BN 52021, a specific PAF-acether antagonist, on cardiac anaphylaxis in Langendorff hearts isolated from passively sensitized guinea-pigs

Hartley guinea-pigs were sensitized passively with antiovalbumin rabbit serum. Their isolated perfused hearts responded to the specific antigen with a marked decrease in contractile force, increase in perfusion pressure, and rhythm disturbances. All these impairments except tachycardia were decreased by BN 52021, a specific PAF-acether receptor antagonist, applied in a constant infusion before ovalbumin challenge. These findings suggest that PAF-acether plays a major role as mediator in cardiac anaphylaxis, and BN 52021 may be a valuable therapeutic agent in allergic conditions.

The arrhythmogenic action of sympathomimetic amines

Abstract Intravenous infusions of different sympathomimetic amines were given to cats under chloraloseurethane anaesthesia. It was found that the action of catecholamines (adrenaline, noradrenaline, isoproterenol) in producing arrhythmia appeared in two distinctly separate forms: 1. A mainly primary (in some cases early and transitory) increase in susceptibility to external stimuli, as indicated by the considerable fall of the electrical fibrillation threshold. 2. A secondary (in some cases late) ventricular arrhythmia. The two forms differ in their underlying mechanism and in their response to therapeutic measures. The first form is mainly due to a stimulation of the adrenergic beta receptors as shown by the fact that the lowering of the fibrillation threshold could be produced only by catecholamines which stimulate beta receptors such as isoproterenol, adrenaline and noradrenaline. The two latter drugs also stimulate the alpha receptors and they produced a biphasic action, i.e., an early transient decrease followed by a lasting increase in the fibrillation threshold. The primary decrease in the fibrillation threshold could be prevented by specific blockade of the adrenergic beta receptors with 1-INPEA, medium doses of MJ 1999 or small doses of propranolol, thus practically excluding the possibility of a nonspecific, ‘quinidine-like’ anti-arrhythmic action. The alpha receptor blocking agents phenoxybenzamine and hydergine were without effect. The secondary arrhythmia is mainly due to over-loading of the heart caused by increased blood pressure, as it appeared only after catecholamines possessing hypertensive effect and could be prevented by inhibiting the rise in blood pressure, e.g., by blockade of the adrenergic alpha receptors. Specific blockade of the beta receptors did not diminish, but sometimes increased the incidence of secondary arrhythmias, as it enhanced the rise in blood pressure caused by the catecholamines. Phenylephrine, methoxamine and synephrine, which act chiefly on the adrenergic alpha receptors, elevated auricular and ventricular fibrillation thresholds, thus showing primarily an anti-arrhythmic tendency. However, after repeated administration of phenylephrine (large doses of single intravenous injections to the anaesthetized dog) arrhythmias of a secondary type could also be seen.

Effect of non-steroid anti-inflammatory drugs in experimental myocardial infarction in rats

Four non-steroid anti-inflammatory drugs, sulfinpyrazone, acetylsalicylic acid, sodium salicylate and indomethacin were tested in the acute phase of experimental myocardial infarction in conscious rats. A single oral dose was administered, then 1 h later the occlusion of the left anterior descending coronary artery was made by using a previously implanted silk loop. It was found that each drug markedly increased the survival rate, reduced the occurrence of ventricular fibrillation and tachycardia, and delayed the appearance and shortened the duration of arrhythmias.

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.