István Leprán

Coronary artery ligation, early arrhythmias, and determination of the ischemic area in conscious rats

A method for studying the acute phase of myocardial infarction in conscious rats has been developed. In preliminary surgery, a loose ligature of atraumatic silk was understitched around the left coronary artery. Its ends were pulled through a polyethylene tube placed within the thorax and fixed under the skin. Seven days later, coronary occlusion was performed by tightening the ligature in conscious animal. Lidocaine and pindolol pretreatment increased the survival rate and attenuated the life-threatening arrhythmias during the first 20 min, but did not influence the infarct size 16 hrs later. An ex vivo perfusion technique for determining the ischemic area has also been developed. 3, 6, and 20 min after coronary ligation, the hearts were excised and perfused with 4% formaldehyde. The ischemic area could not be perfused and remained dark red with a sharp border-line. At the 3rd and 20th min its size was as same as that of the 16-hr infarcted area; however at the 6th min it increased by 50%. Lidocaine and pindolol eliminated this transitory increase. These methods appear to be valuable for large-scale determination of drug effects on the acute phase of experimental myocardial infarction in conscious rats, and for estimating their action on the size of ischemic area very early after coronary occlusion.

Effect of a linoleic acid-rich diet on the acute phase of coronary occlusion in conscious rats: influence of indomethacin and aspirin.

Summary We studied the effect of a long-term diet rich in linoleic acid (LAR diet) on the acute phase of experimental myocardial infarction. Male Sprague-Dawley CFY rats were fed a diet containing 12% sunflower seed oil or standard laboratory chow for 3 months. Gas-chromatographic determination of the fatty acid content in total heart phospholipids showed an increase in the n-6/n-3 fatty acid ratio, resulting from an elevated arachidonic acid content of the membrane. In parallel experiments in conscious animals, the left anterior descending coronary artery was ligated by a previously implanted silk loop. Long-term LAR diet increased the survival rate from 19 to 81% and reduced the occurrence of arrhythmias during the first 20 min after coronary ligation. Oral administration of 10 mg/kg indomethacin 1 hr prior to coronary ligation abolished the protective effect of the LAR diet, while 200 mg/kg aspirin did not. The prevention by indomethacin of the beneficial effect suggests the involvement of an increased prostaglandin synthesis in the protection offered by the diet. The ineffectiveness of aspirin in this respect is discussed. These results provide evidence that a long-term LAR diet may be of therapeutic value in the management of myocardial infarction.

Preconditioning effects of levosimendan in a rabbit cardiac ischemia-reperfusion model

The preconditioning effects of levosimendan were investigated on ischemia-reperfusion induced morphological and functional cardiac damage. Langendorff-perfused rabbit hearts were reserved as controls or subjected either to global myocardial ischemic preconditioning or to perfusion with levosimendan (0.1 μmol/l) for two 5-minute cycles. After a washout period, all hearts were then subjected to 30 minutes of global ischemia and 120 minutes of drug-free reperfusion. Intraventricular pressure and coronary flow were measured, and infarct size determined after nitroblue-tetrazolium staining on completion of the experiments. Levosimendan pretreatment resulted in a significantly smaller elevation from the preischemic level in left ventricular end-diastolic pressure during reperfusion (37 ± 17 mm Hg) compared with controls (56 ± 14 mm Hg) and ischemia-preconditioned hearts (53 ± 34 mm Hg). The left ventricular developed pressure-representing the functional recovery of the heart after ischemia-that was significantly improved by levosimendan pretreatment (38 ± 6% vs 16 ± 5% in controls, P < 0.05). In addition, contractility and relaxability parameters (+dP/dt and -dP/dt, respectively) were better preserved in the levosimendan hearts. The volume of infarcted myocardium after global ischemia-reperfusion was significantly (P < 0.05) decreased by both ischemic preconditioning (38 ± 2%) or levosimendan pretreatment (45 ± 2%) versus controls (52 ± 2%). The results of this study suggest that levosimendan pretreatment is capable of decreasing infarct size in an ischemia-reperfusion model and improving recovery of cardiac function following ex vivo global ischemia.

Proarrhythmic effects of intravenous quinidine, amiodarone, D-sotalol, and almokalant in the anesthetized rabbit model of torsade de pointes.

The proarrhythmic effects of four antiarrhythmic agents were examined during &agr; 1 -adrenoceptor stimulation in chloralose-anesthetized rabbits. Each dose of almokalant (26, 88, and 260 &mgr;g/kg), d -sotalol, quinidine, or amiodarone (each 3, 10, and 30 mg/kg) was infused i.v. over 5 min and there was a 20-min interval between each infusion. d -sotalol and almokalant evoked torsade de pointes (TdP) and other arrhythmics, frequently. The incidences of TdP were 0, 50, and 40% after administering the first, second, and third doses of the nonselective I Kr inhibitor d -sotalol, respectively. Similarly, these values were 20, 40, and 33% after administering the first, second, and third doses, respectively, of the selective I Kr inhibitor almokalant. Quinidine elicited only a few arrhythmics, but not TdP. Quinidine, d -sotalol, and almokalant evoked conduction blocks in a dose-related manner (p < 0.05) and prolonged QT and QT c intervals (p < 0.05). Amiodarone neither prolonged QT and QT c nor evoked ventricular tachyarrhythmias, blocks, or other proarrhythmias. In conclusion, these results show no direct correlation between the occurrence of TdP and the infusion rate or dose of anti-arrhythmics. Furthermore, the lack of TdP with quinidine warns of false-negative results in the applied model.

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 possible mechanism of protection induced by dexamethasone against sudden death due to coronary ligation in conscious rats

Rat isolated peritoneal cells (107 cells ml−1) incubated in the presence of dexamethasone (3 × 10−9 m, for 90 min) were shown to release some factor(s), having a mol. wt. of 15 k, as determined by size exclusion chromatography, which inhibited phospholipase A2 activity and offered significant protection against sudden death due to post‐infarction arrhythmias in conscious rats pre‐treated with actinomycin D (0.5 mg kg−1 i.v. 4 h before coronary ligation). This observation suggests that the cardioprotective effect of glucocorticoids in acute myocardial infarction may result from the de novo synthesis of macrocortin, an antiphospholipase protein.

Relevance of anaesthesia for dofetilide-induced torsades de pointes in α1-adrenoceptor-stimulated rabbits

No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro‐arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α‐chloralose anaesthesia on the pro‐arrhythmic activity of the class III anti‐arrhythmic dofetilide in α1‐adrenoceptor‐stimulated rabbits.

Effect of long-term oral pretreatment with levosimendan on cardiac arrhythmias during coronary artery occlusion in conscious rats

Heart failure is frequently associated with cardiac arrhythmias. The aim of the present study was to investigate the effect of levosimendan, a new cardiotonic drug for the treatment of congestive heart failure, on experimental ischaemic arrhythmias. Acute coronary artery occlusion was produced in conscious rats 7-10 days after placement of ligature around the left main coronary artery. Acute pretreatment with levosimendan (0.2 or 0.6 mg/kg orally 1 h before coronary artery occlusion) did not influence the incidence, onset and duration of arrhythmias. Long-term pretreatment with levosimendan (0.2 or 0.6 mg/kg orally twice a day for 2 weeks) increased the survival rate (50% and 81% vs. 44% in controls) and the number of animals without any arrhythmia (37% and 31% vs. 5% in controls). The present results demonstrate that chronic oral treatment with levosimendan could be beneficial in congestive heart failure and arrhythmias resulting from regional myocardial ischaemia.

Effect of moxonidine on arrhythmias induced by coronary artery occlusion and reperfusion

The aim of the present study was to investigate the influence of moxonidine, a representative of I1-imidazoline-receptor agonist, on arrhythmias induced by myocardial ischemia or reperfusion. Acute myocardial infarction was produced by tightening a previously placed loose silk loop around the coronary artery in conscious rats. Moxonidine (0.01, 0.03, or 0.10 mg/kg i.v., 10 min before coronary ligation) significantly decreased the incidence of ventricular tachycardia during the first 15 min of infarction (70 versus 100% in controls), and the number of animals that survived without developing any arrhythmia was increased (15, 20, and 25%, respectively, versus 0%). Reperfusion-induced arrhythmias were produced by releasing a snare after 6 min of myocardial ischemia in anesthetized, artificially ventilated rats. Reperfusion rapidly induced severe dysrhythmias in all of the control animals. Moxonidine pretreatment (0.03 and 0.10 mg/kg) decreased the incidence of ventricular fibrillation (25 and 30% versus 64%) and increased the number of animals that survived without developing any arrhythmia (20 and 25% versus 0%). We conclude that moxonidine offers significant protection against the development of arrhythmias induced by acute regional myocardial ischemia in conscious rats. Moxonidine pretreatment also provides a beneficial effect during reperfusion-induced arrhythmias that appear after a brief period of myocardial ischemia.