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It has been proposed that the cardioprotective effects of myocardial ischaemic preconditioning may involve the release of mast cell mediators. The aim of the study was to determine whether mast cells are involved in the antiarrhythmic effect of ischaemic preconditioning in rat hearts. Preconditioning was achieved, both in anaesthetised rats and in rat isolated hearts, by a 3-min temporary occlusion of the left main coronary artery followed by 10 min of reperfusion before a 30-min permanent occlusion. Preconditioning had a marked antiarrhythmic effect, reducing the number of ventricular ectopic beats from 1,176 +/- 69 to 490 +/- 139 and the incidence of ventricular fibrillation from 40% to 0. Administration of the mast cell-stabilising drugs lodoxamide tromethamine and sodium cromoglycate (20 mg/kg/h i.v. 30 min before and throughout experimental protocol) did not modify the antiarrhythmic effect of preconditioning. Sodium cromoglycate, but not lodoxamide tromethamine, itself significantly reduced the number of ectopic beats that occurred over a 30-min period of ischaemia (from 760 +/- 181 to 153 +/- 33 in nonpreconditioned animals). Both drugs abolished the decrease in arterial blood pressure that occurred on coronary artery occlusion. The decrease in arterial blood pressure produced by the mast cell-degranulating compound 48/80 (50 microg/kg; i.v.) was attenuated to a similar degree by both drugs (decreases in pressure of 53 +/- 7, 31 +/- 1, and 25 +/- 3 mm Hg in control, sodium cromoglycate-treated, and lodoxamide tromethamine-treated animals, respectively). In rat isolated hearts, degranulation of mast cells with three consecutive doses of 50 microg of compound 48/80 had no antiarrhythmic effects and did not modify the antiarrhythmic effect of preconditioning. It is concluded that cardiac mast cells do not play a major role in the protection offered by ischaemic preconditioning on arrhythmogenesis in rat hearts.

We assessed the changes in the contractile response of rat hearts in vivo after chronic exposure to a range of doses of norepinephrine (NE) and determined whether free radical production played a role in these changes. Osmotic minipumps were implanted subcutaneously (s.c.) in male rats and delivered either NE (0.15-0.35 mg/kg/h) or acid saline for 10-28 days. The animals were then anaesthetised and prepared for haemodynamic measurement, and dose-response curves to acutely administered NE and calcium chloride were constructed. We analysed plasma for evidence of free radical activity by measuring the levels of thiobarbituric acid-reactive substances (TBARS). All doses of NE studied produced left, but not right, ventricular hypertrophy. Treatment with 0.25 mg/kg/h NE for 28 days produced signs of distress and, by 10 days, treatment with 0.35 mg/kg/h resulted in 33% mortality. Treatment with the two lower doses, but not the highest dose, of NE resulted in increases in basal left ventricular (LV) maximum rate of pressure generation and a marked increase in systolic, but not diastolic, arterial blood pressure (SBP, DBP). All doses of NE caused reduced responses to acutely administered NE but no marked change in the response to calcium chloride. Levels of plasma free radicals were increased only with the highest dose of NE. Over the concentration range studied, chronic administration of NE to rats causes beta-adrenoceptor downregulation and free radical production was associated only with the administration of a dose of NE that resulted in high mortality.

The effects of various doses of creatine phosphate have been examined in a rat model of acute myocardial ischaemia. When given directly into the lumen of the left ventricle in pentobarbitone-anaesthetised male rats, creatine phosphate (50 and 100 mg/kg) markedly reduced the incidence of ventricular ectopic beats, and especially the incidence and duration of ventricular tachycardia and fibrillation which normally resulted from acute coronary artery ligation in this model. This protection was observed even if 1 of 2 h elapsed between creatine phosphate administration and coronary artery ligation. Electrophysiological studies on papillary muscles removed from rats 1 h after administration showed that creatine phosphate both decreased the maximum rate of depolarisation and prolonged the duration of the action potential. These results confirm our previous work in dogs that creatine phosphate is effective against early postinfarction ventricular arrhythmias, at least if given locally. It is suggested that these effects are due, at least in part, to a prolongation of the cardiac muscle action potential. Whether this is the result of maintaining energy production early in myocardial ischaemia is unclear.

We examined the effects of late administration of the thromboxane synthetase inhibitor dazmegrel (UK 38485) and the calcium channel blocker nifedipine in anaesthetised greyhounds subject to occlusion of the left anterior descending coronary artery with reperfusion after 40 min of ischaemia. Administration of dazmegrel, 3 mg/kg i.v., or nifedipine, 5 micrograms/kg + 1 microgram kg-1 min-1 i.v., 25 min after coronary artery occlusion failed to reduce the incidence of reperfusion-induced ventricular fibrillation (controls, 70%; dazmegrel, 50%; nifedipine, 70%; n = 10). Measurement of plasma prostanoid concentrations indicated that within 5 min of receiving dazmegrel there was a significant reduction in thromboxane B2 concentrations in the local coronary vein draining the ischaemic myocardium. The results suggest that the occurrence of reperfusion-induced ventricular fibrillation depends upon the severity of changes occurring during ischaemia. Analysis of various factors suggested that the number of ischaemia-induced arrhythmias, heart rate, and the magnitude of changes in local coronary venous PO2 may be important predictors of reperfusion-induced ventricular fibrillation.

The effects of prostacyclin and ZK36374, a more stable analogue of prostacyclin, were examined in greyhounds anaesthetised with chloralose. Intravenous drug administration (100 ng kg-1 min-1) exacergbated the arrhythmias induced by occlusion of the left anterior descending coronary artery. The incidence of ventricular fibrillation (VF) was 50% in both drug groups compared with 10% in controls. An antiarrhythmic effect was observed when a lower dose (5 ng kg-1 min-1) was infused directly into the coronary circulation. The number of extrasystoles occurring during the first 30 min of occlusion was reduced from 720 +/- 136 in the controls to 327 +/- 167 in the prostacyclin group and 309 +/- 110 (p less than 0.05) in the dogs receiving ZK36374. The only haemodynamic change observed in the dogs receiving intracoronary drug infusions was a small decrease in systemic arterial blood pressure. In the intravenous groups systemic hypotension was accompanied by tachycardia, suggesting that there may have been a reflex increase in sympathetic drive. Increased catecholamine release could account for the higher incidence of VF in the dogs treated with intravenous prostacyclin or ZK36374. The intracoronary administration of both drugs markedly reduced the incidence of VF induced by the release of a 40-min coronary artery occlusion. This latter result suggests that the release of endogenous prostacyclin may have protective effects during reperfusion of the ischaemic myocardium.

The purpose of this investigation was to provide a detailed analysis of the effects of the thromboxane antagonist L655,240 (0.3 mg/kg i.v.) on early ischemia- and reperfusion-induced arrhythmias in a canine model of coronary artery occlusion. In a dose that abolished the pulmonary response to U46619, L655,240 attenuated markedly the severity of those arrhythmias that resulted from reperfusion of the myocardium; survival from the combined occlusion-reperfusion insult was increased from 10% in control animals to 70% in dogs administered L655,240. Drug intervention did not significantly alter the total number of arrhythmias during the period of ischemia, but a detailed analysis of the different types of arrhythmia that occurred during this period showed that L655,240 significantly reduced those arrhythmias in phase 1a (0-10 min of occlusion) without affecting the later phase 1b arrhythmias. This was particularly shown in the marked reduction in the number of salvos (couplets and triplets) during this period. Neither those arrhythmias occurring later in the ischaemia period (phase 1b) nor the total number of single ectopics and salvos or the incidence and duration of ventricular tachycardia was modified by L655,240. These results reveal that thromboxane antagonism protects especially against reperfusion-induced ventricular fibrillation and against early (phase 1a) ischemia-induced arrhythmias, possibly implicating a role for thromboxane in the genesis of these cardiac rhythm disturbances.

This article reviews the evidence we found in our study that the local generation of thromboxane and prostacyclin is one important factor involved in determining the severity of the ventricular arrhythmias that result from acute myocardial ischaemia and subsequent reperfusion. The hypothesis examined is that thromboxane release, presumably from platelets, is harmful in the early stages of ischaemia (perhaps because this induces further platelet aggregation and/or a reduction in blood flow as a result of both active vasoconstriction and of mechanical obstruction) and that prostacyclin generation (presumably mainly from endothelial cells) is beneficial at this time. The evidence is that in anaesthetised greyhound dogs, blockade of the thromboxane receptor (AH 23848) or inhibition of thromboxane synthesis (with a variety of "specific" inhibitors of thromboxane synthetase such as dazoxiben, dazmegrel, and "low-dose" aspirin) slightly reduces the severity of ischaemia-induced arrhythmias and markedly increases survival after myocardial reperfusion by reducing reperfusion-induced ventricular fibrillation (e.g., from 80% in control dogs to less than 20% in treated dogs). The evidence that prostacyclin generation is helpful in this situation comes from studies with locally infused prostacyclin or iloprost and with nafazatrom, a drug that increases the amount of prostacyclin released into local coronary venous blood soon after the onset of myocardial ischaemia; these procedures also reduce the number of ventricular extrasystoles occurring during ischaemia and the incidence of reperfusion-induced ventricular fibrillation. These findings do not imply that arachidonic acid derivatives are the only, or even the main, biochemical factor involved in the generation of these arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the effects of prolonged oral administration of oxprenolol (twice daily for 6 weeks) to male Sprague-Dawley rats. At two times (1 or 16-18 h) after the last oral dose, the rats were anaesthetised and subjected to acute coronary artery ligation, and the severity of the resulting arrhythmias was assessed. Ischaemic damage was measured histochemically (using frozen section analysis by toluidine blue dye in nitrobluetetrazolium ) and by myocardial enzyme release. Cardiac muscle (atria and papillary muscle) was also removed and the transmembrane action potentials recorded using conventional microelectrode techniques. When coronary artery ligation was performed 1 h after the last oral dose (at which time there was evidence of substantial myocardial beta 1-adrenoceptor blockade), there was significant reduction in the severity of early arrhythmias, but no evidence that the severity of ischaemic damage was reduced or that the intracellular cardiac action potentials were modified. No protection was observed when coronary artery ligation was carried out 16 h after the last oral dose of oxprenolol. These results support our previous studies with acutely administered beta-adrenoceptor blocking drugs that myocardial beta-adrenoceptor blockade is the main factor involved in the protection afforded by such drugs against early ischaemic arrhythmias and that other possible effects, such as membrane stabilisation and action potential prolongation, are relatively unimportant in this model.

We examined the effects of nifedipine, a calcium slow-channel blocking drug, on haemodynamics, blood gases, cardiac arrhythmias, and prostanoid release in anaesthetised greyhounds before, during, and after a 40-min occlusion of the left anterior descending coronary artery. Fifteen minutes after commencing treatment with nifedipine (5 micrograms/kg + 0.67 micrograms kg-1 min-1), there were significant reductions in arterial blood pressure, left ventricular end-diastolic pressure, and vascular resistance, with increases in cardiac output and stroke volume. Although coronary artery blood flow was unchanged, oxygen extraction was decreased, indicating that nifedipine reduced oxygen consumption. Nifedipine prevented the haemodynamic changes that occur in control dogs during acute myocardial ischaemia and markedly reduced the number of arrhythmias during coronary artery occlusion. The incidence of ventricular fibrillation induced by release of the occlusion was significantly reduced from 88% in the control group to 22% in the group receiving nifedipine. The release of thromboxane B2 and 6-keto PGF1 alpha (stable breakdown products of thromboxane A2 and prostacyclin, respectively) from the acutely ischaemic myocardium was not altered by nifedipine. It is concluded that this low dose of nifedipine had marked antiarrhythmic activity during both coronary artery occlusion and reperfusion. The relationship to dosage and possible mechanisms for this effect are discussed.