Comparative statistical analysis of osteoporosis treatment based on Hungarian claims data and interpretation of the results in respect to cost-effectiveness.

UNLABELLED: The efficacy of interventions used in real life for the treatment of osteoporosis has not been evaluated on a national basis. We analysed the database of the single Hungarian health care provider between 2004 and 2010. A marked reduction in fracture incidence and hospitalization was seen, which also proved to be cost-effective. INTRODUCTION: Osteoporosis and its consequences place a significant burden on the health care systems of developed countries. Present therapeutic modalities are effective in reducing the risk of fractures caused by osteoporosis. However, we do not know whether the interventions introduced in the past 15 years have significantly reduced the number of osteoporotic fractures in real life, and if yes, how cost-effectively. METHODS: The database of the National Health Insurance Fund Administration in Hungary was analysed for the period between 2004 and 2010. Two specific patient groups were identified within the population. Patients, who were under osteoporosis treatment in more than 80% of the potential treatment days in three consecutive years (patients with high compliance), were compared with patients where this ratio was under 20% (patients with low compliance). Several statistical comparative models were implemented in order to capture a complete picture on the differences. Because of natural data heterogeneity of administration databases, propensity matching was applied as well. RESULTS: Comparing treated vs. control subjects, patients with high compliance showed a significant decrease in fracture risk and hospitalization, which was more robust after propensity adjustment. On the basis of the observed statistically significant differences, cost-effectiveness analysis was implemented. Utility loss due the observed fractures was compared with the total cost differences of the two arms based on modelling. Our calculations proved the cost-effectiveness of the long-term high compliance in real world settings. CONCLUSION: Our findings infer that the standardized and uniform health care of osteoporotic patients in a country may reduce general fracture incidence and hospitalization in a cost-effective way.

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.

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.

Transient ischaemia induced by rapid cardiac pacing results in myocardial preconditioning.

STUDY OBJECTIVE: The aim was to determine whether rapid ventricular pacing can protect against the ventricular arrhythmias occurring during a subsequent coronary artery occlusion. DESIGN: The effect was examined of two 2 min periods of pacing (300 beats.min-1) in chloralose-urethane anaesthetised dogs on a subsequent 25 min coronary artery occlusion. Ventricular arrhythmias, ST segment elevation, and inhomogeneity of conduction were analysed. EXPERIMENTAL MATERIAL: 25 anaesthetised mongrel dogs in a restricted body weight range were used. MEASUREMENTS AND MAIN RESULTS: Preocclusion pacing reduced the severity of occlusion induced ST segment elevation, degree of inhomogeneity, and arrhythmias: ventricular premature beats were reduced from 528(SEM 40) to 136(45), and there were lower incidences of ventricular fibrillation (0% v 47%) and ventricular tachycardia (30% v 80%). CONCLUSIONS: Rapid ventricular pacing "preconditions" the myocardium in a manner similar to that following short coronary artery occlusions. Short periods of ischaemia no matter how induced protect the heart against the arrhythmogenic effect of a prolonged coronary artery occlusion.

Protective effects of preconditioning of the ischaemic myocardium involve cyclo-oxygenase products.

STUDY OBJECTIVE: The aim was to determine whether short (preconditioning) occlusions of a coronary artery protect against the arrhythmias occurring during a subsequent more prolonged occlusion and to examine whether the observed protection is mediated by the release of a product of the cyclo-oxygenase pathway of arachidonic acid metabolism. DESIGN: The effects were examined of two short (5 min) coronary artery occlusions, in chloralose-urethane anaesthetised dogs, on a subsequent prolonged (25 min) occlusion; analysis of ischaemia and reperfusion induced arrhythmias and of epicardial ST segment changes was performed. EXPERIMENTAL MATERIAL: 46 anaesthetised mongrel dogs in a restricted body weight range were used. MEASUREMENTS AND MAIN RESULTS: Preconditioning reduced the incidence and severity of ischaemic arrhythmias during a 25 min occlusion. Ventricular premature beats (VPB) reduced from 445 (SEM 140) to 96(22) (p less than 0.01), ventricular fibrillation (VF) from 4/10 to 0/20 (p less than 0.05), and ventricular tachycardia from 9/10 to 6/20 (p less than 0.05). VF following reperfusion was reduced from 6/6 to 6/10 (p less than 0.05). Preconditioning thus increased survival from the prolonged ischaemia-reperfusion insult from 0% to 40%. The protective effect of preconditioning was lost in the presence of the cyclo-oxygenase inhibitor sodium meclofenamate (2 mg.kg-1), eg, VPBs 367(95), VF during occlusion 1/9 and during reperfusion 8/8, survival 0%. CONCLUSIONS: Short, preconditioning periods of myocardial ischaemia protect the myocardium against the arrhythmogenic effects of a more prolonged occlusion. That this protection is lost if the cyclo-oxygenase pathway is blocked suggests a protective role for prostanoids, most likely prostacyclin, as endogenous myocardial protective substances.

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)

Short incubation with 7-oxo-prostacyclin induces long lasting prolongation of repolarisation time and effective refractory period in rabbit papillary muscle preparation.

STUDY OBJECTIVE - To determine whether the long lasting protection from early postocclusion and reperfusion arrhythmias induced by 7-oxo-prostacyclin is due to an anti-ischaemic effect alone or in combination with direct membrane effects. DESIGN - The study was performed on electrically stimulated isolated rabbit papillary muscle preparations with or without incubation with a stable prostacyclin analogue, 7-oxo-prostacyclinephedrine (7-oxo-PgI2). In some experiments, rabbits were pretreated with 7-oxo-PgI2. MEASUREMENTS and RESULTS - Marked prolongation of action potential duration (APD90) and effective refractory period developed 2 h after 20 min incubation with and subsequent washout of 7-oxo-PgI2, 1.1 X 10(-8) mol.litre-1. The same occurred if incubation with 7-oxo-PgI2 was maintained throughout the experiment. The only other change was a small diminution in amplitude of the action potential. During the 20 min incubation period neither APD90 nor effective refractory period was affected and only a transitory increase in the maximum rate of depolarisation, disappearing after washout, was seen. During the 4 h observation period there were no changes in the control preparations. The long lasting electrophysiological changes induced by 7-oxo-PgI2 were not affected by 60 min incubation with indomethacin, 2.8 X 10(-6) mol.litre-1. Pretreatment of rabbits with 7-oxo-PgI2, 50 micrograms.kg-1 intramuscularly, 48 h before the experiments prolonged effective refractory period v untreated controls. CONCLUSIONS - 7-oxo-PgI2 induces prolongation of APD90 and effective refractory period in adequately oxygenated normal papillary muscles as well as in ischaemic hearts. Therefore a direct membrane effect may contribute to its antiarrhythmic action, as well as an indirect anti-ischaemic effect. Such a direct effect is unlikely to be related to activation of the degradation products of the arachidonic acid cascade since it was not influenced by indomethacin.

Antiarrhythmic effects of preconditioning in anaesthetised dogs and rats.

OBJECTIVE: The aim was to determine the relationship of the duration of short coronary artery occlusions and of the reperfusion period to the extent of the antiarrhythmic effect of preconditioning. METHODS: A prolonged occlusion of a coronary artery in 102 anaesthetised rats and 55 anaesthetised dogs was preceded by a variable number of preconditioning coronary artery occlusions, of varying duration and with variable reperfusion periods between them and the prolonged occlusion. RESULTS: Preconditioning in both species reduced the severity of ischaemia induced arrhythmias, epicardial ST segment changes, and alterations in the degree of inhomogeneity of conduction during a subsequent prolonged coronary artery occlusion, provided that the reperfusion time was less than 30 min (in rats) and 1 h (in dogs). This antiarrhythmic effect of preconditioning was marked; eg, in dogs following two preconditioning occlusions survival from a combined ischaemia-reperfusion insult was 40% (cf, 0% in the controls). CONCLUSIONS: Short preconditioning periods of myocardial ischaemia protect the myocardium against the arrhythmogenic effects of a more prolonged occlusion. The optimum time for this preconditioning occlusion in rats is 3 min and protection is still apparent 30 min later. In dogs, the protective effect is especially clear with two short (5 min) coronary artery occlusions. The protection in this species lasts for less than 1 h.

Suppression of reperfusion induced arrhythmias in the isolated rat heart: pretreatment with 7-oxo prostacyclin in vivo.

OBJECTIVE: The aim was to investigate the late effect of pretreatment with 7-oxo prostacyclin on reperfusion induced arrhythmias in the isolated rat heart. METHODS: Forty eight hours after intramuscular administration of drug in vivo (50 micrograms.kg-1 body weight), isolated Langendorff perfused rat hearts were subjected to 30 minutes of regional ischaemia and 5 minutes of reperfusion. Incidence and duration of ventricular arrhythmias in both pretreated and control groups were evaluated on reperfusion. Morphological examination was also performed. RESULTS: In the untreated group reperfusion induced 75% of sustained ventricular fibrillation. Incidence of ventricular fibrillation, its duration, and arrhythmia score were significantly lower in the pretreated group. Pretreatment with 7-oxo prostacyclin had no effect on heart rate and coronary flow throughout the whole course of perfusion. Neither was the occluded zone size affected. Ultrastructure of ischaemic and reperfused myocardium was better preserved in the pretreated group. CONCLUSIONS: Antiarrhythmic action of 7-oxo prostacyclin was unrelated to changes in haemodynamics, thus suggesting the direct influence of the myocardium. The possible mechanism of action may involve maintenance of intracellular cation homeostasis (particularly of Na+ and Ca2+) due to a stimulation of sarcolemmal Na+ pump activity.

Moderate stress by cardiac pacing may induce both short term and long term cardioprotection.

OBJECTIVE: The aim was to investigate whether moderate ischaemic stress induced by brief periods of cardiac pacing to twice the normal heart rate protects the heart from the electrophysiological and haemodynamic consequences of subsequent periods of rapid pacing. METHODS: Conscious rabbits with implanted right ventricular electrodes and a permanent catheter in the left ventricular cavity were studied. Hearts were paced at a rate of 500.min-1 for 5 min. The resulting transient ST segment elevation in intracavital electrogram, the ventricular effective refractory period, and the left ventricular end diastolic pressure were measured. RESULTS: After discontinuation of pacing, a shortlasting ST segment elevation appeared in the endocardial electrogram, together with a transient rise in left ventricular end diastolic pressure. These changes were significantly reduced after a second pacing, provided that this was applied not later than 30 min after the first pacing; maximum protection occurred when there was a 5 min interval between these pacing periods. Serial stimulation (10 pacing periods with a 5 min interval between each) gave a similar protection to that resulting from a single pacing period. The protection was lost after 1 h; however, 24 h and 48 h (but not 72 h) after the end of serial stimulation there was again a reduction in postpacing ST segment and left ventricular end diastolic pressure elevation. At these times the ventricular effective refractory period was prolonged. The cyclo-oxygenase inhibitor sodium meclofenamate (1-2 mg.kg-1) prevented the early protection. CONCLUSIONS: The results suggest that brief periods of rapid pacing induce both short term and long term cardioprotection, as shown by reduced electrophysiological and haemodynamic consequences of subsequent pacing periods. Endogenous prostanoids might play a role in the short term cardioprotection.

Are ATP sensitive potassium channels involved in the pronounced antiarrhythmic effects of preconditioning?

OBJECTIVE: The aim was to determine whether the antiarrhythmic effects of preconditioning are modified by blockade of K+ATP channels with glibenclamide in a model (anaesthetised dogs) in which this procedure has previously been shown to prevent the effects of preconditioning in reducing myocardial infarct size. METHODS: 10 mongrel dogs were preconditioned by two 5 min occlusions of the left anterior descending coronary artery, separated by a 20 min reperfusion period, and then subjected, 20 min later, to a prolonged (25 min) occlusion and to subsequent reperfusion. In another 10 dogs glibenclamide (300 micrograms.kg-1) was given by intravenous injection both after the first preconditioning stimulus and before the prolonged occlusion. Control dogs (25) were subjected to a 25 min occlusion followed by reperfusion; five of these dogs also received glibenclamide. RESULTS: Preconditioning reduced the severity of ventricular arrhythmias, epicardial ST segment elevation, and the degree of inhomogeneity of conduction. The antiarrhythmic effect of preconditioning was attenuated by glibenclamide (twice as many ventricular premature beats and more episodes of ventricular tachycardia) but there was no modification of preconditioning induced reduction in ventricular fibrillation either during ischaemia or during reperfusion, or on survival (0% in controls; 50% in preconditioned dogs with or without glibenclamide). Glibenclamide did, however, prevent the effects of preconditioning on the inhomogeneity of conduction and, less markedly, on epicardial ST segment elevation. CONCLUSIONS: In a similar model to that in which it has previously been shown that glibenclamide prevents the effect of preconditioning in reducing myocardial infarct size (suggesting involvement of K+ATP channels), the most pronounced antiarrhythmic effects of preconditioning (reduction in ventricular fibrillation; increase in survival) were not modified by glibenclamide. This, and other evidence, suggests that the mechanisms of the protective effect of preconditioning in reducing the severity of arrhythmias and on infarct size are not the same.

Investigations on the chemistry of berbanes. 10. Synthesis of raunescinone analogues with hypotensive and antihypertensive activity.

The pharmacologically active (methylenedioxy)- and diethoxyepialloberbane keto esters I have been synthesized with use of the readily available keto esters 2 as starting material. By choice of the appropriate reaction sequence both antipodes of keto ester 2a can be employed to provide any enantiomer of the desired raunescinone analogue 1a. Hypotensive, antihypertensive, and central depressant effects of 1a are described. The principle effect observed for 1a was a potent hypotensive and antihypertensive effect of long duration without depression of the central nervous system.

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

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. 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. 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). 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.

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.

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

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. In this model, infusion of 1 microgram 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. 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. 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 occurring mainly during reperfusion.

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

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. 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. 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. 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.

Preconditioning of the ischaemic myocardium; involvement of the L-arginine nitric oxide pathway.

1. Short periods of coronary artery occlusion protect the heart against the effects of a subsequent prolonged period of ischaemia. This phenomenon is known as preconditioning of the ischaemic myocardium. 2. In mongrel, chloralose-urethane anaesthetized open-chest dogs, within a restricted body weight range, two 5 min periods of occlusion of the anterior descending branch of the left coronary artery markedly reduced the severity of the early ischaemic arrhythmias resulting from a prolonged (25 min) occlusion of the same coronary artery starting 20 min later. Thus, the number of ventricular premature beats (VPBs) was reduced from 528 +/- 140 in controls to 78 +/- 27 in preconditioned dogs, the incidence of ventricular fibrillation (VF) was reduced from 47% to 0% and the incidence of ventricular tachycardia (VT) from 100% to 20%. ST-segment elevation recorded from electrodes within the ischaemic area, and the degree of inhomogeneity of conduction within the ischaemic area were markedly reduced in these preconditioned dogs. 3. The incidence of VF following reperfusion of the ischaemic myocardium at the end of the 25 min occlusion period was reduced in the preconditioned dogs from 100% to 60%; there was thus a 40% survival from the combined ischaemia-reperfusion insult compared with 0% in the controls. 4. NG-nitro-L-arginine methyl ester (L-NAME) an inhibitor of the L-arginine nitric oxide pathway, given in a dose of 10 mg kg-1 intravenously on two occasions, both before the initial preconditioning occlusion and then again before the prolonged occlusion, partially attenuated the protective effects of preconditioning.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of in homogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in dogs not subjected to preconditioning, L-NAME had no significant effect on the severity of arrhythmias except for more periods of VT (a mean of 11.7 +/- 4.7episodes per dog).6. It is concluded from these studies that the generation of nitric oxide contributes to the marked antiarrhythmic effects of preconditioning in the canine myocardium, probably through elevation of cyclic GMP.

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

Rat isolated peritoneal cells (10(7) cells ml-1) incubated in the presence of dexamethasone (3 X 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 pretreated 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.

Local intracoronary infusions of bradykinin profoundly reduce the severity of ischaemia-induced arrhythmias in anaesthetized dogs.

Bradykinin in a dose (25 ng kg-1 min-1) which did not alter coronary flow, or saline, were infused into a small branch of the left anterior descending coronary artery in dogs anaesthetized with chloralose and urethane, for 10 min prior to coronary artery occlusion and throughout the 25 min occlusion period. The degree of inhomogeneity of conduction and epicardial ST-segment changes were measured in the ischaemic zone with a composite electrode. In control dogs, coronary artery occlusion led to severe arrhythmias with an incidence of ventricular fibrillation of 47% and tachycardia of 80% and with a mean of 528 +/- 140 ventricular premature beats. In marked contrast, those dogs administered bradykinin had no ventricular fibrillation or tachycardia and the number of premature beats was significantly less (53 +/- 19). ST-segment changes were also much less in these dogs. These results raise the possibility that bradykinin might contribute to the protective effects of preconditioning and acts as an 'endogenous myocardial protective substance'.

The effects of metoprolol and dazmegrel, alone and in combination, on arrhythmias induced by coronary artery occlusion in conscious rats.

The effects of metoprolol and the thromboxane synthetase inhibitor dazmegrel, alone and in combination, were examined in a model of coronary artery occlusion in conscious rats. In a dose (2 mg kg-1), intravenously, that resulted in a marked bradycardia (of 50-80 beats min -1) metoprolol did not influence the incidence or severity of the ventricular arrhythmias that occur in the first 20 min following occlusion, nor did it improve survival (assessed at both 20 min and 16 h). In a dose (5 mg kg-1), intravenously, that in another conscious rat model involving tissue hypoperfusion inhibited thromboxane production, dazmegrel also did not modify ischaemic arrhythmias or survival. In contrast, metoprolol and dazmegrel (2 mg kg-1 and 5 mg kg-1 i.v.) when given together prior to coronary artery occlusion, produced a significant reduction in mortality both at 20 min and 16 h (e.g. from 60-75% in the control, metoprolol alone and dazmegrel alone groups and only 25% in the combined-treatment group). This was due to a decrease in the incidence of terminal ventricular fibrillation. The results suggest that a combination of beta-adrenoceptor blocking drug with a drug that inhibits thromboxane synthesis may offer more protection against ischaemia-induced ventricular fibrillation than either drug used alone. They suggest a role for both catecholamines and thromboxane in the genesis of ischaemia-induced ventricular fibrillation.