Number Of Ventricular Ectopic Beats Research Articles

Ventricular ectopic activity, left ventricular mass, hyperinsulinemia, and intracellular magnesium in normotensive patients with obesity.

Insulin resistance, a well-known feature of obesity, is associated with several pathological changes, which are potentially arrhythmogenic. Ventricular ectopic activity in normotensive obese patients has not been studied in detail. Therefore the authors designed a study to investigate potential relationships among ventricular ectopic activity, left ventricular mass, hyperinsulinemia, and intracellular magnesium concentration in obese patients. Thirty-two obese patients and 32 nonobese control subjects, who were referred to outpatient department because of ventricular ectopy, participated in the study. The groups were matched for age and gender. All had normal glucose tolerance. All subjects underwent a 75-g glucose tolerance test, and blood samples were obtained at 30, 60, and 120 minutes thereafter for determination of glucose and insulin concentrations. Echocardiography was performed and left ventricular mass index was calculated. The number of ventricular ectopic beats per hour (VEB/hour) was recorded by 24-hour ECG Holter monitoring. Plasma and erythrocyte magnesium concentrations were determined by atomic absorption spectrophotometer. Obese patients had higher body weight, body mass index, heart rate, and left ventricular mass index. Obese subjects had higher fasting insulin as well as insulin/glucose ratio and broader area under the curve of insulin (AUC-I) compared to nonobese subjects. Insulin sensitivity appeared to be lower in the obese group. Holter monitoring showed more VEB/hour in the obese group. Magnesium concentration in serum and in erythrocytes was lower in obese persons. In the obese group a positive correlation was found between left ventricular mass index and fasting insulin (r=0.345, p=0.027), insulin/glucose index (r=0.351, p=0.049), and AUC-I (r=0.405, p=0.011). The number of VEB/hour in obese patients was in positive correlation with age (r=0.681, p<0.001), left ventricular mass index (r=0.542, p=0.001), fasting insulin (r=0.380, p=0.016), and AUC-I (r=0.493, p=0.002) and in negative correlation with magnesium concentration in erythrocytes (r=-0.457, p=0.004). Multiple regression analysis showed that age and AUC-I are the only determinants of VEB/hour and together explained 56% of the variability in the obese subjects. It appears that in obese normotensive subjects, ventricular ectopic beats are related to age, insulin resistance, left ventricular mass index, and decreased intracellular magnesium content.

Effects of extracts from flowering tops of Crataegus meyeri A. Pojark. on ischaemic arrhythmias in anaesthetized rats.

Different species of Crataegus, commonly called Hawthorn, were reported to possess wide pharmacological effects on the cardiovascular system. In the present study, chloroform, ethylacetate and methanol (70%) extracts of the flowering tops of Crataegus meyeri A. Pojark. were studied. The extracts were tested on the incidence and severity of arrhythmias induced by a period of myocardial ischaemia in open-chest anaesthetized male Wistar rats. Infusion of a hydroalcohol extract (1 mg/kg/min) resulted in a significant decrease in the total number of ventricular ectopic beats (from 1494 +/- 362 in the control to 634 +/- 102), mainly by reduction of beats occurring as ventricular tachycardia. A chloroform extract (1 mg/kg/min) also reduced the total number of ventricular ectopic beats but this reduction was due to the decrease of single extrasystoles. A significant reduction in the time spent for ventricular fibrillation was seen by the hydroalcohol and ethylacetate extracts. There were no significant changes in the heart rate and blood pressure during the extract infusion. However, bolus injection of all the extracts caused a significant reduction in the blood pressure. Thus, the extracts of Crataegus meyeri have a hypotensive and a potential antiarrhythmic action on ischaemic myocardium and may possess active principles.

The beneficial effects of peroxynitrite on ischaemia–reperfusion arrhythmias in rat isolated hearts

The simultaneous production of nitric oxide (NO) and superoxide leads to the formation of a potent toxic metabolite peroxynitrite (ONOO −). However, ONOO − at low concentrations has been found to exert cardioprotective effects. The purpose of the present study was to investigate the effects of exogenous ONOO − on ischaemia–reperfusion arrhythmias. We studied the concentration–response effects of ONOO − (0.4, 4, 40 μM ml −1 min −1 for 20 min) in rat isolated hearts perfused with Krebs–Henseleit solution. The 0.4 μM concentration of ONOO − was selected for further experiments since it did not affect the sinus rhythm. In the hearts subjected to 10 min of ischaemia followed by 10 min of reperfusion during 0.4 μM ml −1 min −1 ONOO − infusion, the incidence of ventricular fibrillation was decreased significantly from 93% to 38% ( n=8) and none of the hearts had an irreversible ventricular fibrillation. Urate, a ONOO − scavenger (at 1 mM, n=7), added to the perfusate 5 min prior to the coronary artery occlusion and maintained throughout the experimental period, did not significantly modify the beneficial effects of ONOO −. Although l- N G-nitroarginine methylester ( l-NAME) (100 μM, n=8) had no effect, superoxide dismutase (10 U ml −1)+catalase (100 U ml −1) increased the number of ventricular ectopic beats from 91±32 to 286±83 ( n=5) and augmented the incidence of irreversible ventricular fibrillation from 0% to 60%. There were no marked changes in the time of onset of the first arrhythmias in any group. These results suggest that ONOO − at a low concentration may exert beneficial effects on ischaemia–reperfusion-induced arrhythmias in rat isolated hearts.

The influence of maturation and gender on the anti-arrhythmic effect of ischaemic preconditioning in rats.

The aim of this study was to investigate the influence of maturation and gender on the anti-arrhythmic effect of myocardial ischaemic preconditioning in rats. Coronary artery occlusion was carried out in either rats anaesthetised with sodium pentobarbitone or in rat isolated hearts. Cardiac arrhythmias occurring in the 30 min post-occlusion period were assessed. In anaesthetised 3 month (m) old male rats ischaemic preconditioning, with a 3 min temporary coronary artery occlusion, significantly reduced the total number of ventricular ectopic beats (VEBs) from 2074 +/- 206 to 490 +/- 139 and the incidence of ventricular fibrillation (VF) from 40 to 0% during a subsequent 30 min occlusion (P < 0.05). In middle-aged male rats (16 m) the anti-arrhythmic effect of preconditioning was unaltered (VEBs were reduced from 1958 +/- 121 to 245 +/- 66 and VF from 70 to 0%). In 3 m old anaesthetised female rats the effect of ischaemic preconditioning was also evident (VEBs reduced from 961 +/- 170 to 154 +/- 48; P < 0.05). In non-preconditioned age-matched female animals the total number of VEBs (961 +/- 170), VF (0%) and mortality (0%) were significantly (P < 0.05) lower than in respective male animals. In female rats, attenuation of ischaemia-induced arrhythmic severity was most pronounced in the oestrus state. In hearts isolated from weight-matched male and female rats the incidence of ventricular tachycardia (81 vs 25%) and the total number of VEBs (351 +/- 73 vs 81 +/- 50) were significantly (P < 0.05) different. It is concluded that in rats neither maturation nor gender influence the anti-arrhythmic effect of ischaemic preconditioning. However, female rats exhibit a lower level of arrhythmic activity during sustained coronary artery occlusion than male rats both in vivo and in vitro.

Endothelin and ischaemic arrhythmias-antiarrhythmic or arrhythmogenic?

The aim of this study was to investigate the influence of endogenously released and exogenously applied endothelin-1 (ET-1) on ischaemia-induced arrhythmias. Ischaemia was induced in pentobarbitone-anaesthetised rats by ligation of a coronary artery for 30 min. To determine the role of endogenous ET-1 in ischaemic arrhythmias, either the ETA receptor antagonist BQ123 (50 micrograms/kg/min, i.v.; n = 10) or the ETB receptor antagonist PD161721 (0.1 or 1 mg/kg i.v.; n = 10 per group) was administered before the onset of ischaemia. To assess the influence of exogenous ET-1 on arrhythmias, ET-1 (1.6 nmol/kg i.v.) was administered 5 min before ischaemia in the absence (n = 12) or presence of BQ123 (n = 10) or PD161721 (n = 10). The total number of ventricular ectopic beats (VEB's) were counted and expressed as median (Q1-Q3) and the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) in each group was determined. Mean arterial blood pressure (MABP) and heart rate (HR) were measured. In control animals (n = 20), the incidence of VF was 65% and the total VEB count was 2775 (1870-4041). Both BQ123 and the higher dose of PD161721 reduced the VEB count to 654 (348-1489; P < 0.05) and 782 (432-1153; P < 0.05) respectively. Only PD161721 reduced the incidence of VF (to 10%; P < 0.05). Administration of ET-1 reduced VEB's to 1530 (1204-2017); P < 0.05) and the incidence of VF to 17% (P < 0.05). Neither PD161721 nor BQ123 modified this antiarrhythmic effect of ET-1, but rather enhanced the reduction in arrhythmias. Before occlusion, ET-1 caused a transient fall in MABP (from 107 +/- 3 to 63 +/- 3 mmHg; P < 0.05). PD161721, but not BQ123, partially blocked this effect. Upon occlusion, MABP fell in control animals (from 106 +/- 4 to 67 +/- 4 mmHg at 1 min post-occlusion; P < 0.05). This was significantly attenuated by ET-1, although neither of the antagonists were able to block this effect of ET-1. ET-1 released endogenously during ischaemia is arrhythmogenic whereas exogenous application of ET-1 may, under certain conditions, be antiarrhythmic.

Lack of involvement of mast cell degranulation in the antiarrhythmic effect of preconditioning in rats.

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.

Influence of vertical vibration on heart rate of pigs.

Pigs with a body weight between 15 and 20 kg were vibrated in the vertical direction for 1 h at 2, 8, and 18 Hz, in combination with root mean square (RMS) acceleration magnitudes of 1 or 3 m/s2. Welfare and stress were quantified by comparing heart rate characteristics during a control period (2200 to 0600) before vibration exposure and during vibration (1000 to 1100). The level of maximum heart rate and number of ventricular ectopic beats during vibration at 2 and 8 Hz in combination with a RMS acceleration of 3 m/s2 indicated a larger fear response than at 1 m/s2. Isocomfort contours based on mean heart rate during vibration showed the greatest specific sensitivity of the pigs to vibration at a frequency of 8 and 18 Hz, especially in combination with a RMS acceleration of 3 m/s2. During transport, RMS acceleration should be less than 3 m/s2 to protect pigs' welfare. Pigs were more sensitive to acceleration than to frequencies within the range of treatments in this investigation. Although the response of the pigs in this experiment fit within the model concept for adult humans and for domestic fowl, changes in heart rate are dependent on body weight.

THE ROLE OF PROSTAGLANDIN SYNTHESIS STIMULATION IN THE PROTECTIVE EFFECT OF CAPTOPRIL ON ISCHAEMIA-REPERFUSION ARRHYTHMIAS IN RATSIN VIVO

Attenuation of ischaemia-reperfusion induced arrhythmias by several angiotensin converting enzyme (ACE) inhibitors, such as captopril, has been demonstrated. The role of prostaglandin synthesis stimulation in this protective effect of ACE inhibition was evaluated in anin vivorat model. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion. Captopril (3 mg kg−1) and a prostaglandin synthesis inhibitor, indomethacin (2 mg kg−1) alone or together were administered by intravenous (i.v.) injection 10 min before occlusion. Captopril reduced the incidence of ventricular tachycardia (VT) and the number of ventricular ectopic beats (VEB) on ischaemia and reperfusion as well as the incidence of reversible ventricular fibrillation (VF) on reperfusion. These protective effects of captopril against ischaemia-reperfusion-induced arrhythmias were prevented by indomethacin. Captopril also caused a sustained decrease of preocclusion values in the arterial blood pressure (BP) and heart rate (HR), whereas in the presence of indomethacin, captopril had no significant effect on either HR or arterial BP values except the heart rate value just before occlusion. Indomethacin alone did not affect either the severity of arrhythmias or the haemodynamic parameters. These results suggest that, in this experimental model, the protective effects of ACE inhibitors on the arrhythmias following ischaemia-reperfusion are mediated by the stimulation of prostaglandin synthesis and the haemodynamic effects of these drugs may have a contributory role in their protective effect.

The role of nitric oxide in modulating ischaemia-induced arrhythmias in rats.

The effect of a nitric oxide (NO) donor and the influence of endogenous NO in modulating ischaemia-induced arrhythmias was assessed in anaesthetised rats. The nitric oxide donor C87-3754 (1 mg/kg) caused a significant reduction in arterial blood pressure before coronary artery ligation but did not influence the incidence or severity of ventricular arrhythmias during a 30-min period of myocardial ischaemia [60 and 58% incidence of ventricular fibrillation (VF) in control and treated rats, respectively]. When the hearts were preconditioned by a short (3 min) coronary artery occlusion before the 30-min period of ischaemia, there was a marked reduction in both the number of ventricular ectopic beats (260 +/- 65 vs. 812 +/- 256 beats/min in controls; p < 0.05) and the incidence of ventricular fibrillation (9 vs. 67% in controls; p < 0.05). Neither NG-nitro-L-arginine methyl ester (L-NAME; 10-100 mg/kg) nor methylene blue (1-50 mg/kg) attenuated this marked antiarrhythmic effect of preconditioning. L-NAME caused a significant increase in blood pressure with all doses used, whereas methylene blue did not increase blood pressure. Both L-NAME and methylene blue attenuated ventricular arrhythmias in non-preconditioned hearts. L-NAME reduced the number of ventricular ectopic beats (from 812 +/- 256 to 318 +/- 81 beats/min at 10 mg/kg; p < 0.05), whereas methylene blue decreased the incidence of VF from 67 to 20% at a dose of 50 mg/kg (p < 0.05). These findings suggest that neither endogenous nor exogenously administered NO reduces ischaemic arrhythmias in anaesthetised rats. Furthermore, the antiarrhythmic effect of preconditioning in this species appears to be independent of NO. The antiarrhythmic effects seen with both methylene blue and L-NAME may be the result of actions other than inhibition of the production or actions of NO.

Protective Effect of ACE Inhibitors on Ischemia-Reperfusion-induced Arrhythmias in Rats: Is this Effect Related to the Free Radical Scavenging Action of these Drugs?

The antiarrhythmic effects of captopril, a sulphydrylcontaining angiotensin converting enzyme (ACE) inhibitor, were compared with those of the non-sulphydryl-containing ACE inhibitor lisinopril and the sulphydryl-containing agent glutathione in an in vivo rat model of coronary artery ligation. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion. Captopril (3 mg kg−1) and lisinopril (0.1, 0.3 or 1 mg kg−1) caused marked decreases in mean arterial blood pressure (BP) and heart rate, whereas glutathione (5 mg kg−) had no effect on them. The incidence of ventricular tachycardia (VT) on ischemia and reperfusion was significantly reduced by captopril and lisinopril. Captopril and 1 mg kg−1 lisinopril also significantly decreased the number of VEB during occlusion and the duration of VT on reperfusion, respectively. These drugs also attenuated the incidence of reversible ventricular fibrillation (VF) and the number of ventricular ectopic beats (VEB) during reperfusion. However, glutathione only reduced the incidence of VT on reperfusion, significantly. These results suggest that, in this experimental model, ACE inhibitors limit the arrhythmias following ischemia-reperfusion and free radical scavenging action of these drugs does not have a major contributory role in their protective effect.

Magnesium Substitution and Postoperative Arrhythmias in Patients Undergoing Coronary Artery Bypass Grafting

Sixty coronary artery bypass grafting patients were randomized to receive either magnesium sulphate or placebo for 4 days postoperatively. The magnesium substitution reduced the duration of atrial fibrillation or flutter (p < 0.05), but not the number of patients developing these arrhythmias. The number of ventricular ectopic beats was also reduced among patients receiving magnesium sulphate compared to placebo (p < 0.05). To evaluate whether the anti-arrhythmic effect of magnesium sulphate was explained by a faster resumption of cellular potassium postoperatively, skeletal muscle electrolyte concentrations were measured pre-operatively and on the third day postoperatively. No significant difference was found in skeletal muscle potassium or magnesium contents on the third day postoperatively when comparing the two groups. The serum magnesium level declined postoperatively in the placebo group, whereas an increase was found in patients receiving magnesium sulphate. We suggest magnesium substitution as a routine postoperatively, because this treatment seems to reduce the severity of postoperative arrhythmias.

The effects of creatine phosphate in experimental myocardial infarction

Several clinical and experimental studies have demonstrated the protective mechanisms of exogenous high-energy compounds in treating total or regional myocardial ischemia. To evaluate the effects of creatine phosphate (CP) in an experimental model, rabbits of the New Zealand line were randomly divided into two CP-treated groups (A and B) and one control group (C). In all animals the circumflex coronary artery was ligated, and the size of the infarct zone was planimetrically determined. The contents of the phospholipid degradation products also were measured. Continuous electrocardiogram monitoring revealed a statistically significant reduction in the total number of ventricular ectopic beats in groups A and B and a longer period of both ventricular tachycardia and ventricular fibrillation in the control group than in the treated groups. Our results showed a statistically significant reduction of the necrotic zone in both treated groups versus the control group. Analysis of the degradation products of phospholipid metabolism emphasized an increase of both lysophosphatidylcholine and lysophosphatidylethanolamine in the untreated group versus treated groups. Significant correlation was found between total ventricular ectopic beats and the lysophosphoglyceride contents in groups A and B. On this basis we believe that CP may prevent the ischemic consequences on the myocardium of arrhythmias resulting from electrophysiological alterations produced by an increase of lysophosphoglycerides, and should reduce the extension of the necrotic zone, probably preserving the integrity of the cell membrane.

Potassium and Magnesium Distribution, ECG Changes, and Ventricular Ectopic Beats During β2-Adrenergic Stimulation With Terbutaline in Healthy Subjects

To study the effect of intravenous (i.v.) terbutaline on potassium (K) and magnesium (Mg) distribution, ECG changes, and prevalence of ventricular ectopic beats in healthy subjects. Randomized double-blind, placebo-controlled crossover. Subjects received either placebo or terbutaline (bolus, 0.25 mg; maintenance dose, 5 micrograms/min). University Department of Clinical Chemistry. Ten healthy male volunteers. Mean age was 24.1 (range, 20 to 31) years. Serum potassium and magnesium muscle potassium and magnesium, and muscle sodium-potassium pump number. Urinary excretion of potassium and magnesium. ECG changes (T-wave and QTC interval) and the number of ventricular ectopic beats. Terbutaline produced an immediate decrease in serum potassium level from 4.17 (4.04 to 4.30) mmol/L to a nadir of 3.32 (3.06 to 3.58) mmol/L (p < 0.001). The urinary excretion of potassium decreased from 0.077 mmol/min (0.052 to 0.102) to 0.038 mmol/min (0.025 to 0.051) (p < 0.01). There was an increase in the number of sodium potassium pumps from 1,104.1 nmol/kg dry weight (1,030.6 to 1,177.5) to 1,273.3 nmol/kg dry weight (1,193.5 to 1,353.2) (p < 0.01), but no measurable change in muscle potassium. The QTC interval increased from 395 (385 to 405)ms to 449 (432 to 466) ms (p < 0.003). There was no change in the number of ventricular ectopic beats. Short-term i.v. administration of terbutaline produced hypokalemia partly due to an increase in the number of sodium-potassium pumps. Furthermore, terbutaline induced changes in ECG with a highly significant lengthening of the QTc interval but with an unchanged number of ventricular ectopic beats in healthy subjects.

Verapamil for the suppression of idiopathic ventricular tachycardia of left bundle branch block-like morphology

This study examines the efficacy of verapamil for the suppression of idiopathic ventricular tachycardia (VT) of left bundle branch block LBBB-like morphology. Forty-two patients (mean age 36.2 ± 12.1 years; 20 men and 22 women) with VT and without any underlying cardiac abnormality on clinical examination and noninvasive investigation were studied. The inducibility of clinical VT was examined by treadmill exercise testing and programmed ventricular stimulation (PVS). In 29 patients VT was inducible by exercise testing, in 24 by PVS, and in 23 there was evidence of VT on Holter monitoring. After baseline testing, patients were treated with verapamil 120 mg thrice daily for at least 5 half-lives for the drug to load before evaluation. With Holter monitoring, 74% of patients with evidence of VT at baseline testing demonstrated a change of status from nonsustained VT to no VT or from sustained VT to nonsustained VT. Four patients had nonsustained VT during verapamil treatment but no VT at baseline. There was a significant reduction in the number of ventricular ectopic beats over 24 hours (baseline: 15541 ± 17599 vs verapamil treatment: 8892 ± 15582, p < 0.01). Exercise-induced VT was suppressed in 56% of patients with VT during baseline testing, but no effect of verapamil on the tachycardia was observed in 26%. The remaining patients demonstrated a partial response to verapamil; the rate of VT was unchanged, although the duration of the runs was reduced. Sustained monomorphic VT was inducible in only 5 patients, of whom 4 were rendered noninducible; 1 patient remained inducible. However, of the 13 patients with nonsustained VT inducible at baseline, 4 became sustained, of which 2 were hemodynamically unstable. There was no obvious difference in the age or sex distribution of the patients, axis of VT, presence of abnormal cardiac histology, or late potentials among patients responding to verapamil during Holter monitoring or exercise testing. VT of an inferior axis was more likely to respond to verapamil, whereas VT of a superior axis did not respond to verapamil during Holter monitoring. We conclude that idiopathic VT of LBBB-like morphology can be suppressed in approximately two thirds of the patients by verapamil. In patients with a partial response, the rate of VT is unaffected. Some patients exhibit exacerbation of the arrhythmia and verapamil should be avoided in these cases.

The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs.

1. The effect of R75231, an inhibitor of purine nucleoside transport, were examined on ischaemic arrhythmias in anaesthetized pigs. 2. In closed chest pigs (n = 4), R75231 exerted a moderate dose-dependent decrease in mean arterial blood pressure (from 97 +/- 4 mmHg to 95 +/- 4, 90 +/- 1 and 83 +/- 2 mmHg at 25, 50 and 100 micrograms kg-1 respectively) and produced a dose-related shift to the left of the blood pressure dose-response curve to intravenous bolus doses of adenosine. The degree of inhibition of adenosine uptake by R75231, assessed ex vivo in erythrocyte suspensions, was 43 +/- 5%, 64 +/- 13 and 114 +/- 15% at doses of 25, 50 and 100 micrograms kg-1 respectively. 3. In open chest pigs, intravenous injection of R75231 (50 micrograms kg-1; n = 6 and 100 micrograms kg-1; n = 10) induced a dose-related decrease in both systolic and diastolic arterial blood pressure which was more marked than in closed-chest pigs (mean pressure 86 +/- 4 to 70 +/- 2 mmHg and 88 +/- 6 to 60 +/- 6 mmHg with 50 and 100 micrograms kg-1 respectively), without affecting heart rate or myocardial contractility. Coronary artery occlusion in these pigs caused a secondary decrease in blood pressure. This was not observed in controls (n = 10). The lower dose of R75231 did not exert any antifibrillatory effects, whereas the higher dose significantly reduced the incidence of ventricular fibrillation, from 80% in control pigs to 30%. Neither dose modified the incidence of ventricular tachycardia (33% and 40% with 50 and 100 microg kg-1 respectively, compared to 30% in controls) or had any effect on the total number of ventricular ectopic beats (85 +/- 47 and 130 +/- 31 vs 110 +/- 19 in controls). R75231, at a dose of 100 microg kg-1, also attenuated the ischaemia-induced shortening of QRS-interval, but neither dose modified the ST-segment depression seen following occlusion.4. These results show that the nucleoside transport inhibitor, R75231, exerts an antifibrillatory effect ina model of severe myocardial ischaemia in a dose which completely inhibits adenosine uptake ex vivo.However, while this agent has minimal haemodynamic effects in closed chest animals, the reduction in blood pressure induced by R75231 in open-chest pigs cannot be excluded as a possible contributory mechanism of the antiarrhythmic effects of this drug.

Effects of R-PIA, a selective A1 adenosine agonist, on haemodynamics and ischaemic arrhythmias in pigs

Adenosine has previously been shown to protect against ischaemia induced ventricular arrhythmias. The aim of this study was to determine whether stimulation of A1 adenosine receptors with a selective agonist also protects against arrhythmias, and to attempt to elucidate the underlying mechanisms. Large White/Welsh Landrace cross breed domestic pigs (25-40 kg) subjected to left anterior descending coronary artery occlusion were used. R-PIA [R(-)N6-(2-phenylisopropyl) adenosine; 5 micrograms.kg-1] was given prior to coronary artery occlusion and the effects on haemodynamic variables and early ischaemic arrhythmias in the absence and presence of right atrial pacing were studied. The three experimental groups were: solvent controls, n = 10; R-PIA without pacing, n = 10; R-PIA with atrial pacing, n = 10. Ex vivo assessment of platelet aggregation was also performed to determine any inhibitory effects of R-PIA on platelets. Administration of R-PIA without atrial pacing reduced the total number of ventricular ectopic beats induced by coronary occlusion, from 326(SEM 71) in controls to 121(30) (p < 0.05) and the incidence of ventricular fibrillation from 70% to 20% (p < 0.05). At the dose used, R-PIA reduced heart rate from 102(7) to 74(3) beats.min-1, with a consequent reduction in mean arterial blood pressure from 95(4) to 81(3) mm Hg. Atrial pacing following drug administration, at a rate of 109(5) beats.min-1, restored blood pressure and abolished the antiarrhythmic effects of R-PIA. Drug intervention had no effect on either ex-vivo platelet aggregation or coronary sinus oxygen content, suggesting a lack of activity at A2 adenosine receptors. An A1 adenosine receptor agonist exerts a marked protection against ischaemia induced ventricular arrhythmias and fibrillation in pigs. The reversal of this effect by restoring heart rate suggests that the drug induced bradycardia may be important in the antiarrhythmic action of R-PIA, possibly via an anti-ischaemic effect.

Effects of selective receptor agonists and antagonists during myocardial ischaemia

The antiarrhythmic activities of 16-methylcyprenorphine (M8008), nor-binaltorphimine (NBT) and naltrexone, which are relatively specific opioid receptor antagonists for δ, κ and μ receptors, respectively, were examined during the 30 min following coronary artery occlusion anaesthetised rats. The haemodynamic and electrocardiographic effects of the opioid receptor agonists [D-Ala 2,D-Leu 5]enkephalin (DADLE) (relatively selective for δ receptors), ICI-204448 (κ) and glyol (μ) were also investigated over the 30–90 min post ligation period. When administered intravenously 5 min before ligation, M8008 (0.5 mg kg −1 and 2.5 mg kg −1 reduced the number of ventricular ectopic beats but had no effect on the incidence or duration of ventricular fibrillation. NBT and naltrexone were not antiarrhythmic at a dose of 0.5 mg kg −1 (a concentration at which both drugs block κ receptors) the number of ventricular ectopics beats, the incidence of ventricular fibrillation and mortality were all reduced. All of the opioid receptor agonists caused a transient decrease in heart rate and in arterial blood pressure but none exhibited an arrhythmogenic effect. These studies suggest that the δ and κ opioid receptor antagonists used may be antiarrhythmic as a result of blockade of the action of endogenously released peptides acting on these receptors or that they have a non-specific ‘direct’ antiarrhythmic action.

Inverse relationship between ESR spin trapping of oxyradicals and degree of functional recovery during myocardial reperfusion in isolated working rat heart

The aim of the study was to investigate the generation of free oxyradicals as factors in myocardial ischaemia-reperfusion pathology. Isolated perfused rat hearts were subjected to 30 min global ischaemia followed by reperfusion. The spin trap 5,5-dimethyl-1-pyrroline-1-oxide was added to the effluent of the heart to avoid pharmacological interaction with the heart. The effluent was then analysed by electron spin resonance spectroscopy. Studies were performed on hearts of 51 male Sprague-Dawley rats, weight 300-350 g. During reperfusion, the formation of hydroxyl radical adducts of the trap was observed, with a maximal value after 3 min. The initial amount of radicals trapped during the first 3 min of reperfusion showed an inverse correlation with the degree of heart function restored within 30 min of reperfusion. Spearman's rank correlation coefficients were calculated to be -0.734 for heart rate, -0.825 for left ventricular developed pressure, -0.787 for the maximum of its first derivative, -0.787 for coronary flow, and -0.796 for aortic flow (p less than 0.05, n = 10, in each instance). No statistically significant correlation was found between the cumulative amount of radicals trapped in the effluent during the initial phase of reperfusion and the duration of ventricular fibrillation, duration of ventricular tachycardia, or number of ventricular ectopic beats (registered during 30 min reperfusion). The application of spin trapping to the effluent of isolated perfused hearts allows the generation of oxyradicals to be characterised without interaction of the trap with the heart. It also allows the time course of radical production to be investigated, and can detect relative changes in their intensity. These are important factors in the study of the pathogenic role of free radicals generated during reperfusion of an ischaemic heart.

Cardiac arrhythmias during occupational exposure to fluorinated hydrocarbons.

The effects of occupational exposure to chlorodifluoromethane (FC 22) and dichlorodifluoromethane (FC 12) on cardiac rhythm were examined. The subjects were six men who repaired refrigerators (age 31-56, mean 46 years) and a control group of six plumbers (age 29-54, mean 45 years). Ambulatory electrocardiograms (ECG) were recorded for 24 hours on the day of exposure and on a control day. The ECG tapes were automatically analysed with a Reynolds pathfinder 3 apparatus and all aberrant complexes recorded by the machine were checked. One person read all the tapes without knowing whether or not they were recorded during exposure. The number of ventricular ectopic beats were compared between the day of exposure and the control day and with the tape of the control. In addition, the number of ventricular ectopic beats during exposure was compared with the number occurring during the rest of the day. The concentrations of fluorocarbons were measured in four instances. High peak concentrations of fluorocarbons (1300-10,000 cm3/m3) were measured during refrigerator repair work. No clear connection between fluorocarbons and cardiac arrhythmia was found, although one subject had several ventricular ectopic beats which may have been connected with exposure.

Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds

The effects of first and second generation hypoglycemic sulfonylureas on the incidence of ventricular ectopic beats and on the duration of transitional ventricular fibrillation in the ischemic rat heart were investigated. First generation sulfonylurea compounds (tolbutamide, carbutamide and gliclazide) in 105 preparations increased, while second generation sulfonylurea compounds (glibenclamide and glipizide) in 50 preparations decreased in a dose-dependent manner both the number of ventricular ectopic beats and the duration of transitional ventricular fibrillation during the first 30 min after ligation of the left anterior descending coronary artery. Therefore, second generation sulfonylureas should be preferred in the treatment of type 2 diabetics with ischemic heart diseases, if satisfactory metabolic control cannot be achieved by a treatment regimen and diet alone.