Antiarrhythmic actions of adenosine in the early stages of experimental myocardial ischaemia

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1 The electrophysiological effects of adenosine and adenosine triphosphate (ATP) were examined in sheep Purkinje fibres, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). The ability of adenosine to modify the effects of noradrenaline on action potential characteristics was also investigated. 2 The only statistically significant effects of adenosine (10-6-10-4M) and of ATP (10-6-10-4M) on normal action potential characteristics were a slight dose-dependent shortening of the action potential by adenosine and a depolarization by ATP, 10-4 M. 3 Superfusion with a hypoxic, hyperkalaemic and acidotic PSS caused marked reductions in resting membrane potential, upstroke and duration of the action potential. 4 Both adenosine and ATP attenuated the reduction in the rate of rise of the upstroke and the amplitude of the action potential caused by the modified PSS. 5 Adenosine did not alter the noradrenaline-induced effects on automaticity or on action potentials of normal or depressed Purkinje fibres. 6 Adenosine and ATP had electrophysiological effects on Purkinje fibres, exposed to conditions in vitro that mimic mild myocardial ischaemia, that were different from those observed on normally polarized fibres.

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Electrophysiological effects of adenosine and adenosine triphosphate on sheep Purkinje fibres under normal and simulated ischaemic conditions

Boachie-Ansah¹,

Kane²,

Parratt³

1989

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“…There is a substantial literature (for a recent excellent review see Forman et al, 1993) on the cardioprotective effects of adenosine against myocardial injury induced by reperfusion, involving a variety of mechanisms such as modulation of neutrophil infiltration (Olafsson et al, 1987), preservation of vascular function (Babbitt et al, 1989) and reduction of neutrophil free radical generation (Cronstein et al, 1990). In addition to injury resulting from myocardial ischaemia and reperfusion, adenosine has been shown to protect against coronary occlusion-induced ventricular arrhythmias in rats (Fagbemi & Parratt, 1984) and dogs (Wainwright & Parratt, 1988). Adenosine has long been known to be protective in treating supraventricular arrhythmias in man (Belhassen & Pelleg, 1984) and its clinical use is largely limited to treatment of these arrhythmias (Barber, 1992) because of the frequency of side effects (such as chest pain and dyspnoea; Rankin et al, 1989) associated with its action at A2-adenosine receptors which are universally distributed throughout the body.…”

Section: Introductionmentioning

confidence: 99%

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

Wainwright

Parratt

Belle

1993

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The effect of R75231, an inhibitor of purine nucleoside transport, were examined on ischaemic arrhythmias in anaesthetized pigs. 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 μg 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 μg kg−1 respectively. In open chest pigs, intravenous injection of R75231 (50 μg kg−1; n = 6 and 100 μg 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 μg 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 μg 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 μg kg−1, also attenuated the ischaemia‐induced shortening of QRS‐interval, but neither dose modified the ST‐segment depression seen following occlusion. These results show that the nucleoside transport inhibitor, R75231, exerts an antifibrillatory effect in a 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.

“…Activation of adenosine receptors, which regulate adenylate cyclase activity through guanosine triphosphate binding proteins in the heart, influences the regulation of coronary blood flow, atrioventricular conduction and attenuates the effects of catecholamine stimulation and myocardial oxygen supply/ demand imbalance associated with ischaemia. Endogenous adenosine has been proposed to play the role of 'endogenous myocardial antiarrhythmic substance' (Fagbemi & Parratt, 1984). In addition, evidence that exogenous adenosine reduces the severity of ventricular arrhythmias induced by ischaemia has also been shown in vivo (Fagbemi & Parratt, 1984;Wainwright & Parratt, 1988;).…”

Section: Introductionmentioning

confidence: 99%

“…Endogenous adenosine has been proposed to play the role of 'endogenous myocardial antiarrhythmic substance' (Fagbemi & Parratt, 1984). In addition, evidence that exogenous adenosine reduces the severity of ventricular arrhythmias induced by ischaemia has also been shown in vivo (Fagbemi & Parratt, 1984;Wainwright & Parratt, 1988;). The precise mechanisms underlying this antiarrhythmic effect Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Antiarrhythmic effects of BN‐063, a newly synthesized adenosine A₁ agonist, on myocardial ischaemia in rats

Lee

Chern

Yen

1994

It has been shown that adenosine is able to reduce the severity of arrhythmias induced by myocardial ischaemia. In isolated preparations, the antiarrhythmic effect of adenosine on ventricular myocardium is known to antagonize the catecholamine‐induced stimulation of intracellular cyclic AMP production, an effect mediated via adenosine A1 receptors. The aim of this study was to evaluate the antiarrhythmic effect of BN‐063 (1‐cyclo‐propylisoguanosine), a newly synthesized selective adenosine A1 agonist, on ventricular arrhythmias in rats. Arrhythmias were induced by left coronary artery ligation or by administration of isoprenaline (7 mg kg−1) subcutaneously. Pretreatment with BN‐063 (0.25, 0.5 and 1.0 mg kg−1) 10 min prior to occlusion significantly delayed the onset of ventricular arrhythmias, reduced the total number of ventricular premature contraction (VPC) and ventricular tachycardia (VT), decreased the incidence of VT and ventricular fibrillation (VF) and mortality during the first 30 min following left coronary artery ligation. In contrast, pretreatment with 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX), an adenosine A1 antagonist, was arrhythmogenic during the ischaemic period. The rate‐pressure product, an index for indirect measurement of myocardial oxygen consumption, was also significantly reduced by BN‐063 during ligation time. The incidence of VT, VF and mortality was also significantly reduced when BN‐063 was administered after left coronary artery ligation. BN‐063 converted the VF induced by isoprenaline to normal sinus rhythm and improved the survival rate. It is concluded that, through activation of adenosine A1 receptors, BN‐063 can suppress ventricular arrhythmias induced by myocardial ischaemia and catecholamines. The antiarrhythmic actions of BN‐063 may be mediated by reducing heart rate and antagonizing the stimulatory effects of catecholamine in myocardial ischaemia.