BackgroundIn this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined.MethodsIon currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 μg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts.ResultsORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 μM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 μM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts.ConclusionsThe present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.
The intravenous administration of naloxone 15 min before acute coronary artery ligation in both anaesthetized and conscious male rats markedly reduced the incidence and severity of the ventricular arrhythmias that occur within 30 min of the onset of myocardial ischaemia. The incidence of ventricular fibrillation was especially reduced and, in conscious rats, the survival 16 h after ligation was increased from 27% (in the controls) to 58 and 73% after 2 and 4 mg/kg naloxone respectively. One possible explanation of these results implies a detrimental effect of released endorphin in the early stages of myocardial ischaemia.
Background and purpose: 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 a-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in a 1 -adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or a-chloralose were infused simultaneously with the a 1 -adrenoceptor agonist phenylephrine (15 mg kg À1 min À1 , i.v.) and dofetilide (0.04 mg kg À1 min À1 , i.v.). The electrocardiographic QT interval, the T peak -T end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilideinduced torsades de pointes (TdP) as compared with the results with a-chloralose (40% (P ¼ 0.011) and 70% (P ¼ 0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with a-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the a-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared. (2008) 153, 75-89; doi:10.1038/sj.bjp.0707536; published online 29 October 2007 Keywords: intravenous anaesthesia; pentobarbital; propofol; a-chloralose; torsades de pointes; pro-arrhythmia; dofetilide; a 1 -adrenoceptor stimulation; phenylephrine; rabbit Abbreviations: ECG, electrocardiogram; PNN8, percentage of successive QT intervals that differ by more than 8 ms; RMSSD, root mean square of the successive differences in the RR or QT intervals; SAP MF, spectral power of the systolic arterial pressure in the mid-frequency range British Journal of Pharmacology
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