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Preliminary investigation into possible nongenomic ventricular rhythm effects of aldosterone in rat hearts in vitro Antagonists of aldosterone ( AL) such as spironolactone (SP) reduce mortality following acute myocardial infarction (AMI) by mechanisms that are not clear (Pitt et al., 1999; Struthers 2005). If AL contributes to ventricular fibrillation (VF) during the minutes after the onset of AMI (acute ischaemia, when the risk of VF is greatest), then the rapidity of onset of VF (Curtis 1998) precludes the possibility of genomic receptor involvement. AL is also known to evoke rapid (nongenomic) actions in a variety of experimental settings (Connell & Davies 2005). We tested whether AL and SP have nongenomic actions on ischaemia- and reperfusion-induced VF in an in vitro model. Male Wistar rats (230-300g) were anaesthetized with 60 mg kg-1 pentobarbitone (i.p.) plus 250 iu heparin. Excised hearts were perfused (Langendorff mode) with Krebs’ modified to contain 3 meql-1 K+ . The left main coronary artery was ligated 10 min after switch to test solution. Reperfusion for 10 min was begun 30 min later. Test solutions were control (vehicle: 0.05% ethanol in Krebs’), AL, SP, or AL+SP, with solutions assigned by randomization (n=12/group). AL concentration (10 nM) was based on Barbarto et al., (2004) in which 10 nM caused cardiac nongenomic actions. For SP we chose a concentration (2 μM) well in excess of that tested previously against reperfusion arrhythmias (Chai et al., 2005). Hearts not in sinus rhythm at 30 min of ischaemia (a maximum of 2 per group of 12) were excluded from reperfusion VF analysis. Standard ECG analysis, involved zone (IZ) verification and statistical methods (ANOVA, Dunnett’s test or Mainland’s contingency tables) were used (Farkas et al., 1999). There were no differences between groups in terms of ischaemia- or reperfusion-induced VF incidence (range of values, 83-100%), onset of first ischaemia-induced arrhythmia (range 2.4±0.2 to 2.5±0.2 log10 sec), IZ (range 39±2 to 46±2 % ventricular wt), or other variables (values at 1 min before ligation are shown): PR interval (41±1 to 45±2 msec), QT interval at 90% repolarization (53±2 to 56±2 msec), heart rate (266±8 to 281±5 beats min-1 ) and coronary flow (10.0±0.3 to10.4±0.6 ml min-1 g-1 ). Our findings are not in agreement with a study in which a lower concentration of SP (100 nM) than that used by ourselves reduced the incidence of reperfusion VF in perfused rat hearts (Chai et al., 2005). Unusually flat concentration-response relationships have been reported recently for some of AL’s nongenomic molecular actions (Gómez et al., 2005). Additionally, SP appears to evoke unexpected partial mimicry of some of AL’s nongenomic actions (Barbarto et al., 2004). We conclude that a full concentration response study (varying both SP and AL) will be required to determine the full extent of the nongenomic effects of AL on VF during AMI.
Pitt, B et al.,(1999) N Engl J Med 341:709-717. |
