title: A modified model of global ischaemia: application to the study of syncytial mechanisms of arrhythmogenesis.
abstract: OBJECTIVE
  The aim was to develop a simple modified global ischaemia preparation to study the relation between ischaemic zone size and the incidence of ischaemia induced and reperfusion induced arrhythmias, to test the hypothesis that arrhythmias are initiated by flow of injury current between the ischaemic zone and the uninvolved myocardium. The new model was used to examine whether injury current suppression is involved in the mechanism of action of a new antiarrhythmic intervention, substitution of chloride anion by nitrate.
  
  
  METHODS
  Isolated perfused (Langendorff mode) rat hearts (n = 12 per group) were subjected to 30 min global or regional ischaemia. Ventricular arrhythmia incidence during ischaemia and during reperfusion were related to the size of the involved region. The modified model of global ischaemia employed right intra-atrial superfusion to maintain normal sinus rate and 1:1 atrioventricular (AV) conduction.
  
  
  RESULTS
  Sham ligation, low left coronary ligation, high left coronary ligation, and global ischaemia produced, as a percentage of total ventricular weight, 0%, 21.0(SEM 0.8)%, 47.0(1.0)%, and 100% regions of ischaemia (occluded zones). Heart rates were similar in each group and AV block did not occur. The incidences of ischaemia induced ventricular fibrillation (VF) were 0, 17, 75, and 17% with increasing occluded zone sizes. Incidences of reperfusion induced VF were 0, 8, 92, and 92% respectively. The antiarrhythmic action of substitution of extracellular chloride by nitrate, previously shown using models of regional ischaemia, was confirmed in the modified global ischaemia model.
  
  
  CONCLUSIONS
  These findings strongly support the theory that current of injury between ischaemia and adjacent non-ischaemic zones is necessary for initiation of ischaemia induced VF, since susceptibility was maximal when ischaemic and uninvolved regions were equivalent in size (and the scope for injury current was maximal) whereas susceptibility was negligible when scope was minimal. In contrast, reperfusion induced VF appears to depend only on the presence and amount of reperfused tissue, indicating that flow of injury current between involved and uninvolved tissue is unnecessary for its initiation. Discrimination of the mechanism of action of antiarrhythmic interventions may be possible since drugs effective solely via amelioration of flow of injury current (or incrementation of collateral flow) will not influence arrhythmias in this model. Modification of injury current and collateral flow do not appear to contribute to the antiarrhythmic action of substitution of extracellular chloride by nitrate.
authors.affiliation: Cardiac Surgical Research Department, Harefield Hospital, Middlesex, United Kingdom.
authors.forename: P D
authors.initials: PD
authors.lastname: Ridley
authors.forename: M H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: M J
authors.initials: MJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003327:Coronary Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D015425:Myocardial Reperfusion / Q000009:adverse effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D009566:Nitrates