Delayed protection against ischaemia‐induced ventricular arrhythmias and infarct size limitation by the prior administration of Escherichia coli endotoxin

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Abstract
1 Bacterial endotoxin (lipopolysaccharide derived from Escherichia coli) was injected intraperitoneally in conscious rats in doses ranging from 0.5 to 2.5 mg kg−1. At various times afterwards the animals were anaesthetized and subjected to a 30 min period of left coronary artery occlusion. 2 Under these conditions the severity of ventricular arrhythmias was markedly suppressed, in comparison with saline-injected controls, but this was particularly marked with the higher doses (1.5 and 2.5 mg kg−1); the number of ventricular premature beats was reduced from 1687 ± 227 over the 0.5 h coronary artery occlusion period to 190 ± 46 in those rats administered 2.5 mg kg−1 endotoxin 8 h previously (P < 0.05). The duration of ventricular tachycardia was also significantly reduced (138 ± 26 s to 8.9 ± 4.2 s; P < 0.01) and there was a reduction in the incidence of ventricular fibrillation (from 56% to 10%). 3 The time course of this protection was studied following the administration of a single dose of 2.5 mg kg−1 of endotoxin by anaesthetizing rats 4, 8 or 24 h later. Protection was apparent at each time but was particularly marked at 8 h. 4 No rat given the highest dose of endotoxin (32 in all) died as a result of ventricular fibrillation, or from any other cause, during an occlusion, in contrast to a 26% mortality in the controls (P < 0.01). 5 Infarct size, measured following a 30 min period of coronary artery occlusion followed by a 3 h reperfusion period, was reduced both 8 and 24 h after the administration of 2.5 mg kg−1 endotoxin (reductions of 24.3 and 23.1% respectively; P < 0.05). Endotoxin had no significant effect on the area at risk. 6 The beneficial effects of endotoxin on infarct size and on ventricular arrhythmias were markedly attenuated by the prior administration of dexamethasone, 3 mg kg−1 given 1 h prior to endotoxin administration. Dexamethasone itself reduced infarct size (P < 0.05) but had no direct effect on arrhythmia severity following coronary artery occlusion. 7 The mechanisms of this ‘cross-tolerance’ induced by bacterial endotoxin against ischaemia-reperfusion injury remain to be elucidated but the most likely mechanisms appear to be the induction of protective enzymes or proteins (e.g. nitric oxide synthase, cyclo-oxygenase (COX) 2) probably mediated by cytokine release.