DELAYED PROTECTION AGAINST ISCHEMIA-INDUCED VENTRICULAR ARRHYTHMIAS AND INFARCT SIZE LIMITATION BY THE PRIOR ADMINISTRATION OF ESCHERICHIA-COLI ENDOTOXIN

1 Bacterial endotoxin (lipopolysaccharide derived from Escherichia col i) was injected intraperitoneally in conscious rats in doses ranging f rom 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 arter y occlusion. 2 Under these conditions the severity of ventricular arrh ythmias was markedly suppressed, in comparison with saline-injected co ntrols, but this was particularly marked with the higher doses (1.5 an d 2.5 mg kg(-1)); the number of ventricular premature beats was reduce d from 1687+/-227 over the 0.5 h coronary artery occlusion period to 1 90+/-46 in those rats administered 2.5 mg kg(-1) endotoxin 8 h previou sly (P <0.05). The duration of ventricular tachycardia was also signif icantly reduced (138+/-26 s to 8.9+/-4.2 s; P <0.01) and there was a r eduction in the incidence of ventricular fibrillation (from 56% to 10% ). 3 The time course of this protection was studied following the admi nistration of a single dose of 2.5 mg kg(-1) of endotoxin by anaesthet izing rats 4, 8 or 24 h later. Protection was apparent at each time bu t was particularly marked at 8 h. 4 No rat given the highest dose of e ndotoxin (32 in all) died as a result of ventricular fibrillation, or from any other cause, during an occlusion, in contrast to a 26% mortal ity 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 m g 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 bene ficial effects of endotoxin infarct size and on ventricular arrhythmia s were markedly attenuated by the prior administration of dexamethason e, 3 mg kg(-1) given 1 h prior to endotoxin administration. Dexamethas one itself reduced infarct size (P <0.05) but had no direct effect on arrhythmia severity following coronary artery occlusion. 7 The mechani sms of this 'cross-tolerance' induced by bacterial endotoxin against i schaemia-reperfusion injury remain to be elucidated but the most likel y mechanisms appear to be the induction of protective enzymes or prote ins (e.g. nitric oxide synthase, cyclo-oxygenase (COX) 2) probably med iated by cytokine release.