Ischemic Preconditioning in Pigs: A Graded Phenomenon

Abstract

Background —A threshold concept for ischemic preconditioning (IPc) has been proposed. It is unclear, however, whether IPc, above a certain threshold, is an all-or-nothing or a graded phenomenon. Methods and Results —In 71 enflurane-anesthetized swine, severe left anterior descending coronary artery hypoperfusion for 90 minutes followed by 2 hours of reperfusion resulted in an infarct size (IS, by triphenyltetrazolium chloride) of 16.7±3.4% (SEM) of the area at risk. IPc by 2 minutes of low-flow ischemia and 15 minutes of reperfusion before the 90-minute target ischemia did not reduce IS (21.9±7.0%). IS was decreased to 9.0±2.6% ( P <0.05) by 3 minutes of IPc and reduced further to 1.9±0.9% ( P <0.05) by 10 minutes of IPc. The interstitial adenosine concentration (microdialysis, high-performance liquid chromatography) was unchanged with 2 and 3 minutes of IPc but increased with 10 minutes of IPc (by 573±144%). The interstitial bradykinin concentration (microdialysis, radioimmunoassay) remained unchanged with 2 minutes of IPc but increased to a similar extent with 3 minutes (by 198±32%) and 10 minutes (by 224±30%) of IPc. The IS reduction by 3 minutes of IPc was abolished by blockade of the bradykinin B 2 receptor with intracoronary HOE 140 (16.6±4.3%) but not with intracoronary infusion of adenosine deaminase (8.4±2.5%, P <0.05). HOE 140, however, did not affect the IS reduction (3.5±1.1%, P <0.05) by 10 minutes of IPc. Combined infusion of HOE 140 and adenosine deaminase abolished the IS reduction by 10 minutes of IPc (15.4±6.7%). Conclusions —IS reduction by IPc is a graded phenomenon. Whereas bradykinin is essential during preconditioning ischemia of shorter duration, adenosine is more important during preconditioning ischemia of longer duration.