P H Silva1, D Dillon, D G Van Wylen. 1. Department of Physiology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, USA.
Abstract
OBJECTIVE: The objectives were to determine the effects of the adenosine deaminase inhibitor pentostatin (deoxycoformycin) on interstitial fluid (ISF) adenosine before, during, and after myocardial ischaemia and to ascertain whether augmented endogenous ISF adenosine reduces myocardial infarction. METHODS: Untreated anaesthetised dogs (n = 11) were compared to dogs treated with intravenous pentostatin 30 min before ischaemia (0.2 mg.kg-1; n = 11). The changes in ISF adenosine, adenosine metabolites, and lactate were assessed by cardiac microdialysis, using dialysate concentrations as indices of ISF levels. Both groups were exposed to 60 min of regional myocardial ischaemia followed by 3 h of reperfusion. RESULTS: Although ISF adenosine increased during ischaemia in untreated animals, inosine and hypoxanthine were the predominant purine metabolites which accumulated in the ISF. Pentostatin increased dialysate adenosine 3.5-fold before ischaemia, resulted in a sustained and pronounced augmentation of adenosine during ischaemia, and maintained the raised ISF adenosine during early reperfusion. However, the augmentation of ISF adenosine was not associated with a reduction in infarct size [untreated = 33.3(SEM 4.8)% of the area at risk; pentostatin treated = 35.6(4.6)% of the area at risk], nor did pentostatin alter the ischaemia induced increase in ISF lactate. Plasma adenosine, as measured by a microdialysis probe in the femoral artery, increased in pentostatin treated animals upon reperfusion, leading to systemic hypotension, increased blood flow in the non-ischaemic region, and an attenuated reactive hyperaemia in the ischaemic region. CONCLUSIONS: Although inhibition of adenosine deaminase effectively enhances ISF adenosine before and during ischaemia, the increase before ischaemia does not "precondition" the myocardium, nor does the augmentation of adenosine during and after ischaemia attenuate necrosis in this model of ischaemia. Therefore, the enhancement of ISF adenosine to the extent provided by adenosine deaminase inhibition alone is not sufficient to protect the heart in the way seen with ischaemic preconditioning.
OBJECTIVE: The objectives were to determine the effects of the adenosine deaminase inhibitor pentostatin (deoxycoformycin) on interstitial fluid (ISF) adenosine before, during, and after myocardial ischaemia and to ascertain whether augmented endogenous ISF adenosine reduces myocardial infarction. METHODS: Untreated anaesthetised dogs (n = 11) were compared to dogs treated with intravenous pentostatin 30 min before ischaemia (0.2 mg.kg-1; n = 11). The changes in ISF adenosine, adenosine metabolites, and lactate were assessed by cardiac microdialysis, using dialysate concentrations as indices of ISF levels. Both groups were exposed to 60 min of regional myocardial ischaemia followed by 3 h of reperfusion. RESULTS: Although ISF adenosine increased during ischaemia in untreated animals, inosine and hypoxanthine were the predominant purine metabolites which accumulated in the ISF. Pentostatin increased dialysate adenosine 3.5-fold before ischaemia, resulted in a sustained and pronounced augmentation of adenosine during ischaemia, and maintained the raised ISF adenosine during early reperfusion. However, the augmentation of ISF adenosine was not associated with a reduction in infarct size [untreated = 33.3(SEM 4.8)% of the area at risk; pentostatin treated = 35.6(4.6)% of the area at risk], nor did pentostatin alter the ischaemia induced increase in ISF lactate. Plasma adenosine, as measured by a microdialysis probe in the femoral artery, increased in pentostatin treated animals upon reperfusion, leading to systemic hypotension, increased blood flow in the non-ischaemic region, and an attenuated reactive hyperaemia in the ischaemic region. CONCLUSIONS: Although inhibition of adenosine deaminase effectively enhances ISF adenosine before and during ischaemia, the increase before ischaemia does not "precondition" the myocardium, nor does the augmentation of adenosine during and after ischaemia attenuate necrosis in this model of ischaemia. Therefore, the enhancement of ISF adenosine to the extent provided by adenosine deaminase inhibition alone is not sufficient to protect the heart in the way seen with ischaemic preconditioning.