Effects of ischemia, preconditioning, and adenosine deaminase inhibition on interstitial adenosine levels and infarct size

Abstract

In order to examine the relationship between local adenosine concentrations before, during, and after ischemia and the extent of ischemic myocardial damage, measurements of interstitial fluid (ISF) nucleosides were made using microdialysis probes implanted in the ischemic region of isoflurane anesthetized Micropigs undergoing 60' coronary artery occlusion (CAO) and 3 h of reperfusion (REP). Nucleoside concentrations in the dialysate collected from the microdialysis probes were used as an index of ISF levels. Dialysate nucleoside concentrations (ADO, inosine and hypoxanthine), myocardial infarct size, and myocardial blood flow (MBF) were determined in control animals (n = 6), animals preconditioned with a single 10' cycle of CAO and REP (PC, n = 6), and those treated with the adenosine deaminase inhibitor pentostatin (n = 6, 0.2 mg/Kg i.v. 30' prior to CAO). The brief PC occlusion resulted in a transient but significant increase in dialysate ADO (6.7 +/- 1.8 microM vs. 0.67 +/- 0.1 microM at baseline). Pentostatin administration had no significant effect on either dialysate nucleosides or MBF at baseline. During the 60' CAO, dialysate ADO increased in control animals. In PC animals, however, dialysate ADO during CAO was lower than control. Pretreatment with pentostatin resulted in a six-fold augmentation in dialysate ADO during the 60 min CAO when compared to the control values (110.62 +/- 30.2 microM vs. 16.31 +/- 2.1 microM at 60 min of ischemia). Pentostatin also resulted in a significant reduction in the accumulation of inosine and hypoxanthine, indicating inhibition of adenosine deaminase activity. There were no significant differences in MBF between groups at any time point. Following 3 h REP, infarct size was 35.4 +/- 5.5%, 8.1 +/- 1.5% and 8.3 +/- 1.8% of the region at risk in control, PC, and pentostatin groups, respectively. These data suggest that marked increase in ISF ADO during CAO, may be as effective in reducing INF as a modest increase in ISF ADO prior to prolonged CAO.

Adenosine increases calcium sensitivity via receptor‐independent activation of the p38/MK2 pathway in mesenteric arteries

“…The effects of Ado on vasculature, as demonstrated in this study, may play a role in post-ischaemic situations or after transient hypoxia. Increase in Ado concentrations in the micromolar range has been described in several studies in the kidney and heart (Martin et al 1997, Kloor et al 2002. The results of our study suggest an Ado uptake into cells, when extracellular concentrations are higher than 10 )6 mol L )1 , i.e.…”

“…Increase in Ado concentrations in the micromolar range has been described in several studies in the kidney and heart (Martin et al 1997, Kloor et al 2002. Increase in Ado concentrations in the micromolar range has been described in several studies in the kidney and heart (Martin et al 1997, Kloor et al 2002.…”

Signalling pathways and mechanisms of protection in pre‐ and postconditioning: historical perspective and lessons for the future

“…One hypothesis suggested that preconditioning is protective by increasing tissue adenosine levels through activation of ecto‐5′‐nucleotidase (Kitakaze et al ., ). However, measurements of myocardial adenosine levels revealed that tissue adenosine concentration actually falls in IPC hearts (Goto et al ., ; Martin et al ., ). Our studies have indicated that the initial step of the mediator phase is activation of adenosine A 2B receptors (Philipp et al ., ).…”

Role of A2BAdenosine Receptors in Regulation of Paracrine Functions of Stem Cell Antigen 1-Positive Cardiac Stromal Cells

“…Concentrations of extracellular adenosine were demonstrated to increase in ischemic hearts, where it becomes a part of the pathological environment (Martin et al, 1997;Willems et al, 2006). Adenosine exerts its actions via cell surface receptors of the G protein-coupled receptor family, namely A 1 , A 2A , A 2B , and A 3 (Fredholm et al, 2001).…”