Aging-related changes in myocardial purine metabolism and ischemic tolerance

Impaired tolerance to ischemia-reperfusion in older hearts may stem in part from alterations in purine catabolism, impacting on maintenance of energy state and protective signaling via extracellular adenosine. We characterized effects of aging on normoxic and post-ischemic purine metabolism in hearts from young (2-4 month), middle-aged (12 month), old (18 month), and senescent (24-28 month) C57/Bl6 mice. Normoxic function was similar in all age groups while normoxic purine efflux increased gradually with age. This was the result of enhanced efflux of hypoxanthine, xanthine and uric acid, with extracellular accumulation of adenosine and inosine remaining unchanged. While total purine washout during 60 min reperfusion following 20 min global ischemia was unaltered by aging (1057+/-109 nmoles/g in young vs. 1221+/-127 nmoles/g in senescent hearts), selective changes in purine catabolism were evident. Accumulation of adenosine and inosine were reduced by 50 and 80%, respectively, matched by 400 and 300% elevations in hypoxanthine and xanthine accumulation, respectively. Uric acid remained unchanged. Thus, while adenosine and inosine represented 15+/-2 and 47+/-3% of total purine efflux in young hearts, these values decreased to only 6+/-1 and 9+/-2% in senescent hearts. Efflux of IMP also increased 500% with aging whereas 5'-AMP was unaltered. These changes were associated with a substantial fall in ischemic tolerance, with left ventricular developed pressure recovering to 46+/-3% in young hearts vs. only 24+/-6, 16+/-4, and 19+/-4% in middle-age, old and senescent hearts, respectively. Our data collectively support a pronounced shift in purine catabolism, with reduced accumulation of salvageable and cardioprotective adenosine, and enhanced accumulation of poorly salvaged (and potentially injurious) hypoxanthine and xanthine. Mechanisms underlying this shift have yet to be determined. However, this may play a role in the marked decline in myocardial tolerance to ischemia with aging and senescence.