Age-related changes in A(1)-adenosine receptor-mediated bradycardia

The impact of age on functional sensitivity to A(1)-adenosine receptor acti vation was studied in Langendorff-perfused hearts from young (1-2 mo) and o ld (12-18 mo) male Wistar rats. Adenosine mediated bradycardia in young and old hearts, with sensitivity enhanced similar to 10-fold in old [negative logarithm of EC50 (pEC(50)) = 4.56 +/- 0.11] versus young hearts (pEC(50) = 3.70 +/- 0.09). Alternatively, the nonmetabolized A(1) agonists N-6-cycloh exyladenosine and (R)-N-6-phenylisopropyladenosine were equipotent in young (pEC(50) = 7.43 +/- 0.12 and 6.61 +/- 0.19, respectively) and old hearts ( pEC(50) = 7.07 +/- 0.10 and 6.80 +/- 0.11, respectively), suggesting a role for uptake and/or catabolism in age-related changes in adenosine sensitivi ty. In support of this suggestion, [H-3]-adenosine uptake was approximately twofold greater in young than in old hearts (from 3-100 mu M adenosine). H owever, although inhibition of adenosine deaminase and adenosine transport with 10 mu M erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride and 10 mu M 5-(4-nitrobenzyl)-6-thioinosine increased adenosine sensitivity three- to fourfold, it failed to abolish the sensitivity difference in old (pEC(50) = 4.95 +/- 0.08) versus young (pEC(50) = 4.29 +/- 0.13) hearts. Data indicat e that 1) age increases functional A(1) receptor sensitivity to adenosine w ithout altering the sensitivity of the A(1) receptor itself, and 2) age imp airs adenosine transport and/or catabolism, but this does not explain diffe ring functional sensitivity to adenosine. This increased functional sensiti vity to adenosine may have physiological significance in the older heart.