Age-related changes in A(1)-adenosine receptor-mediated bradycardia.
The impact of age on functional sensitivity to A(1)-adenosine receptor activation was studied in Langendorff-perfused hearts from young (1-2 mo) and old (12-18 mo) male Wistar rats. Adenosine mediated bradycardia in young and old hearts, with sensitivity enhanced approximately 10-fold in old [negative logarithm of EC(50) (pEC(50)) = 4.56 +/- 0.11] versus young hearts (pEC(50) = 3.70 +/- 0. 09). Alternatively, the nonmetabolized A(1) agonists N(6)-cyclohexyladenosine 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 sensitivity. In support of this suggestion, [(3)H]-adenosine uptake was approximately twofold greater in young than in old hearts (from 3-100 microM adenosine). However, although inhibition of adenosine deaminase and adenosine transport with 10 microM erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride and 10 microM S-(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 indicate that 1) age increases functional A(1) receptor sensitivity to adenosine without altering the sensitivity of the A(1) receptor itself, and 2) age impairs adenosine transport and/or catabolism, but this does not explain differing functional sensitivity to adenosine. This increased functional sensitivity to adenosine may have physiological significance in the older heart.
Hinschen
A K
AK
Rotary Center for Cardiovascular Research, School of Health Science, Griffith University Gold Coast Campus, Southport QLD 4217, Australia.
Rose'Meyer
R B
RB
Headrick
J P
JP
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D058892:Adenosine Deaminase Inhibitors; D000375:Aging; D000818:Animals; D001919:Bradycardia / Q000209:etiology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D014316:Tritium
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D018047:Receptors, Purinergic P1; D014316:Tritium; C047235:N-(1-methyl-2-phenylethyl)adenosine; C010192:9-(2-hydroxy-3-nonyl)adenine; D000225:Adenine; D000241:Adenosine