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Age-related changes in adenosine-mediated relaxation of coronary and aortic smooth muscle. Am J Physiol Heart Circ Physiol 280: H2380-H2389, 2001.--We tested whether adenosine mediates nitric oxide (NO)-dependent and NO-independent dilation in coronary and aortic smooth muscle and whether age selectively impairs NO-dependent adenosine relaxation. Responses to adenosine and the relatively nonselective analog 5'-N-ethylcarboxamidoadenosine (NECA) were studied in coronary vessels and aortas from immature (1-2 mo), mature (3-4 mo), and moderately aged (12-18 mo) Wistar and Sprague-Dawley rats. Adenosine and NECA induced biphasic concentration-dependent coronary vasodilation, with data supporting high-sensitivity ([pEC.sub.50] = 5.2-5.8) and low-sensitivity ([pEC.sub.50] = 2.3-2.4) adenosine sites. Although sensitivity to adenosine and NECA was unaltered by age, response magnitude declined significantly. Treatment with 50 [micro]M [N.sup.G]-nitro-L-arginine methyl ester (L-NAME) markedly inhibited the high-sensitivity site, although response magnitude still declined with age. Aortic sensitivity to adenosine declined with age ([pEC.sub.50] = 4.7 [+ or -] 0.2, 3.5 [+ or -] 0.2, and 2.9 [+ or -] 0.1 in immature, mature, and moderately aged aortas, respectively), and the adenosine receptor transduction maximum also decreased (16.1 [+ or -] 0.8, 12.9 [+ or -] 0.7, and 9.6 [+ or -] 0.7 mN/[mm.sup.2] in immature, mature, and moderately aged aortas, respectively). L-NAME decreased aortic sensitivity to adenosine in immature and mature tissues but was ineffective in the moderately aged aorta. Data collectively indicate that 1) adenosine mediates NO-dependent and NO-independent coronary and aortic relaxation, 2) maturation and aging reduce NO-independent and NO-dependent adenosine responses, and 3) the age-related decline in aortic response also involves a reduction in the adenosine receptor transduction maximum. adenosine receptors; aging; coronary vasculature; endothelium; maturation; nitric oxide; rat heart

Hinschen, Andrea K., Roselyn B. Rose'Meyer, and John P. Headrick. Age-related changes in [A.sub.1]-adenosine receptor-mediated bradycardia. Am. J. Physiol. Heart Circ. Physiol. 278: H789-H795, 2000.--The impact of age on functional sensitivity to [A.sub.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 ~10-fold in old [negative logarithm of [EC.sub.50] (p[EC.sub.50]) = 4.56 [+ or -] 0.11] versus young hearts (p[EC.sub.50] = 3.70 [+ or -] 0.09). Alternatively, the nonmetabolized [A.sub.1] agonists [N.sup.6] -cyclohexyladenosine and (R)-[N.sup.6]-phenylisopropyladenosine were equipotent in young (p[EC.sub.50] = 7.43 [+ or -] 0.12 and 6.61 [+ or -] 0.19, respectively) and old hearts (p[EC.sub.50] = 7.07 [+ or -] 0.10 and 6.80 [+ or -] 0.11, respectively), suggesting a role for uptake and/or catabolism in age-related changes in adenosine sensitivity. In support of this suggestion, [[sup.3]H]-adenosine uptake was approximately twofold greater in young than in old hearts (from 3-100 [micro]M adenosine). However, although inhibition of adenosine deaminase and adenosine transport with 10 [micro]M erythro-9 -(2-hydroxy-3-nonyl)adenine hydrochloride and 10 [micro]M S-(4-nitrobenzyl)-6-thioinosine increased adenosine sensitivity three- to fourfold, it failed to abolish the sensitivity difference in old (p[EC.sub.50] = 4.95 [+ or -] 0.08) versus young (p[EC.sub.50] = 4.29 = [+ or -] 0.13) hearts. Data indicate that 1) age increases functional [A.sub.1] receptor sensitivity to adenosine without altering the sensitivity of the [A.sub.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. metabolism; transport