Impact of aging on adenosine levels, A(1)/A(2) responses, arrhythmogenesis, and energy metabolism in rat heart

Adenosine formation, energy metabolism, A(1) and A(2) responses, and arrhythmogenesis were examined in hearts from young adult (4-6 mo) and aged rats (18-20 mo). Aging reduced heart rate from 308 +/- 9 to 252 +/- 13 beats/min and myocardial O-2 consumption (MVo(2)) from 127 +/- 5 to 103 +/- 4 mu l O-2 . min(-1). g(-1) and increased atrioventricular conduction time from 47 +/- 4 to 61 +/- 8 ms. Differences in intrinsic rate were reduced by Al antagonism with 10 mu M 8-cyclopentyl-1,3-dimethylxanthine. Adenosine efflux and cardiac microdialysate [adenosine] in isovolumically working hearts increased twofold with aging, despite reduced MVo(2). Enhanced [adenosine] was not due to altered uptake and catabolism but was associated with twofold higher cytosolic adenosine 5'-monophosphate concentration despite comparable energy state (free energy of ATP hydrolysis = -62.25 +/- 0.38 and -61.78 +/- 0.46 kJ/mol in young adult and aged hearts, respectively). Bradycardia (presumably A(1) mediated) was 10-fold more sensitive in aged [-log dose required to produce 50% ectopy (PEC(50)) = 4.9 +/- 0.1] than in young adult hearts (PEC(50) = 3.9 +/- 0.1) Adenosine also became potently arrhythmogenic with aging (-log dose required to produce 20% ectopy = 3.6 +/- 0.3 in young adult and 5.3 +/- 0.2 and aged hearts). Alternatively, vasodilation (presumably A(2) mediated) was less sensitive with aging (PEC(50) = 6.1 +/- 0.1 in young adult and 4.5 +/- 0.1 in aged hearts; PEC(50) = 3.8 +/- 0.1 in young adult and 3.1 +/- 0.1 in aged aortic rings). The data indicate that aging 2) enhances interstitial [adenosine], probably via elevated myocardial adenosine 5'-monophosphate concentration, 2) enhances A(1) sensitivity and arrhythmogenesis, and 3) reduces adenosine A(2) sensitivity. These changes contribute to altered cardiovascular function in aged hearts.