Impact of aging on adenosine levels, A1/A2 responses, arrhythmogenesis, and energy metabolism in rat heart.
Adenosine formation, energy metabolism, A1 and A2 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 O2 consumption (MVO2) from 127 +/- 5 to 103 +/- 4 microliters O2.min-1.g-1 and increased atrioventricular conduction time from 47 +/- 4 to 61 +/- 8 ms. Differences in intrinsic rate were reduced by A1 antagonism with 10 microM 8-cyclopentyl-1,3-dimethylxanthine. Adenosine efflux and cardiac microdialysate [adenosine] in isovolumically working hearts increased twofold with aging, despite reduced MVO2. 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 A1 mediated) was 10-fold more sensitive in aged [-log dose required to produce 50% ectopy (pEC50) = 4.9 +/- 0.1] than in young adult hearts (pEC50 = 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 A2 mediated) was less sensitive with aging (pEC50 = 6.1 +/- 0.1 in young adult and 4.5 +/- 0.1 in aged hearts; pEC50 = 3.8 +/- 0.1 in young adult and 3.1 +/- 0.1 in aged aortic rings). The data indicate that aging 1) enhances interstitial [adenosine], probably via elevated myocardial adenosine 5'-monophosphate concentration, 2) enhances A1 sensitivity and arrhythmogenesis, and 3) reduces adenosine A2 sensitivity. These changes contribute to altered cardiovascular function in aged hearts.
Headrick
J P
JP
Department of Molecular Sciences, James Cook University of North Queensland, Townsville, Australia.
D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D000375:Aging; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*
D002317:Cardiovascular Agents; D011942:Receptors, Adrenergic, alpha; D000241:Adenosine