Adenosine attenuation of isoproterenol-stimulated adenylyl cyclase activity is enhanced with aging in the adult heart.
Interstitial levels and release of adenosine have been shown to be greater for aged adult hearts compared to young adult hearts. Furthermore, blockade of A1 adenosine receptors in the aged adult heart prevents the reduced contractile and metabolic response to isoproterenol. The aim of this study was to determine whether there is an enhanced antiadrenergic effect of adenosine in the aged adult heart. Ventricular membranes from young and aged adult hearts were incubated in the presence of isoproterenol (ISO) and phenylisopropyladenosine (PIA) either alone or in combination. Basal and ISO-enhanced adenylyl cyclase activity were significantly reduced in the membranes from aged rats. PIA alone, at 0.1 nM to 100 microM, had no direct effect on basal adenylyl cyclase activity in membranes from either group. In the presence of either 100 nM or 1 microM ISO, 100 microM PIA significantly attenuated ISO-enhanced adenylyl cyclase activity to a greater extent in the aged adult heart membranes (78 or 48% for the aged vs. 37 or 25% for the young). Moreover, in the presence of 100 nM ISO the IC50 for the PIA concentration response curve was shifted to the left for the aged ventricular membranes as compared to the membranes from young adults (1.62 x 10(-7) M vs 1.5 x 10(-6) M, aged vs young, respectively). The enhanced inhibition of adenylyl cyclase is associated with an increase in adenosine A1 receptor density (23.7 +/- 3.5 vs 14.7 +/- 1.7 fmol/mg, aged vs young) and Kd (6.1 +/- 1.7 vs 2.2 +/- 0.5 nM, aged vs young) in the aged adult heart membranes as determined by [3H]DPCPX binding. These results suggest that the reduced response to catecholamines in the aged adult heart may be due, at least in part, to an enhanced expression of the antiadrenergic effect of adenosine on beta-adrenergic receptor mediated activation of adenylyl cyclase.
Romano
F D
FD
Department of Physiology, Midwestern University, Downers Grove, IL 60515, USA.
Dobson
J G
JG
D000241:Adenosine / Q000502:physiology*; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D004347:Drug Interactions; D006321:Heart / Q000187:drug effects* / Q000254:growth & development*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure; D010660:Phenylisopropyladenosine / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013268:Stimulation, Chemical; D014316:Tritium; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D000318:Adrenergic beta-Agonists; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D014316:Tritium; D010660:Phenylisopropyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000262:Adenylyl Cyclases; D000241:Adenosine; D007545:Isoproterenol