THE EFFECT OF AGE ON ADENOSINE A(1) RECEPTOR FUNCTION IN THE RAT-HEART

Adenosine is an important regulatory metabolite in the heart where it has a cardioprotective function. In the ventricle, the cardioprotectiv e action of adenosine is mediated through the adenosine A(1) receptor and inhibition of adenylyl cyclase. In order to investigate the effect of age on adenosine signal transduction in the heart, the effect of s pecific adenosine A(1) receptor agonists on adenylyl cyclase activity was measured in crude cardiac ventricular membranes isolated from 1-, 6- and 24-month-old Fisher 344 rats. There were no differences in basa l cyclase activity with age. Consistent with observations from other l aboratories, isoproterenol- and forskolin-stimulated cyclase activity decreased with age. In addition, there was an age-related decline in t he capacity of adenosine to inhibit stimulated adenylyl cyclase. The s pecific A(1) adenosine receptor agonists, N-6-cyclopentyladenosine (CP A) and N-6-p-sulfophenuladenosine (SPA) inhibited isoproterenol- and f orskolin-stimulated adenylyl cyclase activity in cardiac membranes fro m 1-month and 6-month-old rats; however, CPA and SPA did not inhibit a denylyl cyclase in membranes from 24-month-old rats. These data indica te that in addition to the age-related decline in beta-adrenergic rece ptor function with age, there is also a decrease in adenosine A(1) rec eptor-mediated responses. In contrast, carbachol acting through muscar inic receptors, caused the same inhibition of adenylyl cyclase at all ages. Therefore, the age-related decline in inhibitory signal transduc tion is specific to the adenosine A(1) receptor. The age-related defec t is probably at the level of the adenosine/receptor interaction and/o r the receptor/guanine nucleotide binding protein interaction. (C) 199 7 Academic Press Limited.