The effect of age on adenosine A1 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 cardioprotective action of adenosine is mediated through the adenosine A1 receptor and inhibition of adenylyl cyclase. In order to investigate the effect of age on adenosine signal transduction in the heart, the effect of specific adenosine A 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 basal cyclase activity with age. Consistent with observations from other laboratories, isoproterenol- and forskolin-stimulated cyclase activity decreased with age. In addition, there was an age-related decline in the capacity of adenosine to inhibit stimulated adenylyl cyclase. The specific A1 adenosine receptor agonists, N6-cyclopentyladenosine (CPA) and N6-p-sulfophenuladenosine (SPA) inhibited isoproterenol- and forskolin-stimulated adenylyl cyclase activity in cardiac membranes from 1-month and 6-month-old rats; however, CPA and SPA did not inhibit adenylyl cyclase in membranes from 24-month-old rats. These data indicate that in addition to the age-related decline in beta-adrenergic receptor function with age, there is also a decrease in adenosine A; receptor-mediated responses. In contrast, carbachol acting through muscarinic receptors, caused the same inhibition of adenylyl cyclase at all ages. Therefore, the age-related decline in inhibitory signal transduction is specific to the adenosine A1 receptor. The age-related defect is probably at the level of the adenosine/receptor interaction and/or the receptor/guanine nucleotide binding protein interaction.
Gao
E
E
Department of Pharmacology, MCP, Allegheny University of Health Sciences, Philadelphia, PA 19129, USA.
Snyder
D L
DL
Johnson
M D
MD
Friedman
E
E
Roberts
J
J
Horwitz
J
J
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D011916:Rats, Inbred F344; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D013451:Sulfonic Acids; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D000318:Adrenergic beta-Agonists; D002317:Cardiovascular Agents; D018721:Muscarinic Agonists; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D013451:Sulfonic Acids; D005576:Colforsin; C048599:N(6)-cyclopentyladenosine; C031433:8-(4-sulfophenyl)theophylline; D002217:Carbachol; D013806:Theophylline; D000262:Adenylyl Cyclases; D000241:Adenosine; D007545:Isoproterenol