title: Alterations in the properties of beta-adrenergic receptors of myocardial membranes in aging: impairments in agonist-receptor interactions and guanine nucleotide regulation accompany diminished catecholamine-responsiveness of adenylate cyclase.
abstract: The effects of age on cardiac beta-adrenergic receptor linked adenylate cyclase system were studied using homogenates and membrane fractions of ventricular myocardium from young (3-4 months' old) and aged (24-25 months' old) rats. The number of beta-adrenergic receptor sites and the basal adenylate cyclase activities were essentially similar in young and aged hearts. On the other hand, striking age-associated alterations were seen in the properties of beta-receptors and adenylate cyclase in cardiac membranes. (A) The beta-receptor affinities for catecholamine agonists were reduced 10- to 20-fold in aged compared to young heart; the receptor affinity for antagonists were unaffected by age. (B) Guanine nucleotides caused a 9- to 17-fold reduction in beta-receptor affinity for isoproterenol in young heart; this guanine nucleotide-promoted reduction in receptor affinity for agonist was virtually absent in aged heart. (C) Guanine nucleotide-dependent stimulation of adenylate cyclase by isoproterenol was only 20-50% in aged heart compared to three-fold in young heart; beta-receptor-independent activation of the cyclase by guanine nucleotides and NaF were also reduced similarly in aged heart. These results demonstrate a marked age-associated deterioration in the functional integrity of beta-receptor linked adenylate cyclase system in aged heart. Further, the findings identify beta-receptor and guanine nucleotide regulatory protein as the components of the cyclase system affected in aging. It is suggested that the failure to form a "high-affinity" agonist-receptor complex, owing to the age-related decrement in receptor affinity for agonists, and the apparent inability of guanine nucleotide regulatory protein to effect appropriate molecular transitions at the level of both beta-receptor and the catalytic unit (i.e. the cyclase enzyme), contribute to the loss of catecholamine- and guanine nucleotide-responsiveness of adenylate cyclase in aged heart. This age-associated abnormality provides a biochemical basis for the well-recognized decline in adrenergic control of aging myocardium.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000375:Aging; D000818:Animals; D001667:Binding, Competitive; D002395:Catecholamines / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D004082:Dihydroalprenolol / Q000378:metabolism; D006150:Guanine Nucleotides / Q000494:pharmacology; D006321:Heart / Q000254:growth & development*; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D002395:Catecholamines; D006150:Guanine Nucleotides; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; D000262:Adenylyl Cyclases