AGE-RELATED ALTERATIONS IN ADENYLYL CYCLASE SYSTEM OF RAT HEARTS

Cardiac membranes from 26-, 52- and 104-week-old Wister rats were used to investigate the age-related alterations in the beta-adrenergic receptor-adenylyl cyclase system. The densities and affinities of beta-adrenoceptors did not change with aging. There were no significant changes in the total amount of stimulatory G-protein (G(s)), and in G(s) activity measured in a reconstitution assay using human platelet membranes. The major isoform of G(s)alpha, however, changed from a 45,000 to 52,000 dalton peptide with aging. The total amount of pertussis toxin substrates (G(i2) and G(o)) decreased significantly with aging. This finding was supported by the fact that pertussis toxin-induced potentiation of adenylyl cyclase activity was markedly reduced in the aged group. The activity of catalytic protein assessed by forskolin-stimulated adenylyl cyclase activity was decreased at 104 weeks. On the other hand, GTP analogue-stimulated adenylyl cyclase activity was significantly potentiated in the same group. These results suggest that the decreased sensitivity to catecholamines observed in aged hearts is mainly due to a dysfunction of catalytic protein, and that decreased G(i) activity partially compensates for this catalytic dysfunction.