Decreased beta-adrenergic agonist affinity and adenylate cyclase activity in senescent rat lung

Beta-adrenergic receptor affinity for the agonist, isoproterenol, and coupling to adenylate cyclase assessed by Hill plots were investigated at both 23 degrees C and 37 degrees C in Fischer 344 rats of 4, 13, and 25 months of age. Apparent dissociation constants for isoproterenol at 23 degrees C were unaltered in the three age groups (2.0 +/- .3; 2.2 +/- .3; 2.6 +/- .3 X 10(-7)M, respectively). At 37 degrees C, however, the apparent dissociation constants increased progressively with age (6.9 +/- .9;8.6 +/- .6;13.2 +/- 1.4 X 10(-7)M). Hill coefficients were less than 0.7 for all age groups, suggesting the presence of two binding sites that have been described as a low (uncoupled) and a high (coupled) affinity state. In the presence of guanylylimidodiphosphate the apparent dissociation constant increased in all age groups and there was no longer a difference among age groups at 37 degrees C (14.1 +/- 2.7; 13.6 +/- 1.7; 14.8 +/- 2.4 X 10(-7)M). Basal adenylate cyclase activity (17 +/- 1 vs. 25 +/- 3 pmols cAMP/mg/min) as well as isoproterenol (27 +/- 5 vs. 60 +/- 11), NaF (116 +/- 8 vs. 209 +/- 24), and forskolin (70 +/- 6 vs. 124 +/- 14) stimulated activity were reduced in 25 compared to 4-month-old animals. The data suggest that in lungs from senescent rats there is a decrease in beta-adrenergic agonist affinity of the high affinity binding site and no change in the affinity of the low affinity binding site. Additionally, adenylate cyclase activity is reduced in senescent compared with young rats, and this reduction may be due to decreased activity of the catalytic unit. Both these changes may contribute to the diminished hormonal responsiveness of senescence.