cAMP signaling mechanisms with aging in rats.

Blunted cAMP responses to beta-adrenergic agonists play a major role in diminished smooth muscle relaxation in blood vessels from older animals, although the mechanisms remain uncertain. A diminished cAMP response could potentially arise from changes in the expression of adenylyl cyclase-coupled G proteins, such as a diminished expression of Gs or an increased expression of Gi. We tested the hypothesis that a loss in Gs or increased expression of Gi could occur in tissues such as the aorta, heart and kidney with aging, which would provide a unifying explanation for blunted cAMP responses to many hormones with aging in a variety of cells. Using Western blotting with specific antibodies, we found no generalized changes in G protein expression with aging. Also, injection of pertussis toxin (which functionally inactivates Gi) into older animals did not restore vascular relaxation mediated by beta-adrenergic receptors. We previously found an elevated ratio of regulatory to catalytic subunits of protein kinase A in the aorta of older rats, which would tend to impair activation of the catalytic unit; this alteration was not generalized to other organs such as the heart and kidney. Old rats fed a low salt diet did not show the restored beta-adrenergic agonist-induced vasodilation previously found in elderly humans, suggesting that there are species differences in the development of this deficit. Altogether, these results suggest that altered G protein expression does not provide a general explanation for blunted activation of adenylyl cyclase with aging.