Age-associated decrease in vasopressin-lnduced renal water transport: A role for adenylate cyclase and g protein malfunction

Aging is associated with a decline in renal concentrating ability in response to dehydration-induced arginine vasopressin (AVP) release. To examine target tissue sensitivity, cortical collecting tubules (CCT) were individually microdissected from young (3 months), middle-aged (2-3 years) and old (4-5.5 years) rabbits and subjected to in vitro perfusion analysis and tissue culture of defined epithelial monolayers. Osmotic fluid transport was compared with adenylate cyclase activity and an age-associated decline in both parameters detected in response to increasing doses of AVP. [³H]-AVP binding was unchanged in CCT epithelia of different ages, excluding receptor alterations as the underlying mechanism. Also, hydraulic conductivity measurements of isolated young and old CCT were not significantly different, excluding post-cAMP events as a major mechanism of reduced sensitivity. Effects of cholera toxin and forskolin on hydraulic conductivity and adenylate cyclase activity showed a dramatic decrease in the ability of these compounds to elicit a response in CCT epithelia from old rabbits. It was concluded that alterations in Gs proteins and the catalytic unit of adenylate cyclase were responsible for the age-associated decline in CCT response to AVP.