Antidiuretic hormone resistance in the neonatal cortical collecting tubule is mediated in part by elevated phosphodiesterase activity

Neonates cannot concentrate their urine to the same degree as adults. One of the key factors in concentrating the urine is the renal collecting duct osmotic water permeability (P_f) response to antidiuretic hormone (ADH). Neonatal cortical collecting ducts have a blunted P_f response to ADH compared with adult tubules (P_f: 119.0 ± 12.5 vs. 260. 1 ± 29.5 μm/s, P < 0.05). We found that the phosphodiesterase activity in the neonatal collecting ducts was higher than that in the adult collecting ducts (3,970 ± 510 vs. 2,440 ± 220 cpm·μg tubular protein^-1·20 min^-1, P < 0.05). After pretreatment of in vitro microperfused tubules with the nonspecific phosphodiesterase inhibitor IBMX (10^-6 M in the bath), the P _f response to ADH in neonatal collecting ducts was 271.4 ± 51.7 μm/s, which was identical to that of the adult collecting duct [315.3 ± 31.3 μm/s, P = not significant (NS)]. Rolipram, a specific type IV phosphodiesterase inhibitor, lowered the elevated phosphodiesterase activity in the neonatal tubules to that in the adult tubules (2,460 ± 210 vs. 2,160 ± 230 cpm·μg tubular protein^-1·20 min ^-1, P = NS). Neonatal tubules pretreated with rolipram (10 ^-5 M) in the bath also had a P_f response to ADH that was comparable to that of the adult tubules (258.2 ± 17.0 vs. 271.4 ± 32.6 μm/s, P = NS). Thus the elevated phosphodiesterase activity in the neonatal tubules appears to be due to an increase in type IV phosphodiesterase activity. Hence, one of the key factors in the decreased ability of neonates to concentrate their urine is overactivity of phosphodiesterase in the cortical collecting duct that blunts the neonatal collecting duct P_f response to ADH.