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Nitric oxide inhibits superoxide-stimulated urea permeability in the rat inner medullary collecting duct

Department of Medicine, Ottawa Hospital, and the Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 7W9

Submitted 24 February 2003 ; accepted in final form 31 July 2003

The inner medullary collecting duct (IMCD) contains relatively high nitric oxide (NO) synthetic capacity, but the effect of NO on IMCD transport remains unclear. We determined the effect of NO on basal and vasopressin (AVP)-stimulated urea (P_urea) and water (P_f) permeabilities in isolated, perfused rat IMCD. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) increased cGMP production in IMCD, but neither SNAP (10^–4 M) nor 8-BrcGMP (10^–4 M), the cell-permeable analog of cGMP, affected basal or AVP-stimulated P_urea. The free radical superoxide is produced by oxidases in the kidney and can interact with NO. To determine the effect of superoxide generation on transport, IMCDs were incubated with diethyldithiocarbamate (DETC; 10^–3 M), the inhibitor of superoxide dismutase (SOD). DETC significantly increased basal and AVP-stimulated P_urea (control: 28.7 ± 4.5 vs. DETC: 40.9 ± 6.2 x 10^–5 cm/s; P < 0.001; n = 9). Preincubation of IMCD with SNAP or the SOD mimetic tempol completely inhibited DETC-stimulated P_urea. DETC caused a significant increase in superoxide generation by IMCD, and this was blocked by SNAP. Incubation of IMCD with the NO synthase (NOS) substrate L-arginine blocked the stimulatory effect of DETC on P_urea, and this was reversed by the neuronal NOS inhibitor 7-nitroindazole. In contrast, neither basal nor AVP-stimulated P_f was affected by NO donors or DETC. In summary, exogenous or endogenously produced NO does not affect basal urea transport in the IMCD but inhibits superoxide-stimulated P_urea. In the inner medulla, superoxide generation by local oxidases may stimulate urea transport, and the role of endogenous NO may be to dampen this effect by decreasing superoxide levels.

vasopressin; water permeability; nitric oxide synthase; cGMP

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