ANP inhibits Na⁺-H⁺ antiport in proximal tubular brush border membrane: Role of dopamine

Infusion of ANP to rats results in an inhibition of Na⁺-H⁺ antiport and Na⁺-P_i symport in brush border membrane vesicles (BBMV) prepared from kidneys of these animals (J Clin Invest 75:1983). iIn the present study we investigated the intrarenal mechanism by which infused ANP elicits these changes in proximal tubular transport systems. As in rats, infusion of ANP to rabbits resulted in a diuresis, natriuresis, and increase in GFR; however, unlike in rats, the fractional excretion of phosphate (P_i) was not changed. In BBMV prepared from cortices of ANP-infused rabbits, the rate of Na⁺-H⁺ antiport was decreased (Δ -27%), but Na⁺ gradient-dependent uptakes of P_i and L-proline were not different from controls. Incubation of rabbit cortical tubule suspension in vitro with ANP 10^-7 M alone had no inhibitory effect on Na⁺-H⁺ antiport in BBMV prepared from these tubules, whereas incubation with other hormonal agents, 1 U/ml PTH (Δ 61%) or with dopamine (DA) 10^-4 M (Δ -34%), did inhibit the rate of Na⁺-H⁺ antiport in BBMV from the same pool of tubules. However, when tubules were incubated in the presence of (10^-5 M) DA, the addition of 10^-7 M ANP did cause a significant (Δ -21%) decrease in Na⁺-H⁺ antiport activity in BBMV. In contrast, ANP did not show similar inhibitory effect in the presence of submaximal inhibitory doses of PTH. To explore whether ANP may act on proximal tubules in vivo indirectly, via mediation of DA, we evaluated the effect of ANP on some parameters of catecholamine system in vivo. Infusion of ANP, in doses which caused inhibition of Na⁺-H⁺ antiport in BBMV and natriuresis, markedly enhanced (Δ +134%) excretion of non-conjugated DA in urine, indicating increased intrarenal generation of DA, while it had no detectable effect on the plasma levels of DA, its precursor L-dopa, or on DA content in extracts of renal cortical tissue. Taken together, these observations provide evidence for the hypothesis that circulating ANP can inhibit the rate of Na⁺-H⁺ exchange across renal BBM: a) indirectly, via the autocrine DA system in renal proximal tubules, that is, ANP, enhances the intrarenal generation of DA, which in turn inhibits Na⁺-H⁺ antiport; b) in addition, ANP may also directly potentiate the inhibitory action of DA on Na⁺-H⁺ antiport.