Dual Effect of Cyclic GMP on Renal Brush Border Na-H Antiporter

Abstract.

The Na-H antiporter of renal-brush border membranes is inhibited by cyclic AMP and stimulated by protein kinase C. The proximal tubule contains guanylate cyclase and is capable of cyclic GMP production. The effect of cGMP on renal Na-H antiporter activity was analyzed in phosphorylated brush border membranes by ²²Na uptake in the presence or absence of 1 mM amiloride. 8-Bromo cyclic GMP (1 μM) increased the amiloride-sensitive ²²Na uptake in control from 1.26 ± 0.13 to 1.54 ± 0.12 nmol/mg/protein/10 sec, P < 0.01, without altering the amiloride-insensitive component. In the absence of exogenous ATP, cGMP also stimulated the amiloride-sensitive ²²Na uptake, which can be explained by the presence of endogenous ATP in concentrations of up to 50 μM in the membranes. In ATP-depleted membrane vesicles, however, cGMP inhibited the amiloride-sensitive ²²Na uptake. These data indicate that cGMP acts on the Na-H antiporter by at least two different mechanisms, one of which is ATP dependent. It is likely that cGMP-dependent protein kinase mediates the stimulatory effects seen in the presence of ATP, and the inhibition seen in ATP-depleted membranes results from cGMP direct action on the Na-H antiporter.