Parathyroid hormone, dopamine, alpha-adrenergic catecholamines, and angiotensin II regulate renal Na excretion, at least in part through modulation of acute cyclic (c)AMP-induced proximal tubule Na/H antiporter inhibition. The present studies examined the effect of chronic increases in cell cAMP on Na/H antiporter activity in OKP cells. Whereas 8-bromo cAMP acutely inhibited Na/H antiporter activity, chronic application for 6 h led to a 24% increase in Na/H antiporter activity measured 16-20 h after cAMP removal. This chronic persistent activation of the Na/H antiporter required > 2 h exposure. This effect was not a nonspecific effect of 8-bromo cAMP, in that addition of forskolin or forskolin + 3-isobutyl-1-methylxanthine for 6 h also led to a chronic persistent increase in Na/H antiporter activity. Inhibition of protein synthesis with cycloheximide prevented 8-bromo cAMP-induced Na/H antiporter stimulation. Although 8-bromo cAMP addition decreased cell pH by 0.15-0.20 pH U, Na/H antiporter stimulation could be dissociated from cell acidification. In summary, while cAMP acutely inhibits Na/H antiporter activity, it chronically increases antiporter activity. This chronic activation occurs with exogenous addition or endogenous generation of cAMP. These results imply that for hormones that modulate renal Na excretion and proximal tubule Na/H antiporter activity via cAMP and protein kinase A, acute effects may not predict chronic effects.