We studied the effects of a single dose (100 mg orally) and repeated administration (100 mg o.d. for 7 days) FK453, a novel adenosine-1 receptor antagonist, on renal sodium handling and blood pressure in eight patients with essential hypertension. Within 60 minutes after administration of FK453, sodium excretion increased threefold. This occurred in the absence of a change in renal hemodynamics, assessed from inulin and para-aminohippurate clearance, and was accompanied by increased fractional excretion of lithium, phosphate, and uric acid and by increased excretion of calcium and magnesium. Maximal free water clearance data showed an increase in maximal urine flow and distal delivery term and a decrease the diluting segment reabsorption term. FK453 also decreased blood pressure and increased heart rate, but this did not occur until about 3 hours after ingestion, that is, when the natriuresis was already over. The natriuretic effect of FK453 was short-lasting, and continued use of FK453 was in fact accompanied some net sodium retention. Blood pressure on the seventh day before FK4S3 treatment was not different from blood pressure before administration of the first dose of FK453. Again an acute natriuretic response followed, although less than after the first dose. Changes in intrarenal sodium handling parameters, blood pressure, and heart rate were similar to those seen after the first dose. The natriuretic and hypotensive effects of FK453 indicate that adenosine-1 receptor activity plays a role in the regulation of blood pressure and renal sodium handling in patients with essential hypertension. Although these findings are not necessarily specific for this condition, it seems worthwhile to evaluate whether adenosine-1 antagonism can be used as a mode to treat hypertension.