AQUARETIC EFFECT OF A POTENT, ORALLY-ACTIVE, NONPEPTIDE V-2 ANTAGONIST IN MEN

Solute-free water diuretics (aquaretics) that antagonize hydrosmotic v asopressin 2 (V-2) receptors may be useful in treating diseases in whi ch water is retained. An orally active, nonpeptide, selective V, antag onist (OPC-31260) was administered in six dose steps (3, 15, 30, 60, 1 00 and 200 mg) to six healthy, normally hydrated men to investigate th e aquaretic effects in comparison with 12 placebo-treated control subj ects (two at each dose). All subjects tolerated all six doses without serious clinical side effects. OPC-31260 increased the first 6-hr hypo tonic urine volume dose-dependently, Administration at 30 mg raised th e 6-hr urine volume to 2 times, 100 mg to 3 times and 200 mg to 4 time s (1828.0 +/- 130.2 ml/6 hr) that of the placebo group (470.4 +/- 52.1 ml/6 hr). The drug increased urine flow maximally between 1 and 1.5 h r at all doses (e.g., 10.0 +/- 0.7-10.8 +/- 0.4 ml/min at 60-200 mg). The drug rapidly lowered urine osmolality for 4 hr, particularly betwe en 60 and 90 min (e.g., 72.3 +/- 2.3 and 62.3 +/- 5.1 mOsm/kg at 100 a nd 200 mg, respectively). In marked hypotonic diuresis, mean free-wate r clearance of the 6-hr urine increased dose-proportionally into the p ositive range, reaching 2.82 +/- 0.21 ml/min at 200 mg. OPC-31260 at 2 00 mg elevated plasma osmolality dose-dependently (from 287.5 +/- 0.4 before dosing to a maximum of 300.0 +/- 1.0 mOsm/kg at 6 hr; P < .01) and increased plasma sodium and chloride maximally at 6 hr (142.8 +/- 0.3 to 148.5 +/- 0.3 mEq/L for sodium, 109.7 +/- 0.4 to 112.5 +/- 0.6 mEq/L for chloride; P < .01) but did not alter plasma potassium. The d rug at 100 and 200 mg increased plasma arginine vasopressin to almost 3 times the predosing value without altering urinary electrolyte excre tion, blood pressure or heart rate. Thus, this orally active agent saf ely induced a strong aquaretic effect in men.