Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.
Solute-free water diuretics (aquaretics) by antagonizing hydrosmotic vasopressin receptors (V2) may be useful in treating water-retaining diseases. The effects of intravenous administration of a newly developed nonpeptide, selective V2 antagonist, OPC-31260, at doses ranging from 0.017 to 1.0 mg/kg to groups of healthy, normally hydrated men were compared with those of 0.33 mg/kg furosemide and placebo. OPC-31260 increased the hypotonic urine volume dose dependently for the first 4 h, while furosemide induced sodium diuresis for 2 h. The absolute increase in the cumulative response in the urine to the highest doses of OPC-31260 was not significantly different from that to furosemide. The higher doses of OPC-31260 rapidly lowered urine osmolality for 2 h, particularly between minutes 15 and 45 (e.g., 1.0-mg/kg dose: 63 +/- 2 mOsm/kg in urine collected between minutes 30 and 45). In a marked hypotonic diuresis, mean free water clearance of the 4-h urine increased dose proportionally into the positive range, reaching 1.80 +/- 0.21 ml/min at 1.0 mg/kg. Whereas furosemide induced marked Na and K diuresis, OPC-31260 increased urinary Na excretion only slightly. At 4 h, 0.75 and 1.0 mg/kg of OPC-31260 almost doubled the plasma arginine vasopressin; and the higher doses increased plasma osmolality and plasma Na slightly, but did not alter plasma K, blood pressure, or heart rate. OPC-31260 thus safely induced a potent aquaretic effect in men.
Ohnishi
A
A
Department of Internal Medicine (I), Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan.
Orita
Y
Y
Okahara
R
R
Fujihara
H
H
Inoue
T
T
Yamamura
Y
Y
Yabuuchi
Y
Y
Tanaka
T
T
D000328:Adult; D000450:Aldosterone / Q000097:blood; D000704:Analysis of Variance; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000097:blood*; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002712:Chlorides / Q000652:urine; D004231:Diuresis / Q000187:drug effects*; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005665:Furosemide / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D009994:Osmolar Concentration; D011188:Potassium / Q000652:urine; D012083:Renin / Q000097:blood; D012964:Sodium / Q000097:blood / Q000652:urine; D013997:Time Factors; D014556:Urine
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D002712:Chlorides; D004232:Diuretics; D001127:Arginine Vasopressin; C076251:mozavaptan; D000450:Aldosterone; D005665:Furosemide; D012964:Sodium; D012083:Renin; D011188:Potassium