Diuretic effects of a novel uricosuric antihypertensive S‐8666 in rats, mice, monkeys, and dogs: Comparison with furosemide and trichlormethiazide

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Abstract
Oral dose‐response relationships of S‐8666 to Na excretion were established in male and female Sprague‐Dawley rats (3–100 mg/kg), male and female ddy mice (3–300 mg/kg), female cynomolgus monkeys (2–50 mg/kg), and female beagle dogs (3–100 mg/kg). The natriuretic potency of S‐8666 was almost comparable to that of furosemide in rats but was lower in mice, monkeys, and dogs. The maximal effects were similar for S‐8666 and furosemide, which had higher ceiling values than trichlormethiazide (TCM) in rats, mice, monkeys, and dogs. Thus, S‐8666 seems to have a “loop diuretic” property like furosemide. After oral administration of S‐8666 to rats (20–100 mg/kg), the onset of natriuresis was rapid, with the peak effect occurring within 1–2 hr. TCM showed a longer lasting pattern of natriuresis than S‐8666 and furosemide. With intravenous administration (1–10 mg/kg) to rats, the t1/2 for natriuresis was 16–20 min for S‐8666 and furosemide in rats. S‐8666 showed enantioselectivity; its (S)‐(–)‐form was natriuretic, whereas the (R)‐(+)‐form was inactive. These results indicate that S‐8666 is a diuretic with a high ceiling property that has a lower potency than TCM and a longer lasting effect than furosemide.