NATRIURETIC AND DIURETIC EFFECTS OF CICLETANINE IN CONSCIOUS, HYDRATED, NORMOTENSIVE RATS

The natriuretic and diuretic actions of cicletanine, a novel agent with vasorelaxant and antihypertensive properties, were examined in conscious, hydrated, normotensive rats. Cicletanine, the (+)- and (-)-enantiomers of cicletanine, hydrochlorothiazide (HCTZ), or vehicle(s) were administered orally or intravenously (1, 3, 10, 30 mg base/kg) to waterloaded (27 ml/kg) rats and 3 hr urine volume, Na+ and K+ were measured. Racemic cicletanine (3 mg/kg, p.o.) caused a significant increase in urinary Na+ (+174%) and K+ (+46%) excretion, unaccompanied by diuresis. Diuresis was detected only with larger oral doses of racemic cicletanine (10-30 mg/kg). Oral administration of a 1-mg/kg dose of (+)-cicletanine caused significant natriuresis that was not detected with either racemic or (-)-cicletanine. The (+)-enantiomer (3-30 mg/kg) produced natriuresis and diuresis quantitatively similar to that of racemic cicletanine. By contrast, (-)-cicletanine induced only slight natriuresis, kaliuresis, and diuresis upon administration of the largest dose (30 mg/kg, p.o.). Intravenous administration of the racemate and enantiomers of cicletanine caused natriuretic/diuretic activity that was very similar to that seen with oral administration. The natriuresis caused by a 3-mg/kg dose of racemic cicletanine was unaffected by indomethacin. However, indomethacin attenuated the natriuresis and eliminated the diuresis produced by the 10- and 30-mg/kg doses of cicletanine. Indomethacin had no effect on the kaliuretic actions of cicletanine. Indomethacin blunted the natriuresis and eliminated the diuresis caused by all doses of HCTZ. In conclusion, the natriuretic, kaliuretic, and diuretic effects of racemic cicletanine in the conscious, hydrated, normotensive rat appear to be mediated primarily by the (+)-enantiomer. A dose-dependent separation exists between the natriuretic and diuretic actions of cicletanine, with only natriuresis noted at smaller doses. The natriuresis caused by racemic cicletanine has both indomethacin-resistant and indomethacin-sensitive components, while cicletanine-induced diuresis appears to be mediated exclusively by prostaglandins.