Evidence for (+)-cicletanine sulfate as an active natriuretic metabolite of cicletanine in the rat.
It was previously shown that the urinary sulfo-conjugate metabolite of cicletanine (cicletanine sulfate), and not free cicletanine, is salidiuretic in rats. Here we investigated potential differences between the resolved (+/-) enantiomers of cicletanine sulfate. Two groups of rats (n = 10) received either (+)- or (-)-cicletanine p.o. High performance capillary electrophoresis revealed that the 24-h urinary excretion of (+)-cicletanine sulfate was 5 times higher than that of (-)-cicletanine sulfate (18.9% vs. 3.8% of the oral dose). The same relative trend was observed after 5 and 10 days of oral administration. Following direct administration into the renal artery of anesthetized rats, (+)-cicletanine sulfate was 3-4 times more potent, in terms of active doses, than (-)-cicletanine sulfate to increase sodium excretion (ED50 = 1.86 +/- 0.28 mg/kg vs. 6.1 +/- 1.0 mg/kg, mean +/- S.E.M., n = 4). The maximal natriuretic potency of (+)-cicletanine sulfate was intermediate between that of furosemide and DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonate). In rat erythrocytes, (+)-cicletanine sulfate was between 2 and 3 times more potent to inhibit the Na(+)-dependent Cl-/HCO3- anion exchanger than (-)-cicletanine sulfate (IC50 = 61 +/- 3 microM vs. 142 +/- 31 microM, n = 4). In conclusion, (+)-cicletanine was more sulfo-conjugated and more potent natriuretic agent in rats than (-)-cicletanine. These results strongly suggest that (+)-cicletanine sulfate is the active natriuretic metabolite of racemic cicletanine in rats. This compound may probably act by inhibiting the Na(+)-dependent Cl-/HCO3- anion exchanger at the cortical diluting segment.
Garay
R P
RP
INSERM U400, Faculté de Médecine, Paris, France.
Rosati
C
C
Fanous
K
K
Allard
M
M
Morin
E
E
Lamiable
D
D
Vistelle
R
R
D000085:Acetates / Q000652:urine; D000284:Administration, Oral; D000818:Animals; D002712:Chlorides / Q000652:urine; D004232:Diuretics / Q000494:pharmacology* / Q000652:urine; D004586:Electrophoresis; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007269:Injections, Intra-Arterial; D017136:Ion Transport / Q000187:drug effects; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery; D013237:Stereoisomerism
D000085:Acetates; D002712:Chlorides; D004232:Diuretics; D011725:Pyridines; C077249:cycletanide sulfate; C038068:cicletanine