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 salid iuretic in rats. Here we investigated potential differences between th e resolved (+/-) enantiomers of cicletanine sulfate. Two groups of rat s (n = 10) received either (+)- or (-)-cicletanine p.o. High performan ce capillary electrophoresis revealed that the 24-h urinary excretion of (+)-cicletanine sulfate was 5 times higher than that of (-)-cicleta nine sulfate (18.9% vs. 3.8% of the oral dose). The same relative tren d was observed after 5 and 10 days of oral administration. Following d irect administration into the renal artery of anesthetized rats, (+)-c icletanine sulfate was 3-4 times more potent, in terms of active doses , than (-)-cicletanine sulfate to increase sodium excretion (ED(50) = 1.86 +/- 0.28 mg/kg vs. 6.1 +/- 1.0 mg/kg, mean +/- S.E.M., n = 4). Th e maximal natriuretic potency of (+)-cicletanine sulfate was intermedi ate between that of furosemide and DIDS (4,4'-diisothiocyanostilbene-2 ,2'-disulfonate). In rat erythrocytes, (+)-cicletanine sulfate was bet ween 2 and 3 times more potent to inhibit the Na+-dependent Cl-/HCO3- anion exchanger than (-)-cicletanine sulfate (IC50 = 61 +/- 3 mu M vs. 142 +/- 31 mu M, n = 4). In conclusion, (+)-cicletanine was more sulf o-conjugated and a more potent natriuretic agent in rats than (-)-cicl etanine. These results strongly suggest that (+)-cicletanine sulfate i s the active natriuretic metabolite of racemic cicletanine in rats. Th is compound may probably act by inhibiting the Na+-dependent Cl-/HCO3- anion exchanger at the cortical diluting segment.