Cicletanine sulfate: inhibition of anion transport systems and natriuretic activity

In contrast with cicletanine, its urinary sulfoconjugate metabolite (cicletanine sulfate) was active on membrane ion transport in human red blood cells. Cicletanine sulfate was a more potent inhibitor of the Na+ dependent [Cl-/HCO3-] exchanger (IC50 = 9 +/- 3 x 10(-5) mol/l; mean +/- SD of 4 experiments) than cicletanine (IC50 = 10(-3) mol/l). This inhibitory potency was intermediate between that of xipamide (IC50 = 2 x 10(-5) mol/l) and that of furosemide (IC50 = 2 x 10(-4) mol/l). Moreover, cicletanine sulfate exhibited modest inhibitory potency against the [Na+,K+,Cl-]-cotransport system (IC50 = 1 +/- 0.3 x 10(-3) mol/l; mean +/- SD of 4 experiments) and poor inhibitory activity against the [K+,Cl-]-cotransport system. Cicletanine sulfate was unable to modify the activity of Cl(-)-independent membrane carriers (Na+:H+ exchanger, Ca2+ pump, Na+:Li+ countertransport system and Na+,K+ pump). Following renal intraarterial administration in rats, cicletanine sulfate and not cicletanine, exhibited salidiuretic activity. In conclusion, the urinary sulfo-conjugate of cicletanine is an active anion transport inhibitor and natriuretic metabolite. In fact, this metabolite may be responsible for the salidiuretic action of cicletanine.