Mechanisms of the hyperkalaemia caused by nafamostat mesilate: effects of its two metabolites on Na+ and K+ transport properties in the rabbit cortical collecting duct.
1. The present experiments were undertaken to determine the mechanism(s) of hyperkalaemia caused by nafamostat mesilate (NM), a serine-protease inhibitor. 2. We investigated the effects of luminal addition of two metabolites of NM, p-guanidinobenzoic acid (PGBA) and 6-amidino-2-naphthol (AN), on Na+ and K+ transport properties of the collecting duct (CD) cell in the isolated perfused cortical collecting duct (CCD) from rabbit kidneys, because these metabolites, but not NM, were mainly excreted into the urine. 3. Addition of PGBA at 10(-5) and 10(-4) M in the lumen resulted in a hyperpolarization of VA in parallel with increases in transepithelial resistance (RT) and fractional apical membrane resistance (fRA). PGBA added to the luminal perfusate at 10(-5) and 10(-4) M changed VA, RT and fRA in a dose-dependent manner. These effects were completely inhibited by pretreatment with luminal amiloride (50 microM). PGBA at 10(-6) M in the lumen had no effect on the electrical parameters. 4. Luminal addition of AN at 10(-4) M also caused the apical membrane to hyperpolarize in parallel with increases in RT and fRA. These effects were also completely inhibited by pretreatment with luminal amiloride (50 microM). AN at 10(-5) M in the lumen had no effect on the electrical parameters. 5. We conclude that two metabolites of NM, PGBA and AN, act on the apical membrane of the CD cell and inhibit the amiloride-sensitive Na+ conductance, resulting in an inhibition of K+ secretion. This direct action of these metabolites, rather than NM, on the CCD might contribute to the NM-induced hyperkalaemia.
Department of Nephrology, Jichi Medical School, Tochigi, Japan.
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D000818:Animals; D001550:Benzamidines; D001565:Benzoates / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced / Q000378:metabolism; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D009284:Naphthols / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*
D001550:Benzamidines; D001565:Benzoates; D006146:Guanidines; D009284:Naphthols; D015842:Serine Proteinase Inhibitors; C023856:4-guanidinobenzoate; C058874:6-amidino-2-naphthol; D012964:Sodium; D011188:Potassium; C032855:nafamostat; D010634:Phenobarbital