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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Nitric Oxide Production Modulates Cyclosporin A-Induced Distal Renal Tubular Acidosis in the Rat

Department of Clinical Pharmacology, Jichi Medical School, Tochigi, Japan (S.T., M.W., K.N., H.Y., A.F.); and Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York (G.J.S., J.M.P.)

Cyclosporine A (CsA) causes distal renal tubular acidosis (dRTA) in humans and rodents. Because mice deficient in nitric-oxide (NO) synthase develop acidosis, we examined how NO production modulated H⁺ excretion during acid loading and CsA treatment in a rat model. Rats received CsA, L-arginine (L-Arg), or N-nitro-L-arginine methyl ester (L-NAME), or combinations of CsA and L-NAME or L-Arg, followed by NH₄Cl (acute acid load). In vehicle-treated rats, NH₄Cl loading reduced serum and urine () and urine pH, which was associated with increases in serum [K⁺] and [Cl^–] and urine NH₃ excretion. Similar to CsA (7.5 mg/kg), L-NAME impaired H⁺ excretion of NH₄Cl-loaded animals. The combination CsA and L-NAME reduced H⁺ excretion to a larger extent than either drug alone. In contrast, administration of L-Arg ameliorated the effect of CsA on H⁺ excretion. Urine pH after NH₄Cl was 5.80 ± 0.09, 6.11 ± 0.13*, 6.37 ± 0.16*, and 5.77 ± 0.09 in the vehicle, CsA, CsA + L-NAME and CsA + L-Arg groups, respectively (*P < 0.05). The effect of CsA and alteration of NO synthesis were mediated at least in part by changes in bicarbonate absorption in perfused cortical collecting ducts. CsA or L-NAME reduced net absorption, and, when combined, completely inhibited it. CsA + L-Arg restored absorption to near control levels. Administration of CsA along with L-NAME reduced NO production to below levels observed with either drug alone. These results suggest that CsA causes dRTA by inhibiting H⁺ pumps in the distal nephron. Inhibition of NO synthesis may be one of the mechanisms underlying the CsA effect.

Address correspondence to: Dr. Shuichi Tsuruoka, Department of Clinical Pharmacology, Jichi Medical School, 3311 Yakushiji, Minamikawachi, Kawachi, Tochigi 329-0498, Japan. E-mail: tsuru{at}jichi.ac.jp

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