Nitric oxide production modulates cyclosporin A-induced distal renal tubular acidosis in the rat.
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 omega-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 (HCO3-) 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 HCO3- absorption, and, when combined, completely inhibited it. CsA + L-Arg restored HCO3- 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.
Tsuruoka
Shuichi
S
Department of Clinical Pharmacology, Jichi Medical School, 3311 Yakushiji, Minamikawachi, Kawachi, Tochigi 329-0498, Japan. tsuru@jichi.ac.jp
Schwartz
George J
GJ
Wakaumi
Michi
M
Nishiki
Kenta
K
Yamamoto
Hisashi
H
Purkerson
Jeffrey M
JM
Fujimura
Akio
A
D000141:Acidosis, Renal Tubular / Q000139:chemically induced* / Q000503:physiopathology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003401:Creatine / Q000652:urine; D016572:Cyclosporine / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation
D007166:Immunosuppressive Agents; D009566:Nitrates; D011522:Protons; C026512:arginine methyl ester; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D003401:Creatine; D019331:NG-Nitroarginine Methyl Ester