Nitric Oxide Production Modulates Cyclosporin A-Induced Distal Renal Tubular Acidosis in the Rat (original) (raw)
Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
, George J. Schwartz, Michi Wakaumi, Kenta Nishiki, Hisashi Yamamoto, Jeffrey M. Purkerson and Akio Fujimura
Journal of Pharmacology and Experimental Therapeutics June 2003, 305 (3) 840-845; DOI: https://doi.org/10.1124/jpet.102.048207
Abstract
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_ω-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.
Footnotes
A portion of this study was supported by a grant-in-aid for scientific research and by Uehara Memorial foundation (to S.T.). G.J.S. was supported by U.S. Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK 50603.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
DOI: 10.1124/jpet.102.048207.
ABBREVIATIONS: CsA, cyclosporine A; NO, nitric oxide; CCD, cortical collecting duct; dRTA, distal renal tubular acidosis; l-NAME, _N_ω-nitro-l-arginine methyl ester; l-Arg, l-arginine; GFR, glomerular filtration rate; RTA, renal tubular acidosis; ET-B, endothelin-B.
- Received December 16, 2002.
- Accepted February 21, 2003.
The American Society for Pharmacology and Experimental Therapeutics
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