Citrate reverses cyclosporin A-induced metabolic acidosis and bone resorption in rats.
BACKGROUND
Cyclosporine A (CsA) causes distal renal tubular acidosis (RTA) and osteoporosis. We have recently reported that the reduction of nitric oxide (NO) exacerbates this condition. Distal RTA may deplete bone mineral due to the chronic buffering of acid in the blood. The interaction of CsA and NO in causing metabolic acidosis and bone demineralization has not been studied previously. Nor has the salubrious effect of citrate therapy.


OBJECTIVE
To examine the effect of systemic pH correction by citrate on renal electrolyte (Na, K, Cl, NH3, HCO3) excretion following acute water loading in CsA-treated and NO-reduced rats. We further evaluated femoral bone density and bone demineralization activity after the same treatments.


METHODS
Rats received CsA, L-arginine (L-Arg), or nitro-L-arginine-methyl ester (L-NAME), or a combination of CsA+L-NAME plus or minus citrate. Urine and blood electrolytes were examined, as well as the urine excretion of deoxypyridinoline and the bone density of both femurs.


RESULTS
CsA and L-NAME reduced urine pH and the serum HCO3- concentration, and increased serum K+ and Cl- concentrations. The combination of CsA with L-NAME caused more severe deficits in the serum HCO3- concentration and elevations in serum K+ and Cl- concentrations than either drug alone. Both CsA and L-NAME reduced urinary nitrate excretion, which was reversed by co-administration of L-Arg. Co-administration of citrate or L-Arg improved the CsA- and L-NAME-induced acidosis and hyperkalemia. Bone resorption and density of the femurs were decreased by CsA and L-NAME and were additive for both drugs. Co-administration of citrate or L-Arg restored both bone resorption and density to normal levels.


CONCLUSIONS
CsA induces a hyperchloremic metabolic acidosis with hyperkalemia and a reduction in NO. The ensuing systemic acidosis causes bone resorption and demineralization. These effects were corrected by co-treatment with citrate. Citrate, at least in part, directly reduces the protonation of bone in animals treated with CsA and is recommended as a potential adjunct drug to prevent bone demineralization in patients chronically receiving CsA.
Tsuruoka
Shuichi
S
Department of Pharmacology, Division of Clinical Pharmacology, Jichi Medical School, 3311 Yakushiji, Mimamikawachi, Tochigi, Japan. tsuru@jichi.ac.jp
Schwartz
George J
GJ
Ioka
Takashi
T
Yamamoto
Hisashi
H
Ando
Hitoshi
H
Fujimura
Akio
A
D000138:Acidosis / Q000139:chemically induced* / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced* / Q000503:physiopathology*; D019343:Citric Acid / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004573:Electrolytes / Q000097:blood; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D008297:Male; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D014556:Urine / Q000737:chemistry
D004573:Electrolytes; D009566:Nitrates; D009573:Nitrites; D019343:Citric Acid; D016572:Cyclosporine