A possible role for nitric oxide in modulating the functional cyclosporine toxicity by arginine.
The renal damage consequent to cyclosporine A (CsA) administration ranges from hemodynamic alterations to irreversible chronic lesions. The initial vasoconstriction depends upon the imbalance between the various modulators of the renal vascular tone, among which the most powerful are endothelins and nitric oxide (NO). CsA could play a crucial role by inhibiting the Ca++/calmodulin-mediated activation of the constitutive NO synthase (NOS) isoform, which converts L-arginine (L-Arg) into NO and citrulline, with a 1:1 stoichiometry. To investigate the possibility of modulating CsA nephrotoxicity with L-Arg we studied six groups (G) of Lewis rats treated with daily gavage up to eight weeks: G1, CsA 40 mg/kg; G2, G1 plus L-Arg 300 mg/kg; G3, G2 plus the competitive inhibitor of NOS, NG-nitro-L-Arg (L-NNA); G4, L-Arg alone; G5, L-NNA alone; and G6, controls receiving vehicle alone. After eight weeks L-Arg treated rats were protected against the toxic effects of CsA [creatinine (Cr) values, G2, 0.62 +/- 0.05 mg/dl vs. G1, 0.99 +/- 0.16 mg/dl, P < 0.001; proteinuria (P), G2, 7.2 +/- 1.02 mg/day vs. G1, 15.1 +/- 1.9 mg/day, P < 0.01]. The administration of L-NNA abolished the protective effect of L-Arg (G3, Cr 1.23 +/- 0.16 mg/dl; P 16.9 = 2.3; P < 0.02 and P < 0.005, respectively vs. G2). The levels of Cr in G2 rats were superimposable to control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Amore
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A
Nephrology and Dialysis Department, Regina Margherita Children's Hospital, Torino, Italy.
Gianoglio
B
B
Ghigo
D
D
Peruzzi
L
L
Porcellini
M G
MG
Bussolino
F
F
Costamagna
C
C
Cacace
G
G
Picciotto
G
G
Mazzucco
G
G
D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000502:physiology*; D003404:Creatinine / Q000097:blood; D006152:Cyclic GMP / Q000652:urine; D016572:Cyclosporine / Q000097:blood / Q000633:toxicity*; D006439:Hemodynamics; D007527:Isoenzymes / Q000235:genetics; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D011507:Proteinuria / Q000652:urine; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012079:Renal Circulation
D007527:Isoenzymes; D012333:RNA, Messenger; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D003404:Creatinine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP