A possible role for nitric oxide in modulating the functional cyclosporine toxicity by arginine

Abstract

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)

Calcineurin Inhibitor Nephrotoxicity

“…Another approach has been to use l-arginine or molsidomine for the prevention of CNI nephrotoxicity. In rats, l-arginine greatly ameliorated kidney dysfunction induced by cyclosporine (373,374), but not in all studies (375). In humans, no effect of l-arginine was observed (376).…”

Modulation of nitric oxide improves cyclosporin A-induced hypertension in rats and primates

“…[24][25][26] Bloom et al 25 and Gallego et al 18 found that L-arginine reversed CsA-induced vasoconstriction in anaesthetised and conscious rats. Gallego also showed that simultaneous administration of L-arginine with CsA significantly prevented the toxic effects of CsA.…”

Endothelial Nitric Oxide Synthase Gene Variation Associated With Chronic Kidney Disease After Liver Transplant

“…The vasoconstriction is thought to result from impaired endothelial cell function, leading to reduced production of vasodilators. 7,8 The results of sustained renal vasoconstriction include vascular angiopathy, altered mesangial cell contraction, tubular atrophy, and eventually interstitial fibrosis, leading to permanent reduction in renal function. 6,32 The principal finding of the current study was an association between the Glu298Asp SNP of the NOS3 gene and an increased risk of CKD after LT.…”

“…8,[38][39][40][41][42][43][44][45][46][47][48][49] In animals, increased NO production by agents such as L-arginine or molsidomine has been shown to ameliorate the CNI nephrotoxicity, whereas depletion of NO by L-NAME, a competitive inhibitor of eNOS, augments the nephrotoxicity. 48 These data indicating the importance of NO in the pathogenesis of CNI nephrotoxicity suggest that the NOS3 SNP found in this study may have a mechanistic role.…”

“…The exact mechanism of vasoconstriction is unclear, but there appears to be substantial impairment of endothelial cell function, leading to reduced production of vasodilators (such as nitric oxide [NO]) and enhanced release of vasoconstrictors (endothelin and thromboxane). 7,8 Additionally, transforming growth factor beta-1, endothelin-1, and reactive oxygen and nitrogen species may contribute. [9][10][11] Although some reduction in renal function is common among LT recipients, some maintain intact renal function many years after LT.…”