Indinavir (IDV) is a protease inhibitor widely used in AIDS
treatment. A sustained elevation of creatinine was identified in IDV-treated patients. We have
previously demonstrated that IDV causes renal vasoconstriction in rats. The objective of this
study was to investigate the mechanism of IDV-induced vasoconstriction and the effect that the
vasodilator agents L-arginine (LA), nifedipine (NF), as well as magnesium supplementation (Mg),
have on IDV-induced nephrotoxicity. Male Wistar rats were kept on fast overnight and given free
access to water. IDV (80 mg/kg BW) and NF (3 mg/kg BW) were given by gavage for 15 days. LA
(1.5%) and MgCl(2)center dot 6H(2)O (11%) were added to drinking water. Six groups were studied:
Control (n=6): normal rats treated with vehicle, a 0.05 M citric acid solution; IDV (n=7): IDV-
treated rats; IDV+LA (n=6): IDV- and LA-treated rats; IDV+NF (n=7): IDV- and NF-treated rats;
IDV+Mg (n=7): IDV- and MgCl2-treated rats; IDV+Mg+L-NAME (n=9): IDV- and MgCl2-treated rats,
supplemented with L-NAME (2.5 mg/l in drinking water). Clearance studies and evaluations of
urinary nitrite (NO2) excretion were performed on day 16. No changes in blood pressure were
observed. NO2 excretion decreased in IDV-treated rats. LA and NF protected against IDV effects,
improving GFR (IDV+LA, 1.95 +/-0.10; IDV+NF, 1.94 +/-0.07 vs IDV, 1.15 +/-0.07 ml/min, P<0.001)
and RBF (IDV+LA, 7.83 +/-0.09; IDV+NF, 7.63 +/-0.14 vs IDV, 6.17 +/-0.25 ml/min, P<0.001). These
results suggest that IDV-induced vasoconstriction is mediated by NO and Ca2+ channels. Magnesium
also ameliorated GFR and RBF in IDV-treated rats (GFR IDV+Mg, 1.77 +/-0.08 ml/min, P<0.001; RBF
IDV+Mg, 7.35 +/-0.158 ml/min, P<0.001). Magnesium protection is not NO-mediated since it was not
blocked by L-NAME. In conclusion, LA, NF and Mg protect against IDV-induced nephrotoxicity in
rats. This study may have potential clinical implications for prevention of IDV-induced
nephrotoxicity.