Sulfur amino acids in Cushing's disease: insight in homocysteine and taurine levels in patients with active and cured disease.

BACKGROUND: Cushing's syndrome is associated with an increased cardiovascular risk. Although a series of cardiovascular risk factors have been identified, sulfur amino acids (SAAs), recently indicated as independent cardiovascular risk factors, have been poorly investigated in patients with Cushing's syndrome. AIM: The aim of this cross-sectional controlled study was to evaluate serum and urinary levels and urinary excretion rate (ER) of SAAs in patients with Cushing's disease (CD) during the active disease and after long-term disease remission. SUBJECTS AND METHODS: Forty patients with CD (20 with active disease and 20 with cured disease for at least 5 yr) and 40 controls entered the study. Serum and urinary concentrations and urinary ER of SAAs, namely methionine, cystine, homocysteine, and taurine, were measured by means of cationic exchange HPLC. Serum folic acid and vitamin B12 levels were also evaluated in patients and controls and correlated to SAA levels. RESULTS: CD patients with active disease had higher serum and urinary concentrations of cystine and homocysteine, and lower serum and higher urinary concentrations and ER of taurine than cured patients and controls. Vitamin B12 levels were significantly decreased in patients with active disease compared with cured patients and controls, whereas folic acid levels were slightly decreased in patients than in controls. In patients with active CD, urinary cortisol concentrations were significantly and inversely correlated to serum taurine and directly correlated to taurine urinary ER, and fasting serum glucose levels were significantly correlated to taurine urinary ER. At the multiple regression analysis, urinary cortisol concentrations were the best predictors of taurine ER. CONCLUSIONS: CD is associated with hyperhomocysteinemia and hypotaurinemia. Glucocorticoid excess, acting directly or indirectly, seems to be the most responsible for this imbalance in SAA levels. The long-term disease remission is accompanied by normalization of SAA levels. Hyperhomocysteinemia and hypotaurinemia might contribute to the increased cardiovascular risk of CD.

Arginase inhibition slows the progression of renal failure in rats with renal ablation.

Exogenous arginine slows the progression of chronic renal failure (CRF) in remnant rats through a nitric oxide (NO)-dependent mechanism. We tested whether the inhibition of arginase could induce similar results through the increased availability of endogenous arginine. Three groups of remnant rats were studied for 8 wk: 1) untreated rats (REM); 2) remnant rats treated with 1% l-arginine (ARG); and 3) remnant rats administered a Mn(2+)-free diet to inhibit arginase (MNF). Normal rats (NOR) were used as controls. Liver arginase activity was depressed in MNF rats (-35% vs. REM, P < 0.01). No difference in metabolic data was detected among the groups throughout the study; blood pressure was significantly lower in MNF vs. ARG and REM rats after 6 wk (P < 0.001). The glomerular filtration rate (GFR) was greatly depressed in REM rats (-47% vs. NOR, P < 0.03) but was higher in ARG and MNF rats (+40 and +43% vs. REM, respectively, P < 0.05), with comparable changes in renal hemodynamics. Despite the better GFR, proteinuria was decreased in both ARG and MNF rats (-42%, P < 0.05, and -57%, P < 0.01, respectively, vs. REM rats). Arginine plasma levels, significantly reduced in REM rats (-41% vs. NOR, P < 0.01), were partially restored in MNF rats (+38% vs. REM), and urinary nitrite excretion, greatly depressed in REM rats (-76% vs. NOR, P < 0.01), was significantly increased in MNF rats (+209% vs. REM, P < 0.05). At the renal level, arginase activity was only slightly depressed in MNF rats (-18% vs. REM), but intrarenal concentrations of arginine were lower in this latter group (P < 0.05 vs. other groups). Beyond the hemodynamic modifications, MNF rats showed a lower glomerular sclerosis index (P < 0.05 vs. REM and ARG). Inhibition of arginase slows the progression of CRF in remnant rats similarly to arginine-treated rats; the better histological protection in MNF rats, however, suggests that additional factors are involved in these modifications.