Peroxynitrite versusnitric oxide in early diabetes

Abstract Background Peroxynitrite is a toxic compound formed during the inactivation of nitric oxide (NO) by the superoxide anion. The physiologic significance of this pathway of NO metabolism has never been documented in vivo. Because peroxynitrite provides a pathway for the inactivation of NO we postulated that peroxynitriteʹs correlation with physiologic parameters would be the opposite of those associated with NO, which is a vasodilator and suppresses sudomotor function. We assessed the significance of peroxynitrite by comparing its associations with blood pressure (BP) and sudomotor responses with those of NO. Methods Thirty-seven patients with type 1 diabetes enrolled in a longitudinal study of oxidative stress. Nitric oxide was assessed from nitrite and nitrate (collectively NOx) and peroxynitrite was assessed from the nitrotyrosine (nTy) content of protein. Results nTy was 13.3 ± 2.0 μmol/L in the control subjects and 26.8 ± 4.4 μmol/L, 26.1 ± 4.3 μmol/L, and 32.7 ± 4.3 μmol/L in the diabetic patients (P< .01) at the time of the first, second, and third evaluations, respectively. Patients with increased nitrotyrosine/tyrosine (nTy/Ty) had higher mean BP than those with low nTy/Ty (81.1 ± l.9 mm Hg v 75.5 ± 1.7 at the third evaluation, P< .025). The ratio of nTy/NOx correlated with BP at the first (P< .05), second (P< .05), and third (P< .01) evaluations. Patients with high nTy/Ty had increased sudomotor responses (5.85 ± 0.75 μL of total sweat) at the third evaluation compared to those with low nTy/Ty (3.32 ± 0.43 μL, P< .005) and normal controls (3.90 ± 0.41 μL, P< .05). The associations of nTy with BP and sudomotor responses were the opposite of those with NOx. Conclusions The conversion of NO oxide to peroxynitrite is physiologically significant in humans.