Nitric oxide/L-arginine in uremia

Nitric oxide (NO), a gaseous free radical derived from L-arginine, is a pot ent modulator of vascular tone and platelet functions. A number of recent s tudies, both in the experimental model of renal mass reduction (RMR) in rat s and in uremic patients, have raised the hypothesis that abnormalities of NO synthetic pathway could have a key role in mediating the complex hemodyn amic and hemostatic disorders associated to the progression of renal diseas e. Thus, kidneys from rats with RMR produce less NO than normal rats and NO generation negatively correlates with markers of renal damage. The abnorma lity is due to a strong defect of inducible NO synthase (iNOS) content in t he kidney. Recent in vitro and in vivo data have raised the possibility tha t excessive renal synthesis of the potent vasoconstrictor and promitogenic peptide endothelin-1 (ET-1) is a major determinant for progressive iNOS los s in the kidney of RMR rats, In contrast, uremia is associated with excessi ve systemic NO release, both in experimental model and in human beings. In the systemic circulation of uremic rats, as well as uremic patients, NO is formed in excessive amounts. Possible cause of the increased NO levels is h igher release from systemic vessels due to the augmented expression of both iNOS and endothelial NOS. A putative cause for excessive NO production in uremia can be guanidinosuccinate, an uremic toxin that accumulates in the c irculation of uremic patients and upregulates NO synthesis from cultured en dothelial cells, Upregulation of systemic NO synthesis might be a defense m echanism against hypertension of uremia, On the other hand, more NO availab le to circulating cells may sustain the bleeding tendency, a well-known com plication of uremia. Copyright (C) 2000 S. Karger AG, Basel.