Objective: Nitric Oxide (NO) is a "vital poison" for the immune and the inflammatory pathways: overproduction, through upregulation of inducible NO synthase (iNOS) may contribute to the evolution of several commonly encountered renal diseases, but it is also essential for the upregulation of the inflammatory response. Since classical, non specific NOS inhibitors block both inducible and constitutive NOS, they are detrimental for the renal function; thus we investigated the use of a selective iNOS inhibitor (H4 biopterin analogue) to block the noxious NO release, but maintain the protective basal NO levels. Methods: Using a tubular epithelial-endothelial co-culture model, we compared the effects of unspecific and specific NOS inhibition on cell morphology, apoptosis, electrochemical properties adherence, fibronectin expression cell membrane integrity and the cytokine release, under physiological and simulated inflammatory conditions. Results: The arginine-based NOS inhibitor (non selective) appears to be harmful at a cellular level, inducing a concentration-dependent increase in electrical resistance of the bilayer (p= 0.02, at 1mM), affecting the fibronectin expression and release, the cell membrane integrity (at 10mM, p=0.005 in endothelial cells of the bilayer). The specific iNOS inhibitor, instead, did not show these injurious effects, except on cell membrane integrity when used at high concentrations (>=1mM, p=0.004 in the epithelial monolayer, >=100mM, p=0.002 in endothelial cells of the bilayer). Conclusions: The selective iNOS inhibitor, used at controlled concentrations, has a potential in the treatment of a range of inflammatory and other conditions, in which iNOS is upregulated, due to its ability to downregulate NO overproduction, preserving any renal protective effect of eNOS.