P5: Enhanced expression of xanthine oxidase and NO synthases causing the overproduction of NO in kidneys of diabetic animals can be reduced by 1,4-dihydropyridines

Abstract

Pathogenic action of nitric oxide (NO) is responsible to a large extent for development of complications of the diabetes mellitus (DM). NO overproduction is largerly responsible for development of diabetic nephropathy. Thus search for compounds modifying NO production appears to be important for development of pharmacological remedies for treatment of DM complications. Dihydropiridines (DHP) appear to be prospective compounds from this point of view. The goal of the present work was to study alterations of NO production in streptozotocin model of DM in rats and ability of several DHPs and to normalize NO synthesis in kidneys of these animals. Diabetes mellitus was induced in rats by streptozotocin injection. Development of the disease was checked by monitoring blood glucose level. Production of nitric oxide was monitored by means of ESP spectroscopy of Fe-DETC-NO complex. Transcription intensity was monitored by means of the real time RT-PCR, expression of proteins-by immunohistochemistry. Development of streptozotocin diabetes was followed by an almost 10-fold increase of NO production in kidneys. To evaluate possible mechanisms of the increase in NO production in diabetic animals the inhibitor analysis was performed. Neutrophil migration inhibitor GdCl3 did not produce any effect. Nonselective NOS inhibitor aminoguanidine decreased the NO production, iNOS specific inhibitor 1400 W also decreased the NO production, but not significantly. To evaluate contribution of NO produced by reduction of nitrites, xantine oxidase inhibitor allopurinol was administered to diabetic animals; the drug effectively decreased NO production. Treatment by 1,4 dihydropyridines (cerebrocrast, etaftorone and fenoftorone 0.5 mg/kg per os for 3 days) was followed by normalization of NO production in the kidneys. Etaftoron decreased expression of iNOS and xanthine oxidase in kidneys, expression of eNOS was increased. Overproduction of nitric oxide in animals with streptozotocin diabetes mellitus is due to both induction of iNOS and activation of nitrite reduction by xanthine oxidase. Overproduction is down-regulated by cerebrocrast, etaftoron and fenoftoron, the effect is achieved in part by inhibition of iNOS and xanthine oxidase expression. This makes these compounds to be prospective for treatment of DM complications. The work was supported from National Research Program 2010.10.-4/VPP4; participation in the Conference was enabled due to the European Regional Development Foundation project 2DP/2.1.1.2.0./10/APIA/VIAA/002/. Nothing to disclose.