New 1,4‐Dihydropyridines Down‐regulate Nitric Oxide in Animals with Streptozotocin‐induced Diabetes Mellitus and Protect Deoxyribonucleic Acid against Peroxynitrite Action

Abstract

Diabetes mellitus (DM) and its complications cause numerous health and social problems throughout the world. Pathogenic actions of nitric oxide (NO) are responsible to a large extent for development of complications of DM. Search for compounds regulating NO production in patients with DM is thus important for the development of pharmacological drugs. Dihydropyridines (1,4-DHPs) are prospective compounds from this point of view. The goals of this study were to study the in vivo effects of new DHPs on NO and reactive nitrogen and oxygen species production in a streptozotocin (STZ)-induced model of DM in rats and to study their ability to protect DNA against nocive action of peroxynitrite. STZ-induced diabetes caused an increase in NO production in the liver, kidneys, blood and muscles, but a decrease in NO in adipose tissue of STZtreated animals. Cerebrocrast treatment was followed by normalization of NO production in the liver, kidneys and blood. Two other DHPs, etaftorone and fenoftorone, were effective in decreasing NO production in kidneys, blood and muscles of diabetic animals. Furthermore, inhibitors of nitric oxide synthase (NOS) and an inhibitor of xanthine oxidoreductase (XOR) decreased NO production in kidneys of diabetic animals. Treatment with etaftorone decreased expression of inducible NOS and XOR in kidneys, whereas it increased the expression of endothelial NOS. In vitro, the studied DHPs did not significantly inhibit the activities of NOS and XOR but affected the reactivity of peroxynitrite with DNA. These new DHPs thus appear of strong interest for treatment of DM complications.

Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [disodium-2,6-dimethyl-1,4-dihydropyridine- 3,5-bis(carbonyloxyacetate) derivatives] in intact and diabetic rats

“…The mixture was mixed thoroughly and titrated with 7.48 mmol L -1 of sonicated pTZ57R plasmid DNA solution, 5 μL each time to both sample and reference cells. Spectra were recorded in 400-200 nm interval at room temperature (10 …”

“…Rat kidney, heart, eye and sciatic nerve tissue specimens were processed and examined essentially as described (10). Tissue specimens were fixed in 10 % neutral buffered formalin and embedded in paraffin.…”

“…Gene expression studies were performed as described (10). Total RNA was isolated from kidneys and blood using TRI reagent and purified using DNA-free kit (Ambion, Austin, TX, USA).…”

“…For example, cerebrocrast promoted decrease of food intake (6), protected pancreatic cells from streptozotocin (STZ)-induced damage and reduced glucose level in blood of animals with developed DM (7,8), and acted synergistically with insulin on heart functions and metabolism in diabetic rats (9). The same 1,4-DHP derivative and its analogues normalised nitric oxide (NO) production in diabetic animals and modified expression of genes involved in NO metabolism (10). Besides its antioxidant properties, 1,4-DHP derivative AV-153 turns out to be a DNA repair enhancer (11) capable of interacting directly with DNA (12); cerebrocrast and its analogues manifest identical properties (10).…”

“…The same 1,4-DHP derivative and its analogues normalised nitric oxide (NO) production in diabetic animals and modified expression of genes involved in NO metabolism (10). Besides its antioxidant properties, 1,4-DHP derivative AV-153 turns out to be a DNA repair enhancer (11) capable of interacting directly with DNA (12); cerebrocrast and its analogues manifest identical properties (10). We have shown that AV-153 down-regulates poly(ADP)ribose polymerase 1 (PARP1) and inducible NO synthase (iNOS) protein expression and increases the level of endothelial NO synthase (eNOS) protein and H2A histone family member X (H2afx) gene expression in kidneys of animals with experimental DM (13).…”