New 1,4‐Dihydropyridines Down‐regulate Nitric Oxide in Animals with Streptozotocin‐induced Diabetes Mellitus and Protect Deoxyribonucleic Acid against Peroxynitrite Action
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 imp...
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Published in | Basic & clinical pharmacology & toxicology Vol. 119; no. 1; pp. 19 - 31 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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01.07.2016
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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 STZ‐treated 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. |
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AbstractList | 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 STZ-treated 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. 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‐ DHP s) are prospective compounds from this point of view. The goals of this study were to study the in vivo effects of new DHP s 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 STZ ‐treated animals. Cerebrocrast treatment was followed by normalization of NO production in the liver, kidneys and blood. Two other DHP s, 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 DHP s did not significantly inhibit the activities of NOS and XOR but affected the reactivity of peroxynitrite with DNA . These new DHP s thus appear of strong interest for treatment of DM complications. |
Author | Boucher, Jean‐Luc Baumane, Larisa Sjakste, Tatjana Sjakste, Nikolajs Rostoka, Evita Leonova, Elina Sokolovska, Jelizaveta Isajevs, Sergejs |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26663724$$D View this record in MEDLINE/PubMed |
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Snippet | Diabetes mellitus (DM) and its complications cause numerous health and social problems throughout the world. Pathogenic actions of nitric oxide (NO) are... Diabetes mellitus ( DM ) and its complications cause numerous health and social problems throughout the world. Pathogenic actions of nitric oxide ( NO ) are... |
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SubjectTerms | Animals Blood Glucose - metabolism Deoxyribonucleic acid Diabetes Diabetes Mellitus, Experimental - drug therapy Dihydropyridines - pharmacology DNA DNA - chemistry Down-Regulation Kidney - drug effects Kidney - metabolism Liver - drug effects Liver - metabolism Male Nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase Type II - antagonists & inhibitors Nitric Oxide Synthase Type II - metabolism Nitric Oxide Synthase Type III - antagonists & inhibitors Nitric Oxide Synthase Type III - metabolism Peroxynitrous Acid - chemistry Protective Agents - pharmacology Rats Rats, Wistar Reactive Nitrogen Species - metabolism Reactive Oxygen Species - metabolism Rodents Xanthine Dehydrogenase - antagonists & inhibitors Xanthine Dehydrogenase - metabolism |
Title | New 1,4‐Dihydropyridines Down‐regulate Nitric Oxide in Animals with Streptozotocin‐induced Diabetes Mellitus and Protect Deoxyribonucleic Acid against Peroxynitrite Action |
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