Nitric Oxide Production In Kidney Research Articles

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 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.

Electrochemical Assessment of Possible Melatonin Effect On Nitric Oxide Production From Kidneys Of Sub-Acute Lead Treated Rats

Nitric oxide (NO) is known to be implicated in various renal diseases induced by lead poisoning and recent works have shown the effect of some antioxidants in reducing the toxic effects of lead. Melatonin is attractive for its direct and indirect antioxidant effects; furthermore it is naturally produced in mammalians, including humans. Recently, it has been shown that melatonin attenuates the toxic effects of sub-acute lead intoxication in kidneys without altering NO metabolites concentration. This work demonstrates the use of nickel tetrasulfonated phthalocyanine/polyphenol-modified ultramicroelectrodes to monitor in vivo and in situ changes of NO within rat kidneys. NO itself was detected directly and in real-time inside the kidney of lead and melatonin treated rats after induction by L-arginine. The results indicate that NO production decreases in lead treated rats, likewise in co-treated with melatonin rats. In addition, melatonin administration did not affect the production of NO respect to the control. By means of these experiments was verified that melatonin does not alters NO production in kidneys during sub-acute lead intoxication.

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

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.

Inflammation, Immunity, and Hypertension

Aprominent pathology textbook used in the United States includes an image illustrating the renal histopathology caused by malignant hypertension. The legend describes striking “onion skin” changes of a renal arteriole. Curiously, a sea of mononuclear inflammatory cells surrounding this arteriole is overlooked both in the legend and in the related text. Moreover, nothing regarding inflammation or immune reactions is discussed. This lack of attention to inflammatory cells is, however, not surprising. Although many experimental studies have implicated inflammation in hypertension, these have largely been performed in experimental animals; there is no proof that inflammation contributes to human hypertension. In fact, some anti-inflammatory or immune-suppressing drugs (eg, nonsteroidal anti-inflammatory drugs and cyclosporine) paradoxically cause hypertension in humans, likely via off-target effects. Often the term “inflammation” is used in the context of cardiovascular disease as a catchall referring to nonspecific phenomena, such as elevation of C-reactive protein or the presence of macrophages in a tissue. Most clinicians and investigators find this vague and difficult to understand. Even more puzzling is that many studies now implicate the adaptive immune response, and in particular, lymphocytes, in hypertension and vascular disease. Traditionally, bacterial, viral, or tumor antigens activate this arm of immune defense. As such, it has been hard to imagine how adaptive immunity could be involved in a disease such as hypertension. In this article, we will attempt to address some of these puzzling questions. We will briefly review components of the innate and adaptive immune response, discuss data from many groups, including our own, that suggest that common forms of hypertension are immune mediated, and provide a working hypothesis of how signals from the central nervous system trigger an immune response that causes hypertension. ### General Concepts Regarding Inflammation and Immunity #### Innate Immunity The first line of defense against pathogens is the innate immune response. Important components of this system include epithelial …

Endothelin receptor antagonist reverses decreased NO system in the kidney in vivo during exercise.

Vascular endothelial cells produce endothelin (ET)-1, a potent vasoconstrictor peptide, and nitric oxide (NO), a potent vasodilator substance. There are interactions between ET-1 and NO. Exercise results in a marked decrease in renal blood flow. We previously reported that exercise causes an increase of ET-1 production in the kidney, whereas production of NO in the kidney is decreased. Furthermore, we recently revealed that the magnitude of decrease in blood flow to the kidney during exercise was significantly attenuated by the administration of the endothelin-A (ET(A)) receptor antagonist, strongly suggesting that endogenously increased ET-1 participates in the decrease of blood flow in the kidney during exercise. Because it was demonstrated that ET-1 depresses NO synthase (NOS) activity of cultured cells in vitro, we hypothesized that an increase of ET-1 production in kidney during exercise contributes to a decrease of NO production in kidney in vivo. We studied whether administration of the ET(A) receptor antagonist attenuates the decreases of NOS activity and NO production in the kidney during exercise. Rats performed treadmill running for 30 min after pretreatment with an ET(A) receptor antagonist (TA-0201, 0.5 mg/kg; TA-0201-treated exercise group) or vehicle (vehicle-treated exercise group). Control rats remained at rest (vehicle-treated sedentary group). Blood flow in the kidney was decreased by this exercise, but the magnitude of the decrease after pretreatment with TA-0201 was significantly smaller than that after pretreatment with vehicle. NOS activity in kidney was significantly lower in the vehicle-treated exercise group than in the vehicle-treated sedentary group, whereas that in the TA-0201-treated exercise group was significantly higher than that in the vehicle-treated exercise group. Expressions of endothelial NOS protein and NOx, the stable end product of NO, i.e., nitrite/nitrate, concentration in the kidney were significantly lower in the vehicle-treated exercise group than in the vehicle-treated sedentary group, whereas those in the TA-0201-treated exercise group were significantly higher than those in the vehicle-treated exercise group. The data suggest that increased ET-1 production in the kidney during exercise contributes to the decreases of NOS activity and NO production. Therefore, the present study provides a possibility that the exercise-induced increase in production of ET-1 in the kidney causes a decrease in blood flow in the kidney through two pathways, i.e., vasoconstrictive action and the action of attenuating NO production.