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PubMed2001

Evidence for inducible nitric-oxide synthase expression and activity in vascular smooth muscle of streptozotocin-diabetic rats.

Experiments were performed to investigate whether nitric-oxide synthase (NOS) activity can be detected in vascular smooth muscle (VSM) from 12- to 14-week streptozotocin (STZ)-diabetic rats. Concentration-response curves to norepinephrine (NE) of superior mesenteric arteries from diabetic and age- and gender-matched control rats were obtained in the presence of dexamethasone (0.1 microM) to prevent in vitro induction of iNOS. Incubation of endothelium-intact arteries from diabetic rats with the nonselective NOS inhibitor, N(5)-(1-iminoethyl)L-ornithine (L-NIO) (300 microM), increased the NE sensitivity (expressed as the pD2 or -log EC50) from 6.58 +/- 0.05 to 8.39 +/- 0.12 (mean +/- S.E.M., n = 8). L-NIO produced a significantly smaller increase in the NE pD2 value in endothelium-intact arteries from control rats (from 6.51 +/- 0.03 to 7.08 +/- 0.03, p < 0.05). On endothelium removal, L-NIO still increased the NE pD2 value in diabetic arteries, from 7.48 +/- 0.03 to 8.38 +/- 0.15 (p < 0.05), but had no effect in control arteries. The selective iNOS inhibitor S-ethylisothiourea (EIT), but not the selective nNOS inhibitor 7-nitroindazole (7-NINA), produced an increase in the NE pD2 value in endothelium-denuded mesenteric arteries from diabetic but not control rats. Immunohistochemical staining indicated the presence of iNOS (but not eNOS or nNOS) in the medial and adventitial layers of mesenteric arteries from diabetic but not control rats. Quantitative measurement of cytosolic NOS activity indicated no significant calcium-dependent (nNOS) activity in control or diabetic arteries, or calcium-independent (iNOS) activity in control arteries. However, significant calcium-independent (iNOS) activity was detected in diabetic arteries. These data suggest that iNOS is functionally expressed in VSM of arteries from 12- to 14-week STZ-diabetic rats. The possible causes and consequences of the iNOS induction are discussed.

Animals↗
PubMed2000

In vitro comparison of inhibitors of inducible nitric oxide synthase in a macrophage model.

Nitric oxide (NO) has been shown to decrease cardiac performance, induce global hypotension, and generate oxygen free-radicals. Nitric oxide is produced from the conversion of L-arginine to L-citrulline by inducible nitric oxide synthase (iNOS) and is a component of many cellular second messenger systems. It is not clearly understood if NO and iNOS are compensatory mechanisms or pathological processes in heart failure, and this study was designed to understand better inhibition of iNOS in a cell culture model. Inhibitors of iNOS were compared for in vitro capability of inhibiting the production of NO. Ethanol and S-methylisothiourea (MITU) were applied to macrophage populations in 120 microM and 1 microM, 100 and 10 nM for an 8-h incubation. Level of iNOS expression was measured in the ethanol-treated populations using an anti-iNOS primary antibody with a fluorescent labeled secondary antibody. Serum nitrites were measured in both treatment groups by the nonenzymatic Griess method to determine enzyme function. Our data indicate that ethanol demonstrates a stimulation and simultaneous inhibition of iNOS during an 8-h incubation. No dose-dependent correlation between amount of serum nitrites produced and ethanol treatment was observed. However, MITU demonstrated a clear inhibition of iNOS at 120 microM with a serum nitrite value of 25.7002 +/- 0.0647, with control values of 24.3421 microM. Lower concentrations of MITU also demonstrated no correlation. Although both agents display inhibitory effects upon iNOS, MITU seems to have no apparent simultaneous stimulation and may hold more potential as a post-translational inhibitor of iNOS.

Animals↗
PubMed2000

[Protective effects of SMT on myocardial ultrastructure of ischemia reperfusion injury in heart of rat].

AIM: To Investigate the myocardial ultrastructure effects of SMT on the ischemia reperfusion injury (IRI) in the rat heart. METHODS: Eighteen Spraqua-Dawley rats were randomly divided into three groups: ischemia reperfusion group (IR), subjected to 60 min of o-cclusion and 20 min of reperfusion of the anterior descending branch of left coronary artery; IR + SMT group (SMT), given the selective iNOS inhibitor S-methylisothiourea sulfate (SMT, 5 mg/kg, i.v.) before reperfusion; control group (C), didn't occlude coronary artery after exposing heart and observed 80 min. Electrocardiogram (ECG) was recorded. Nitrite and nitrate content were measured in myocardium and blood serum. The changes of myocardial ultrastructure were observed with electron microscope. RESULTS: Ischemia reperfusion induced ST segment elevation and T waves inversion or tallness in ECG, damaged myocardial ultrastructure, increased nitrite and nitrate content in myocardium and blood serum after IR compared with before IR(P < 0.01). Administration of SMT improved the changes of ECG and the injury of myocardial ultrastructure. Nitrite and nitrate content of myocardium were lower than IR group (P < 0.05). The change of nitrite and nitrate level of blood serum in SMT group was nearly in C group. CONCLUSION: SMT can prevent myocardium injury from reperfusion following ischemia.

Animals↗
PubMed2001

Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice.

Cathepsin D (CD) deficiency has been shown to induce ceroid-lipofuscin storage in lysosomes of mouse CNS neuron (Koike et al., 2000). To understand the behavior of microglial cells corresponding to these neuronal changes, CD-deficient (CD-/-) mice, which die at approximately postnatal day (P) 25 by intestinal necrosis, were examined using morphological as well as biochemical approaches. Light and electron microscopic observations revealed that microglia showing large round cell bodies with few processes appeared in the cerebral cortex and thalamus after P16. At P24, microglia often encircled neurons that were occupied with autolysosomes, indicating increased phagocytic activity. These morphologically transformed microglia markedly expressed inducible nitric oxide synthase (iNOS), which was also detected in the intestine of the mice. To assess the role of microglial nitric oxide (NO) in neuropathological changes in CD-/- mice, l-N(G)-nitro-arginine methylester (l-NAME), a competitive NOS inhibitor, or S-methylisothiourea hemisulfate (SMT), an iNOS inhibitor, was administered intraperitoneally for 13 consecutive days. The total number of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells counted in the thalamus was found to be significantly decreased by chronic treatment of l-NAME or SMT, whereas neither the neuronal accumulation of ceroid-lipofuscin nor the microglial phagocytic activity was affected by these treatments. Moreover, the chronic treatment of l-NAME or SMT completely suppressed hemorrhage-necrotic changes in the small intestine of CD-/- mice, resulting in normal growth of the body weight of the mice. These results suggest that NO production via iNOS activity in microglia and peripheral macrophages contributes to secondary tissue damages such as neuronal apoptosis and intestinal necrosis, respectively.

Animals↗
PubMed2002

Effects of ornithine 2-oxoglutarate on neutrophils in stressed rats: evidence for the involvement of nitric oxide and polyamines.

Diets enriched in ornithine 2-oxoglutarate (ornithine alpha-ketoglutarate; OKG) improve immune status during stress. We described previously the ability of OKG to increase the respiratory burst in polymorphonuclear neutrophils (PMNs), but the underlying mechanisms remain unclear. OKG is usually recognized as generating glutamine, arginine and polyamines. The aim of the present study was first to determine the effects of OKG on PMN bactericidal functions (chemotaxis and respiratory burst) in stressed rats, and whether these effects could be reproduced by glutamine- or arginine-enriched diets. Secondly, we investigated the metabolic pathway involved in these actions, using three metabolic inhibitors: methionine sulphoximine (an inhibitor of glutamine synthetase), S-methylthiourea (an inhibitor of inducible nitric oxide synthase) and difluoromethylornithine (an inhibitor of ornithine decarboxylase). OKG, arginine and glutamine all increased the production of reactive oxygen species (evaluated by chemiluminescence, ferricytochrome c reduction and flow cytometry). Only OKG markedly enhanced the chemotaxis index (5-fold). Inhibition of glutamine synthetase showed that glutamine production was not involved in the action of OKG. The use of S-methylthiourea and difluoromethylornithine demonstrated that OKG modulated the respiratory burst via nitric oxide (NO*) and polyamine generation. Moreover, OKG stimulated PMN migration via NO*, but arginine administration failed to reproduce this effect. These data suggest that OKG (or its metabolites) and arginine are channelled differently in PMNs. This hypothesis deserves further study.

Animals↗
PubMed2002

[Long-term effect of nitric oxide synthase inhibitor on repair of articular cartilage defects repairing].

OBJECTIVE: To discuss the long-term effect of inducible nitric oxide synthase inhibitor S-methylisothiourea (SMT) on repair of articular cartilage defects. METHODS: Twenty-four adult New Zealand White rabbits with full-thickness defects of cartilage created in the trochlear groove of their bilateral femurs were divided into three groups randomly, 8 in each group: (1) control group in which nothing was filled into the defects; (2) BMP group in which the defects were filled with collagen fibrin gel impregnated with recombinant human bone morphogenic protein (rhBMP); and (3) SMT group in which the defects were filled with collagen fibrin gel impregnated with rhBMP and hypodermic injection of SMT (5 mg .(-1) 12 h(-1)) was given. The animals were killed one year later. The gross appearance of the defects was assessed. The amount of released NO and the activity of NOS were examined by chemical colorimetry. The distribution of collagen was examined by immunohistochemistry. The proteoglycan synthesis and cell activity was assessed by incorporation of radiolabelled sodium sulphate Na(2)(35)SO(4) and bromodeoxyuridine. RESULTS: One year after the defects in SMT group showed greater improvement in margin integration, cellular morphology, and architecture within defect than those in BMP group and control group (P < 0.01). Immunohistochemistry showed that there was less type-I collagen and more type-II collagen in SMT group than in the other two groups. Radiolabelled sodium sulphate (Na(2)(35)SO(4)) incorporation test showed that the proteoglycan synthesis in defects was higher in SMT group than in the other two groups (P < 0.01). BrdU incorporation test showed cells in repaired tissue with remarkable proliferous activity. CONCLUSION: iNOS inhibitor SMT significantly improves the quality of repair of defected cartilage and delays its degradation.

Animals↗
PubMed1975

Distribution and behaviour of isoselenium salts in organism. III. Radioprotective effect of selenium derivatives.

Radioprotective properties of Se-2-aminoethylioselenouronium bromide hydrobromide, 2-aminoselenoazoline and of selenium analogue of mercaptoethylguanidine were followed. Radio-protective effectiveness comparable with classical thiol radioprotectiva was manifested by 2-aminoselenoazoline. In the other two compounds there was on the contrary found a synergism of toxicity and radiation.

Animals↗
PubMed1975

[Clinical and experimental study on an anti-inflammatory preparation of topical use. The 10-undecentil-l-ll pseudothiourea (AHR-1911)].

Our previous studies led to the development of a drug, 10-undecen-1- pseudothiourea iodide (AHR-1911), with the characteristics of a broad spectrum of antibacterial-antimycotic action and anti-inflammatory properties in experimental lesions induced by burns, dextran, albumin, carrageenin and kaolin. Using different vehicles for topical use, these two types of therapeutic property were separated, yielding two pharmaceutical preparations with different indications. One is a 0,25% AHR-1911 preparation in a polyoxyethyleneglycol base, which in in vivo experiments has the antimicrobial efficacy of gentamycin ointment; the other, containing 10% AHR-1911 in a vanishing cream base with triethanolamine stearate, possesses the anti-inflammatory efficacy of the newer topical steroid preparations. The clinical data for this latter preparation agree with the experimental findings. Its activity in clinical conditions was found first by Di Prisco in dermatological cases and confirmed in contact dermatitis patients by Riobueno. Its usefulness in burns and contusions with excoriations, without a single instance of secondary infection was reported by Rojas Mratínez; its effectiveness in bursitis and tenosynovitis may extend its field of application beyond that of dermatology. Particularly impressive were the good results obtained in insect bites, due possibly to the antihistaminic effect of the drug acting synergistically with the anti-inflammatory one. In the experience of all the clinicians the preparation was very well tolerated.

Bacterial Infections↗
PubMed1976

Distribution and behavior of isoselenouronium salts in the body. V. Acute toxicity and metabolic fate of selenium derivatives.

The acute toxicity of AESe, 2-ASe, and Se-MEG was estimated in mice after i.v., i.p. and s.c. application. In all forms of application, 2-ASe was found to have the lowest toxicity. The study of excretion showed that administered compounds are excreted practically completely within seven days, mostly by urine. The excretion by faeces is very low and by exhalation is under the threshold of demonstrability. The metabolism of 2-ASe is slow, most of it is excreted without any change; AESe is transformed into a mixture of 2-ASe and Se-MEG. Se-MEG is excreted by urine totally metabolized as trimethylselenium ion.

Acute Disease↗
PubMed1976

Distribution and behavior of isoselenouronium salts in the body. VI. Comparative study of distribution and radioprotectivity of selenium derivatives.

The protective effect of AESe, 2-ASe, and Se-MEG during irradiation with a dose rate of 500 R/min was followed. The protective effect of 2-ASe is substantially lower during the dose rate of 20 R/min and even during an increased dose. AESe and Se-MEG are noneffective. The time of duration of the protective effect of 2-ASe corresponds to the period of its high concentration in the organism after the administration, i.e. ca. 45 min.

Animals↗
PubMed2003

Effect of nitric oxide synthase inhibitor on proteoglycan metabolism in repaired articular cartilage in rabbits.

OBJECTIVE: To study the effect of nitric oxide synthase inhibitor, S-methyl thiocarbamate (SMT), on proteoglycan metabolism in repaired articular cartilage in rabbits. METHODS: Twenty-four male New Zealand white rabbits, aged 8 months and weighing 2.5 kg+/-0.2 kg, were used in this study. Cartilage defects in full thickness were created on the intercondylar articular surface of bilateral femurs of all the rabbits. Then the rabbits were randomly divided into 3 groups (n=8 in each group). The defects in one group were filled with fibrin glue impregnated with recombinant human bone morphogenetic protein-2 (rhBMP-2, BMP group), in one group with fibrin glue impregnated with rhBMP-2 and hypodermic injection with SMT (SMT group) and in the other group with nothing (control group). All the animals were killed at one year postoperatively. The tissue sections were stained with safranine O-fast green and analyzed by Quantiment 500 system to determine the content of glycosaminoglycan through measuring the percentage of safranine O-stained area, the thickness of cartilages and the mean gray scale (average stain intensity). Radiolabelled sodium sulphate (Na(2)(35)SO(4)) was used to assess the proteoglycan synthesis. RESULTS: At one year postoperatively, the percentage of safranine O-stained area, the mean gray scale and the cartilage thickness of the repaired tissues in SMT group were significantly higher than those of BMP group (P<0.01) and the control group (P<0.05). Result of incorporation of Na(2)(35)SO(4) showed that the proteoglycan synthesis in SMT group was higher than those of BMP group and the control group (P<0.01). CONCLUSIONS: SMT, a nitric oxide synthase inhibitor, can significantly increase the content of glycosaminoglycan and proteoglycan synthesis, and computer-based image analysis is a reliable method for evaluating proteoglycan metabolism.

Analysis of Variance↗
PubMed2004

Intracerebroventricular administration of histamine H3 receptor antagonists decreases seizures in rat models of epilepsia.

The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.

Amygdala↗