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Etiron is capable to recover arterial pressure reduced by phentolamine, and to correct, to a certain degree, other parameters of the systemic hemodynamics, that change after administering an alpha-adrenoblocker. The recovery of arterial pressure occurs mainly at the expense of the increased general peripheral resistance, whereas the minute circulatory volume remains almost unchanged.
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A study was made of the effect of mexamine, etiron and gutimine on the pattern of distribution of cystamine within the body and the rate of its conversion in tissues of albino mice. It was shown that the potentiation and prolongation of the radioprotective effect is based on the ability of the complex of these preparations to inhibit the conversion of the S-containing radioprotective agent.
A procedure was developed for enumeration and separation of bovine lymph node T-lymphocyte subpopulations. An evaluation was made of T-lymphocyte rosetting with sheep erythrocytes treated with aminoethylisothiouronium bromide and neuraminidase (Ea and En) in RPMI and L-15 media. The effect of holding the lymphocytes in culture over a period of 7 days on the En and Ea markers was established. The optimal period of incubation at 0 C for isolation of the rosetting populations with respect to initial rosette formation, enrichment of the rosetting population in the recovered cells, viability after incubation, and recovery of the cells after the separation was determined. An estimate of the overlap of the Ea and En populations also was made from the separation data. We found that approximately 32% of the lymph node lymphocytes marked with En and Ea rosettes, 11% with only En, and 27% with only Ea.
Acute toxicity of ethylphosphate, diethylphosphate and metaphosphate of S-ethylisothiuronium does not differ significantly when the drugs are administered to albino female mice intraperitoneally, intramuscularly or subcutaneously. However, this toxicity diminishes 4--5-fold during intragastric administration. The substances are approximately 100 mg/kg more toxic for Wistar rats as compared to mice. The radioprotective doses of the compounds administered intramuscularly ten times exert no effect on the rat behaviour, weight, peripheral blood composition, weight coefficients or histological structure of the internal organs.
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S-Ethylisothiourea was a potent competitive inhibitor of human nitric oxide synthase (NOS), with Ki values of 17, 36, and 29 nM for the inducible (i), endothelial (e), and neuronal (n) isozymes, respectively. Unlike some potent inhibitors of NOS, no time dependence was observed. S-Ethylisothiourea was not a detectable substrate for eNOS. S-Ethylisothiourea was also a potent inhibitor of mouse iNOS (Ki value of 5.2 nM), and its binding perturbed the spectrum of iNOS consistent with its altering the environment of the bound heme. The optimum binding of S-ethyl- and S-isopropylisothiourea relative to 70 other analogs suggested that these alkyl substitutions fit into a small hydrophobic pocket. Most isothioureas were 2-6-fold selective for the human iNOS (Ki for iNOS versus Ki for eNOS), with one being 19-fold selective. The cyclized mimics of S-ethylisothiourea, 2-NH2-thiazoline, and 2-NH2-thiazole, were also competitive inhibitors of human NOS. A third structural class of inhibitors, bisisothioureas, were, in general, the most selective in their inhibition of human iNOS. S,S'-(1,3-Phenylenebis(1,2-ethanediyl))bisisothiourea was 190-fold selective (Ki value of 0.047 microM against iNOS versus 9.0 microM against eNOS). These results demonstrate that potent and selective inhibition of human NOS isozymes is achievable.
We have identified two novel potent and selective inhibitors of inducible nitric oxide synthase, S-ethylisothiourea and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. Ki values of 14.7 nM for S-ethylisothiourea and 4.2 nM for 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine were obtained with partially purified preparations of inducible nitric oxide synthase. These compounds demonstrate about 1000-fold greater potency than prototypical inhibitors, and the inhibitions are 10-40-fold more selective for murine inducible nitric oxide synthase, compared with the rat neuronal and bovine endothelial isoforms of nitric oxide synthase. These compounds also potently inhibit the nitric oxide synthase activity in intact J774 mouse macrophages. The inhibition is competitive with the substrate L-arginine and reversible in both enzymatic and intact cell assays. These potent and selective inhibitors of inducible nitric oxide synthase may have potential therapeutic applications in the treatment of inflammatory and autoimmune diseases.
Nitric oxide (NO), an unstable radical, is synthesized from L-arginine by the constitutive (cNOS) and inducible (iNOS) forms of NOS. cNOS is present mainly in endothelial cells and plays a role in the regulation of blood flow. iNOS, the dominant enzyme in heart muscle during myocardial infarction, allograft rejection, and cardiomyopathy, is activated in macrophages. We recently described a significant increase of iNOS activity in macrophages of infarcted rabbit myocardium 24 hours after coronary occlusion, with peak activity occurring 3 days following coronary artery ligation. Inhibitors of NOS are L-arginine derivatives that inhibit both cNOS and iNOS; S-methylisothiourea (SMT) and aminoguanidine (AMG) are specific inhibitors of iNOS. Cyclosporin A and dexamethasone inhibit by interfering with protein synthesis. iNOS inhibition by SMT, NG-nitro-L-arginine (L-NNA), AMG, cyclosporin A and dexamethasone was examined in homogenates of normal, risk and infarcted myocardium. Three days after coronary artery ligation, the heart was excised and divided into normal, risk and infarcted regions. The inhibitory effect was calculated as IC50. Results shows that SMT was the most potent inhibitor with the lowest IC50; its effect, as well as the effects of L-NNA and AMG, depended on the location in the myocardium. Inhibition for SMT and AMG was greater in the normal area than in the risk and infarcted regions. AMG induced an initial rise of iNOS followed by gradual decline in the area of risk and infarction. No inhibitory effects in cyclosporin A and dexamethasone were noted.
OBJECTIVE: To investigate the effects of S-methylisothiourea sulfate (SMT), a selective inducible nitric oxide synthase (iNOS) inhibitor, on hyperdynamic endotoxic shock sheep. METHODS: Endotoxic shock was induced by Escherichia coli endotoxin in both control (n = 8) and SMT groups (n = 8). SMT was given intravenously. Hemodynamic data, oxygen delivery derived parameters and intramucosal pH (pHi) were measured. RESULTS: The control group had a hyperdynamic state, similar to that of human septic shock. In the SMT group, blood pressure was maintained at baseline, and cardiac index (CI) was lower than that in the control group (P < 0.05). Oxygen extraction ratio (O2 ext) was increased up to 40% +/- 5% and was much higher than that of the control group (P < 0.01). Pulmonary artery pressure (PAP) was higher than that of the control group (P < 0.01), and pHi decreased gradually similarly to the control group. CONCLUSION: SMT restored the blood pressure and increased O2 extespecially in the gut, but decreased CI and oxygen delivery and increased PAP. So over inhibition of iNOS should be cautiously considered.
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In this study we compared the circulatory effects of the arginine analogue non-specific nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine (NNA), and the specific inducible NOS (iNOS) inhibitor S-methylisothiourea (SMT) and S-(2-aminoethyl)-isothiourea (AEST) in a hyperdynamic endotoxemic dog model. Mean arterial pressure (MAP), cardiac output (CO), and myocardial contractility (MC) were measured. A hyperdynamic circulatory response was elicited with a 2-h infusion of a total dose of 5.3 micrograms/kg E. coli endotoxin (ETX). NOS inhibitory treatment (2 mg/kg) was administrated from the 45th min of endotoxemia. ETX induced a hyperdynamic circulatory response, and a significant myocardial depression. NNA induced a prolonged, SMT a transient increase in MC, both drugs elevated MAP, but decreased CO. AEST significantly prolonged the elevation in CO, but did not affect MAP. Selective inhibition of the iNOS may be a beneficial in sepsis.
Nitric oxide (NO) is produced by inducible NO synthase (iNOS) after LPS stimulation, and reacts with superoxide to form peroxynitrite. We hypothesize that in LPS-induced lung injury, NO generated by iNOS plays a key role through the formation of peroxynitrite. We developed an acute lung injury dog model by injecting LPS, and examined the effects of selective iNOS inhibitors, aminoguanidine (AG) and S-methylisothiourea sulfate (SMT), on the LPS-induced lung injury. At 24 h after LPS injection, arterial oxygen tension and mean arterial pressure decreased, and shunt ratio and lung wet-to-dry weight ratio increased. On histology, the LPS group had marked neutrophil infiltration and widening of the alveolar septa. On immunohistochemistry, iNOS and nitrotyrosine, a major product of nitration of protein by peroxynitrite, were observed in the interstitium, capillary wall, and neutrophils in the airspaces of the LPS group. Treatments with AG and SMT prevented worsening of gas exchange, hemodynamics, and wet-to-dry weight ratio. On histology, AG and SMT treatments markedly suppressed lung injury, iNOS protein, and nitrotyrosine production. We conclude that NO released by iNOS may play a critical role in the pathogenesis of LPS-induced acute lung injury. This study suggests that iNOS inhibitors may have potential in the treatment of LPS-induced acute respiratory distress syndrome.
Studies were carried out to assess the importance of nitric oxide (NO) production in vivo in resistance to Eimeria tenella infections through treatment of resistant SC and susceptible TK strains of chickens with compounds proven to be effective inhibitors of induced nitric oxide synthase. The SC strain produced higher levels of plasma NO2- + NO3- in response to primary infection than did the TK strain. SC chickens were also more responsive in reduction of NO2- + NO3- levels and increased oocyst output in response to treatments with S-methylisothiourea or NG-methyl-L-arginine (LNMA) during primary infection. However, the SC strain, regardless of drug treatment, consistently yielded higher oocyst output during primary infection, indicating it could be susceptible to a higher parasite burden. On the other hand, the SC strain seemed to develop immunity more rapidly than the TK strain, in that oocyst output was decreased in both untreated and LNMA-treated chicks upon challenge infection compared with that of the TK strain. Oocyst output from both SC and TK strains was further decreased by LNMA treatment during challenge infection rather than increased, suggesting minimal involvement of NO production in the immune response to challenge. These results indicate that NO production during primary E. tenella infection may be only one of several immune responses and may not be the main anticoccidial effector.