Attenuation of bleomycin induced lung fibrosis by erdosteine and inhibition of the inducible nitric oxide synthase.

BACKGROUND AND OBJECTIVES: Despite advances in treatment modalities, the discovery of optimal medical therapies still remains a necessity in the management of pulmonary fibrosis. MATERIAL AND METHODS: The experiments were performed in 35 adult Sprague Dawley rats, randomly allotted into one of five groups (n=7). The control group was treated with 1 ml/kg, 0.9 % saline; the BLM group was given a single dose of BLM (2.5 U/kg); the BLM+ER group was treated with ER (10 mg/kg/day po) for 14 days after BLM administration; the BLM+SMT group was treated with i.p injections of SMT (20 mg/kg/ day) for 14 days after BLM administration; the BLM+ER+SMT group was treated with ER and SMT for 14 days after BLM administration. At the end of day 14, the results of histopathological, biochemical, and immunohistochemical investigations were analyzed. RESULTS: Serum TNF-α, nitrate/nitrite, and TBARS levels significantly increased in BLM group compared to control group (p < 0.001, p < 0.001 and p < 0.05 respectively). Lung tissue content of IL-6 was found to be lower in BLM+ER, BLM+SMT and BLM+ER+SMT groups compared to BLM group by immunhistochemical examinations (p < 0.01, p < 0.01 and p < 0.001, respectively). Similarly, the TNF-α reactions (p < 0.01 for each group) and NF-kB expressions were shown to be significantly different among the study groups (p < 0.05, p < 0.05 and p < 0.001, respectively). CONCLUSION: Based on our study, ER and SMT attenuate BLM-induced pulmonary fibrosis; the combination of two agents has a greater protective efficacy against fibrosis than one alone, reducing the inflammatory markers (Tab. 2, Fig. 2, Ref. 31).

Effect of iNOS inhibitor S-methylisothiourea in monosodium iodoacetate-induced osteoathritic pain: implication for osteoarthritis therapy.

Much information is available on the role of nitric oxide (NO) in osteoarthritis (OA). However, its role has not been studied in the monosodium iodoacetate (MIA)-induced model of osteoarthritic pain. The present study was undertaken in rats to investigate the effect of iNOS inhibitor S-methylisothiourea (SMT) in MIA-induced osteoathritic pain and disease progression in rats. Osteoarthritis was produced by single intra-articular injection of the MIA in the right knee joint on day 0. Treatment groups were orally gavazed with different doses of SMT (10, 30 and 100mg/kg) and etoricoxib (10mg/kg) daily for 21 days. On days 0, 3, 7, 14 and 21, pain was measured and histopathology of right knee joint was done on day 21. SMT produced analgesia in a dose-dependent manner as shown by mechanical, heat hyperalgesia, knee vocalization, knee squeeze test, and spontaneous motor activity test. SMT reduced NO production in synovial fluid. Histopathological findings indicated that SMT reduced disease progression as evident from complete cartilage formation in rats treated with SMT at 30 mg/kg. In conclusion, the results indicate that SMT attenuates the MIA-induced pain and histopathological changes in the knee joint. The antinociceptive and antiarthritic effects of SMT were mediated by inhibiting cartilage damage and suppression of NO in synovial fluid. It is suggested that SMT has potential as a therapeutic modality in the treatment of osteoarthritis.

Effect of S-methylisothiourea in acetaminophen-induced hepatotoxicity in rat.

Nitric oxide synthesized from inducible nitric oxide synthase (iNOS) plays role in acetaminophen (APAP)-induced liver damage. The present study was undertaken to evaluate the effect of iNOS inhibitor S-methylisothiourea (SMT) in APAP-induced hepatotoxicity in rats (1 g/kg, i.p.). SMT was (10, 30, and 100 mg/kg; i.p.) given 30 min before and 3 h after APAP administration. At 6 and 24 h, blood was collected to measure alanine transaminase (ALT), aspartate transaminase (AST), and nitrate plus nitrite (NOx) levels in serum. At 48 h, animals were sacrificed, and blood and liver tissues were collected for biochemical estimation. SMT reduced significantly the serum ALT, AST, and NOx levels at 24 and 48 h and liver NOx levels at 48 h as compared with APAP-treated control. The amount of peroxynitrite measured by rhodamine assay was significantly reduced by SMT, as compared with APAP-treated control group. SMT treatment (30 mg/kg) has significantly reduced the lipid peroxidation and protein carbonyl levels, increased SOD and catalase, and reduced glutathione and total thiol levels significantly as compared with APAP-treated control. SMT 30 mg/kg dose has protected animals from APAP-induced hypotension and reduced iNOS gene expression. Hepatocytes were isolated from animals, and effect of SMT on apoptosis, MTP, and ROS generation was studied, and their increased value in APAP intoxicated group was found to be significantly decreased by SMT (30 mg/kg) at 24 and 48 h. In conclusion, nitric oxide produced from iNOS plays important role in toxicity at late hours (24 to 48 h), and SMT inhibits iNOS and reduces oxidative and nitrosative stress.

Neuroprotective effect of s-methylisothiourea in transient focal cerebral ischemia in rat.

Over production of NO by nitric oxide synthase (NOS) in the brain parenchyma has been demonstrated to contribute to tissue damage. NO may be toxic by formation of peroxinitrite after a reaction between NO and superoxide appears to be one of the major pathways leading to cell death. Of three types of NOS, nNOS is neurotoxic in early and iNOS in late stage of transient cerebral ischemia (TFCI), while eNOS is neuroprotective in all stages. We examined the neuroprotective effect of a preferential iNOS inhibitor s-methylisothiourea (SMT) at 0, 8, 24 and 48h as multiple injections (30 and 100mg/kg, i.p.) in ischemia and reperfusion injury in a rat model of middle cerebral artery occlusion (2h) and reperfusion (72h). After 2h of ischemia and 72h of reperfusion, animals were sacrificed for studying the infarct volume, brain edema and apoptosis and neuro-behavioral abnormality was assessed at 24, 48 and 72h of reperfusion. SMT reduced significantly the infarct volume, neuro-behavioral abnormality, brain edema, number of apoptotic cells in penumbra and NOx levels in plasma and brain both at 30 and 100mg/kg in dose-dependent manner. The amount of peroxynitrite measured by rhodamine assay was significantly reduced by SMT, as compared to control group. SMT protected Neuro 2a cells against sodium azide-induced damage. It is concluded that, SMT may possibly targeting both constitutive as well as inducible NOS at varying time interval to elicit neuroprotection in TFCI rats.

Sympathoinhibitory mechanism of moxonidine: role of the inducible nitric oxide synthase in the rostral ventrolateral medulla.

AIMS: The central antihypertensive drug moxonidine lowers blood pressure (BP) through stimulating an imidazoline receptor within the rostral ventrolateral medulla (RVLM). Nitric oxide (NO) generated by the inducible NO synthase (iNOS) in the RVLM has been suggested to be involved in tonic sympathetic inhibition. The aim of this study was to determine the role of NO generated by iNOS in mediating moxonidine-induced cardiovascular inhibition in rats. METHODS AND RESULTS: In anaesthetized rats, the cardiovascular response to local or systemic injection of moxonidine was observed after treatment with the selective iNOS inhibitor S-methylisothiourea (SMT) in the brain. Using immunohistochemical staining and western blot techniques, the protein expression of iNOS in the RVLM was measured in the moxonidine-infused rats. Intracerebroventricular (ICV) injection of SMT (1-100 nmol) dose-dependently attenuated the moxonidine (20 nmol, ICV)-induced decrease in BP and heart rate. Prior injection of SMT (20 and 200 pmol) into the RVLM also dose-dependently prevented the decrease in BP and renal sympathetic nerve activity evoked by RVLM microinjection of moxonidine (5 nmol) or intravenous injection of moxonidine (50 microg/kg). We further found that expression of iNOS protein following chronic ICV infusion of moxonidine (20 nmol, 2 weeks) is selectively upregulated in the RVLM but not in the nucleus tractus solitarius. CONCLUSION: The present data suggest that an NO mechanism generated by iNOS in the RVLM plays an important role in mediating the sympathetic inhibition of the centrally acting drug moxonidine.

Protective effects of S-methylisothiourea sulfate on different aspiration materials-induced lung injury in rats.

OBJECTIVES: The aim of this study was to evaluate the efficiency of inducible nitric oxide synthase (iNOS) specific inhibitor, S-methylisothiourea sulfate (SMT) in preventing lung injury after different pulmonary aspiration materials in rats. MATERIAL AND METHODS: The experiments were performed in 80 Sprague-Dawley rats, ranging in weight from 220 to 250 g, randomly allotted into one of the eight groups (n=10): normal saline (NS, control), Biosorb Energy Plus (BIO), sucralfate (SUC), hydrochloric acid (HCl), NS+SMT treated, BIO+SMT treated, SUC+SMT treated, and HCl+SMT treated. NS, BIO, SUC, HCl were injected in to the lungs in a volume of 2 ml/kg. The rats received twice daily intraperitoneal injections of 20 mg(kg day) SMT (Sigma Chemical Co.) for 7 days. Seven days later, rats were killed, and both lungs in all groups were examined immunohistochemically and histopathologically. RESULTS: Our data show that SMT inhibits the inflammatory response significantly reducing (p<0.05) peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudate, alveolar histiocytes, interstitial fibrosis, granuloma, and necrosis formation in different pulmonary aspiration models. Furthermore, our data suggest that there is a significant reduction in the activity of iNOS and arise in the expression of surfactant protein D in lung tissue of different pulmonary aspiration models with SMT therapy. CONCLUSION: It was concluded that SMT treatment might be beneficial in lung injury, therefore shows potential for clinical use.

Nitric oxide synthase inhibitor (MTR-105) during open-heart surgery. A pilot double-blind placebo-controlled study of hemodynamic effects and safety.

OBJECTIVES: Hypotension is common immediately following cardiopulmonary bypass. Experimentally, MTR-105 (S-ethylisothiuronium diethylphosphate), a fast-acting synthetic nitric oxide synthase inhibitor, rapidly increases blood pressure. The purpose of the current study was to assess the influence of MTR-105 on hemodynamics early after cardiopulmonary bypass in patients undergoing open-heart surgery. METHODS: Thirty-six patients with an ejection fraction >50% undergoing open-heart surgery were randomly assigned to either 50 microg kg(-1) min(-1) MTR-105 (M50, n = 12), 10 microg kg(-1) min(-1) MTR-105 (M10, n = 12) or buffered phosphate solution (placebo control, n = 12). Half suffered from atrial fibrillation and 75% had severe tricuspid regurgitation. Patients received the drug for 6 h after cross-clamp removal. Hemodynamic variables were measured before drug administration until 24 h after operation. Adverse events were recorded from study drug initiation through 30 days after the operation. RESULTS: Compared with control, both MTR-105 doses were associated with an immediate increase in systemic blood pressure (16%) and systemic vascular resistance and a decrease in cardiac index. Half-life time of MTR-105 was calculated to be 4.1 +/- 0.8 h (M10) and 4.45 +/- 0.92 h (M50). Three patients died during hospitalization, unrelated to the study medication. CONCLUSIONS: At the doses employed, MTR-105 appears hemodynamically active in increasing both blood pressures.

Comparison of the binding distribution of agonist and antagonist ligands for histamine H3 receptors in pig brain by quantitative autoradiography.

The relationship between the abundances of agonist and antagonist-binding sites for monoamine receptors is poorly established. Therefore, we used quantitative autoradiography to investigate the distribution and concentration of binding sites for histamine H(3) receptor ligands in cryostat sections of pig brain. As in other species, binding of the histamine H(3) receptor agonist [(3)H]N(alpha)-methylhistamine was highly heterogeneous in the pig brain, with highest B(max) in the substantia nigra, followed by the nucleus accumbens and caudate, intermediate binding in frontal cortex, diencephalon, and mesencephalon, and absent specific binding in cerebellum: the affinity of [(3)H]N(alpha)-methylhistamine was close to 1 nM in all regions of pig brain. Thus, the saturation binding parameters for this H(3) receptor agonist in pig brain were similar to the earlier reports in rat, guinea pig, and human. The distribution of histamine H(3) receptors labeled with the receptor antagonist [(125)I]iodophenpropit in adjacent cryostat sections from the same group of pigs was very similar to that of [(3)H]N(alpha)-methylhistamine. However, the B(max) of the receptor antagonist was 40% higher in the basal ganglia than was the B(max) of the receptor agonist. The K(d) for the receptor antagonist ligand was close to 0.9 nM in all regions. These results suggest that histamine H(3) receptor agonist-binding sites, i.e. those linked to intracellular G-protein, comprise a subset of the total receptor antagonist-binding sites in the basal ganglia, as has been reported for dopamine D(2) receptors.

Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats.

1. In the present study, we investigated the effects of the inducible nitric oxide (iNOS) inhibitors S-methylisothiourea (SMT) and l-N(6)-(1-iminoethyl)-lysine (l-Nil) on endotoxin-induced acute lung injury (ALI), as well as the associated physiological, biomedical and pathological changes, in anaesthetized Sprague-Dawley rats and in rat isolated perfused lungs. 2. Endotoxaemia was induced by an intravenous (i.v.) infusion of lipopolysaccharide (LPS; Escherichia coli 10 mg/kg). Lipopolysaccharide produced systemic hypotension and tachycardia. It also increased the lung weight/bodyweight ratio, lung weight gain, exhaled nitric oxide (NO), the protein concentration in bronchoalveolar lavage and microvascular permeability. 3. Following infusion of LPS, plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-1beta) were markedly elevated. Pathological examination revealed severe pulmonary oedema and inflammatory cell infiltration. Pretreatment with SMT (3 mg/kg, i.v.) or l-Nil (3 mg/kg, i.v.) significantly attenuated the LPS-induced changes and ALI. 4. The results suggest that the inflammatory responses and ALI following infusion of LPS are due to the production of NO, free radicals and pro-inflammatory cytokines through the iNOS system. Inhibition of iNOS is effective in mitigating the endotoxaemic changes and lung pathology. Inhibitors of iNOS may be potential therapeutic agents for clinical application in patients with acute respiratory distress syndrome.

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.

Inhibition of NOS2 ameliorates cardiac remodeling, improves heart function after myocardial infarction in rats.

OBJECTIVE: Previous studies have shown increased expression of nitric oxide synthase 2 (NOS2) in rat heart several weeks after myocardial infarction (MI). The aim of this study was to examine the effect of chronic administration of S-methylisothiourea (SMT), a selective NOS2 inhibitor, commenced one week after MI on hemodynamic parameters and left ventricular (LV) remodeling in rats. METHODS: Rats with MI induced by left coronary ligation were given SMT (0.5 mg/kg/d) or saline by gavage starting one week after MI. After chronic administration for five weeks, hemodynamic and cardiac morphologic studies were performed, and lung water content, plasma NO(x) concentration, NOS2 protein level, myocyte size and collagen volume fraction of noninfarct LV area were quantified. RESULTS: The NO(x) concentration in plasma and the NOS2 protein level in noninfarct myocardium in MI rats were higher than controls. When compared with the MI rats receiving saline, chronic administration of SMT reduced myocyte size (15.1 +/- 1.6 microm vs 16.9 +/- 2.3 microm, P < 0.05), collagen volume fraction of noninfarct LV area (4.4% +/- 1.1% vs 5.7% +/- 1.2%, P < 0.01) and lung water content (77.4% +/- 1.4% vs 79.3% +/- 0.9%, P < 0.01), without affecting infarct size. Administration of SMT had no significant effect on heart rate and mean arterial pressure, but decreased LV end-diastolic pressure (8.7 +/- 2.1 mmHg vs 13.4 +/- 3.1 mmHg, P < 0.01), central venous pressure (0.9 +/- 0.3 mmHg vs 1.5 +/- 0.5 mmHg, P < 0.01) and inner LV diameter (6.9 +/- 0.3 mm vs 7.2 +/- 0.3 mm, P < 0.05) in the MI rats. Plasma level of NO(x) in the MI rats receiving SMT was reduced to control level. CONCLUSIONS: Chronic administration of SMT had beneficial effects on LV remodeling and cardiac dysfunction in MI rats, suggesting the possibility that inhibition of NOS2 could be a therapeutic tool for cardiac dysfunction after MI.

Effect of venom from the scorpion Leiurus quinquestriatus on rat vascular aortic rings.

The present study was designed to examine the effects of venom from the scorpion Leiurus quinquestriatus hebraeus (Lqh) on the contractility of rat aortic rings. We first examined the effect of Lqh venom on the contractile tension of isolated rat vascular aortic rings and then whether long-term exposure to the venom reduces the contractility of vascular smooth muscle by increasing the production of nitric oxide. Following the administration of 33 microg/mL of crude Lqh venom, contractile tension increased by 18.9 +/- 11.4 percent. The administration of 2.4 x 10(-7) M noradrenaline (NA) led to a 31.6 +/- 8.2 percent increase in tension (p < 0.01). The effects induced by NA and Lqh venom were similar and additive (p < 0.01). Pretreatment with the alpha-adrenergic blocker phenoxybenzamine (0.2 microM) eliminated the effect of the venom, whereas the calcium-channel blocker verapil (8.3 microM) merely attenuated the effect. Incubation of the rings with Lqh venom for 16 to 18 h, followed by NA stimulation, led to a 15 to 20 percent decrease in tension (p < 0.001). Treatment with N-omega-nitro-L-arginine methyl ester (110 microM), a constitutional nitric oxide inhibitor, restored the tension to control values. Treatment with S-methyl-isothiourea (0.1 microM), an inducible nitric oxide synthesis inhibitor, had no effect on contractile tension. The results of the present study suggest that the effect of Lqh venom on isolated aortic rings is induced via sympathetic nerve terminals. Calcium had little effect on the smooth muscle contractility of aortic rings incubated with the venom. No evidence was found to support nitric oxide synthesis after the long-term exposure of the rings to Lqh venom.

Intestinal motility in an in vivo rat model of intestinal ischemia-reperfusion with special reference to the effects of nitric oxide on the motility changes.

BACKGROUND: To clarify the relation between intestinal ischemia-reperfusion (IR) and dysmotility, the authors investigated changes in the motility pattern in the duodenum and jejunum in an in vivo rat model of IR when artery- (and vein-) fed jejunum was clamped transiently. The authors also studied the effect of nitric oxide on the motility changes in this model by means of the administration of L-NAME (N(G)-nitro-L-arginine methyl ester) or S-methylisothiourea sulfate (SMT). MATERIALS AND METHODS: A force transducer was sutured onto the serosal side of the duodenum or jejunum. After a 3-to 4-day recovery period, contractions were recorded during periods of preischemia, ischemia (60 minutes), and reperfusion (90 minutes). An intestinal IR was produced by clamping and releasing the mesenteric artery and vein with artery forceps. RESULTS: In the jejunum, there was a prolongation in the duration of contraction and there were decreases in the number of contractions (NC) during the IR. When treated with L-NAME, no decrease in the NC was observed during the 45 to 90 minutes after reperfusion. S-methylisothiourea sulfate did not affect the IR-induced motility changes significantly. In the duodenum, there was a prolongation in the duration of contraction and a decrease in the NC and AC only during the reperfusion. L-NAME or S-methylisothiourea sulfate inhibited the decreases in the NC during the reperfusion. CONCLUSIONS: Intestinal IR causes motility changes in the ischemic site during the IR and in the nonischemic site during the reperfusion. The IR-induced motility changes partly depend on nitric oxide production.

A novel method of studying wound healing.

In order to study wound healing, it is often necessary to administer various wound-active substances by the systemic route. It is unclear whether the observed effects are the result of local or systemic influence of the agent administered. Furthermore, high systemic doses are often required to achieve activity at the wound level. Direct intrawound administration of substances is traumatic and disruptive to the fragile wound environment and increases the risk of infection. We devised a system for continuous atraumatic delivery of substances directly to subcutaneously implanted polyvinyl alcohol sponges, an adaptation of a well-established model of wound healing. Sponge-catheter constructs were fashioned by feeding identical lengths of silicone catheters through two 40-mg sponge disks (on edge). The distal sponge was fixed 0.5 cm from the distal, ligated end of the catheter and centered over two 1-mm holes in the catheter tubing. The proximal sponge was fixed over nonperforated catheter with its edge 2 cm proximal from the close edge of the distal sponge. Each construct was connected to a mini-osmotic pump (infusion rate 1 microl/h) loaded with an appropriate infusate and inserted subcutaneously on the dorsum of anesthetized male Sprague-Dawley rats. Hydroxyproline (OHP) content of sponges, a measure of collagen deposition, was determined at 7 days postwounding. Infusion of India ink confirmed selective delivery to the distal sponge. Saline infusion alone significantly elevated OHP content compared to noninfused sponges (450 +/- 43 vs 328 +/- 36 microg OHP/100 mg sponge, P < 0.05). Infusion of S-methylisothiourea (a selective iNOS inhibitor, 84 microg/sponge/24 h) successfully inhibited NO production (35.9 +/- 3.1 vs 49.6 +/- 3.6 microM, P < 0.05) and decreased sponge OHP content (385 +/- 60 vs 568 +/- 70 microg OHP/100 mg sponge, P < 0.05) without the toxic side effect (i.e., weight loss) seen with systemic administration. Infusion of an adenoviral solution containing mouse iNOS cDNA resulted in successful transduction of wound cells demonstrating the ability to deliver genes to a healing wound model. The data demonstrate that manipulation of wound physiology is possible by local delivery of low doses of wound-active compounds to the wound site. This promises to be a powerful tool for the study of both normal and impaired wound healing.

Nitric oxide regulates wound healing.

Nitric oxide (NO) synthesis occurs during wound healing, but its role has not been defined. To study the effect of NO on wound repair, S-methyl isothiouronium (MITU, a competitive inhibitor of NO synthase) was administered at a dose of 10, 50, and 100 mg/kg body weight/day, using intraperitoneally implanted miniosmotic pumps. Groups of 10 male Balb/C mice underwent a dorsal skin incision and polyvinyl alcohol sponges were inserted subcutaneously. The animals were sacrificed 10 days postwounding and wound breaking strength and hydroxyproline content of sponges, an index of reparative collagen deposition, were determined. Some sponges were used to harvest wound fluid and infiltrating cells, which were then incubated overnight with or without 1 mM MITU. Nitrite and nitrate, stable end products of NO, were measured in wound fluid and in wound cell culture supernatants. Continuous intraperitoneal infusion of MITU significantly decreased wound fluid nitrite/nitrate concentrations in a dose dependent manner (P < 0.01). Inhibition of wound NO synthesis by 100 mg MITU/kg/day was paralleled by lowered wound collagen accumulation (P < 0.01) and wound breaking strength (P < 0.01). In vitro NO synthesis by wound cells obtained from animals treated with 100 mg MITU/kg/day was not significantly different from controls (12.6 +/- 1.2 vs 10.7 +/- 0.6 nmole NO2 + NO3/microgram DNA), reflecting the reversible inhibition of NO synthase by MITU. However, NO production was equally inhibited in wound infiltrating cells by the in vitro addition of MITU (83% vs 85%, respectively). These data suggest that nitric oxide synthesis is critical to wound collagen accumulation and acquisition of mechanical strength.

S-ethylisothiourea, a nonamino acid inhibitor of nitric oxide synthase, reverses septic vasodilation in sheep.

S-ethylisothiourea (3936W92) is a nonamino acid antagonist of nitric oxide synthase. Its selectivity for the inducible form of nitric oxide synthase is twice as high as for the constitutive form of the enzyme. We tested 3936W92 in 20 sheep, which were surgically prepared for chronic study. In all sheep, a hyperdynamic sepsis was induced by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, nine sheep received a continuous infusion of 3936W92 over the next 24 h, whereas the control group (n = 9) received saline instead. Two sheep died within the first 24 h of sepsis. 3936W92 caused a complete reversal of the hyperdynamic circulation, while sheep in the control group remained hyperdynamic. Although the cardiac index decreased significantly during treatment with 3936W92 (7.9 +/- .8 vs. 6.0 +/- .7 l/min/m2), a simultaneous increase in oxygen extraction prevented oxygen consumption from falling.

[Application of the methods of the mathematical theory of experiments to the development of multicomponent radioprotective preparations]. / Primenenie metodov matematicheskoi teorii éksperimenta pri razrabotke mnogokomponentnykh radiozashchitnykh retseptur.

A study was made of the possibility of using a mathematical theory of experiment in developing effective many-component radioprotective preparations. The preparations composed of cystamine or S-(omega-aminopropyl)-beta-aminoethyl thiophosphate, as the basis, and mexamine, ethyron and gutimine were used as an example to prove the adequacy of such an approach in solving the problems of optimization of composing the radioprotective complexes according to their efficiency and toxicity.

[Toxicity of single and multiple administrations of phosphorus-containing isothiuronim derivatives possessing radioprotective properties]. / Toksichnost' pri odnokratnom i mnogokratnom vvedenii nekotorykh fosforsoderzhashchikh proizvodnykh izotiuroniia, obladaiushchikh radiozashchitnymi svoistvami.

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.