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PubMed1992

The first radiolabeled histamine H3 receptor antagonist, [125I]iodophenpropit: saturable and reversible binding to rat cortex membranes.

We describe the binding to rat cortex membranes of [125I]iodophenpropit, the first radiolabeled histamine H3 antagonist. The binding of [125I]iodophenpropit is selective, saturable, readily reversible, and of high affinity (KD 0.32 nM; Bmax 209 fmol/mg of protein). Specific binding at a concentration of 0.3 nM accounted for 45-55% of the total binding. [125I]Iodophenpropit seems to fulfill the criteria for a suitable ligand for histamine H3 receptor binding studies.

Animals↗
PubMed1985

Schistosoma mansoni: neurotransmitters and the mobility of cercariae and schistosomules.

The concentration-dependent action of alkyl-isothiouroniums on Schistosoma mansoni cercariae, ranging from partial to total abolition of locomotor and flame cell movements, and/or suppression of virulence, is due to H1-histamine receptor inhibition. Correspondingly, H1-receptor inhibitors of widely different chemical structure, such as clemizol, diphenhydramine, brompheniramine, and promethazine, in 0.03-0.06 nM concentrations, induced an analogous cercarial immobilization reversed by addition of excess histamine. In contrast, the H2-receptor inhibitors cimetidine and metiamide did not immobilize cercariae. Histamine, acetylcholine, and serotonin, added to cercarial suspensions, showed no direct activity. Their participation in the mechanism of cercarial mobility was shown by the dose-dependent effects of antagonists, such as the serotonin antagonist methysergide and the acetylcholinesterase inhibitor physostigmine. These effects were not reversible by addition of serotonin and acetylcholine, respectively. A histamine-irreversible cercarial immobilization induced by the H-liberator 48/80 suggested that, besides H1-receptor inhibition, H-liberation and/or depletion also participated in mobility and survival. The detection of histamine in the cercaria corroborated the participation of histaminergic mechanisms. S. mansoni schistosomules collected from the mouse lung reacted to H1 antihistamines like cercariae, with a dose-dependent reduction of mobility and somatic deformation, such as vacuolization, granulation, and caecal enlargement.

Acetylcholine↗
PubMed1996

U-19451A: a selective inducible nitric oxide synthase inhibitor.

Drugs with high selectivity for iNOS inhibition may be useful for treatment of neurodegenerative disorders, chronic inflammatory diseases, and septic shock. Therefore, U-19451A (2-benzyl-2-thio-pseudourea hydrochloride), a potential NOS inhibitor, has been investigated for its selectivity for iNOS using tissues, primary cerebellar granule cell cultures and glial cell cultures. Lungs isolated from rats treated with intravenous injection of E coli lipopolysaccharide and glial cell cultures treated with the same bacterial toxin plus gamma-interferon were used for iNOS activity. Rat cerebellum and primary cerebellar granule cell cultures were utilized for neuronal NOS (nNOS) activity. S-methylthiourea (SMT) and L-nitroarginine methyl ester (L-NAME), selective iNOS and nNOS inhibitors, respectively, were chosen as standards. Both U-19451A and SMT were 4-times more selective for iNOS as compared to nNOS in tissues. U-19451A was more selective than SMT for iNOS inhibition using cultures. L-NAME was 16-31 times more selective for inhibiting nNOS activity. Based on the selectivity of U-19451A for iNOS inhibition, this drug would be expected to be effective in the treatment of diseases with inflammatory pathology without producing side effects associated with nNOS inhibition.

Animals↗
PubMed1995

Involvement of inducible nitric oxide synthase in the inflammatory process of myocardial infarction.

Inducible nitric oxide synthase (iNOS), which catalyzes the reaction of L-arginine to L-citrulline and nitric oxide (NO), plays an important role in immune-mediated cardiac disorders. The present report summarizes and discusses findings on the induction of NOS in myocardial infarction of rabbits. iNOS was significantly increased in infarcted myocardium 48 h after coronary artery ligation. The effect persisted for 14 days and declined thereafter. Immunohistochemical localization revealed macrophages as a major source of iNOS expression; iNOS expression was also present in infarcted human myocardium. Increased iNOS activity appeared to be related to the induction of apoptosis in infiltrating macrophages and cardiomyocytes. Moreover, preferential inhibition of iNOS by S-methylisothiourea sulfate (SMT) resulted in significant improvement of left ventricular performance and increased regional myocardial blood flow. These findings suggest that selective inhibition of iNOS activity may provide a therapeutic strategy in cardiac disorders such as myocardial infarction.

Animals↗
PubMed2004

Improvement of intestinal motility using S-methylisothiourea in postoperative ileus.

BACKGROUND: The inflammatory mediator nitric oxide (NO) plays an important role in postoperative gastrointestinal motility. METHODS: Using S-methylisothiourea sulfate (SMT), a selective inducible nitric oxide synthase inhibitor, we studied the physiological role of the endogenous NO in the modulation of intestinal motility. The study was performed in vivo in a canine postoperative model. Ten mongrel dogs were treated with a continuous intravenous infusion of SMT after a surgical intestinal manipulation. Small intestine transit time was fluoroscopically measured using barium sulfate as it passed through a gastrostomy tube on postoperative days (POD) 1, 2, and 3. RESULTS: Average transit times on POD 1 in the 4 mg/kg/h and 2 mg/kg/h SMT groups significantly decreased compared with that of the saline group. However, the transit times on POD 2 and 3 were not significantly different among the three groups. CONCLUSIONS: S-methylisothiourea sulfate improves small intestine motility at an early postoperative stage.

Animals↗
PubMed2004

Down-regulation of cytochrome P450 proteins and its activities by Shiga-like toxin II from Escherichia coli O157:H7.

Escherichia coli O157:H7 infection frequently induces clinical complications such as hemolytic uremic syndromes and intestinal dysfunctions. These changes could alter the disposition of drugs, consequently changing their efficacy. However, the possible changes of drug-metabolizing activities by E. coli O157:H7 infection have not been addressed. Thus, we have investigated the effect of Shiga-like toxin type II (SLT-II), derived from E. coli O157:H7, on the hepatic cytochrome P450 (CYP) content and its activity in rats. SLT-II (2microg per animal, i.v.) time-dependently decreased total CYP content and the contents of CYP2C11 and CYP3A2 in hepatic microsomal preparations up to 24hr following injection. Consistently, SLT-II time-dependently decreased CYP activity in vivo, as represented by systemic clearance of antipyrine. An inhibitor of inducible nitric oxide synthase, S-methylisothiourea, restored the decreased systemic clearance of antipyrine by SLT-II, suggesting the involvement of the overproduction of nitric oxide by SLT-II. Moreover, dexamethasone restored the decreased systemic clearance of antipyrine by SLT-II. In the hepatic microsomal preparation, dexamethasone restored the SLT-II-induced decrease of CYP3A2 whereas S-methylisothiourea did not affect both CYP subtypes. Taken together, these results suggest that SLT-II might alter hepatic drug-metabolizing function during E. coli O157 infection and that more than one cytokines induced by SLT-II, including nitric oxide, might make a critical contribution to the decrease of CYP content and its activity.

Animals↗
PubMed2006

Surface and biocidal activity of some synthesized metallo azobenzene isothiouronium salts.

A novel series of azobenzene isothiouronium salts of different alkyl chains (propyl, hexyl and dodecyl) were synthesized by reaction of 4-((4-methylphenyl)azo)phenol with 1,3-dibromopropane, 1,6-dibromohexane and 1,12-dibromododecane, respectively. These salts were reacted with copper (II) halide to give their corresponding metallo complexes. The surface tension measurements for the synthesized compounds show that the metallo complexes have adsorption and micellization better than that of the parent azobenzene isothiouronium salts. The pathogenic Gram-negative bacteria, Gram-positive bacteria, fungi and yeast were used to determine the biocidal activity of these compounds using gradient plate technique. The results indicate that the copper complexes of the synthesized azobenzene isothiouronium salts have a relatively better biocidal activity than the parent salts.

Anti-Bacterial Agents↗
PubMed2006

Microglia induce neural cell death via a proximity-dependent mechanism involving nitric oxide.

Microglial cells play a major role in the pathogenesis of many neurological diseases by exacerbating neuronal and non-neuronal cell death, but the mechanisms involved are unclear. To investigate the microglial-neuronal interactions, we used the murine BV-2 microglial cell line and the human neuronal-like SK-N-SH neuroblastoma cell line in a co-culture system that enabled proximity-dependent interaction and communication, a trans-well system that allowed proximity-independent communication through diffusible molecules only, and a conditioned media system through which no proximity-dependent interactions or cell-to-cell communication is possible. Activation of BV-2 cells with lipopolysaccharide and interferon-gamma (LPS/IFN-gamma) decreased viability of the BV-2 cells alone and in co-cultures with SK-N-SH cells, but not SK-N-SH cells grown alone. In contrast, activation of BV-2 cells in the trans-well and conditioned media system did not have any effect on the viability of SK-N-SH cells, suggesting that microglia must be in close proximity to the neural cells to elicit cytotoxicity. To determine the molecules involved in proximity-dependent cell death, inhibitors of microglial activation were investigated. Only the specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea, and hypothermia, which is known to suppress microglial iNOS expression, prevented cell death after LPS/IFN-gamma activation. These results suggest that activated microglia release nitric oxide that is, at least partially, responsible for proximity-dependent microglial-mediated neural toxicity.

Analysis of Variance↗
PubMed2004

Inhibitory effect of iodophenpropit, a selective histamine H3 antagonist, on amygdaloid kindled seizures.

The effect of histamine H(3) antagonist, iodophenpropit on amygdaloid kindled seizures in rats was studied in comparison with those of other H(3) antagonists. Under pentobarbital anesthesia, the rats were fixed to a stereotaxic apparatus and bipolar electrodes were implanted into the amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. To cause kindled seizures, electrical stimulation was applied to the amygdala bipolarly every day by a constant current stimulator, and electroencephalogram and convulsive behavior were observed. Drug effects were estimated in rats showing generalized kindled seizures. Intraperitoneal injection of H(3) antagonists, iodophenpropit, thioperamide, AQ0145 and clobenpropit, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of iodophenpropit on amygdaloid kindled seizures was more potent than those of thioperamide, AQ0145 and clobenpropit. In conclusion, iodophenpropit may be useful for the treatment of partial epilepsy and/or secondary generalized seizures in humans.

Amygdala↗
PubMed2005

Phenotypic adaptation of the late preconditioned heart: myocardial oxygen consumption is reduced.

OBJECTIVES: Although the signalling pathways of late preconditioning have been extensively investigated, its consequence for myocardial metabolism remains unknown. Thus, myocardial oxygen consumption (MVO2) was evaluated before and under late preconditioning. METHODS: In 7 chronically instrumented dogs, we measured MVO2 in vivo at baseline and during inotropic stimulation with dobutamine (10 and 20 microg/kg/min, i.v.) before (Day 0) and 24 h after (Day 1) a 10-min circumflex coronary artery occlusion. RESULTS: At Day 0, dobutamine dose-dependently increased the triple product (heart ratexleft ventricular systolic pressurexleft ventricular maximum dP/dt), MVO2, coronary blood flow, and coronary sinus pO2. At Day 1, the triple product was similar at baseline and at each dose of dobutamine but MVO2 was significantly blunted as compared to Day 0 (-15+/-4%, -22+/-3% and -19+/-4% at baseline, dobutamine 10 and 20 microg/kg/min, respectively). Importantly, the relationship between MVO2 and triple product was significantly rightward shifted with late preconditioning, i.e., MVO2 was reduced for any level of triple product. At Day 1, the relationship between coronary blood flow and MVO2 was not altered as compared to Day 0 but coronary sinus pO2 was significantly increased vs. Day 0 for any level of coronary blood flow, suggesting that late preconditioning exerted no vasomotor effect but rather changed myocardial oxygen handling. These effects were abolished by administration of S-methyl-isothiourea (1.5 mg/kg, i.v.), a iNOS inhibitor. CONCLUSION: This study demonstrates that ischemic late preconditioning is characterized by a major reduction in MVO2, both at baseline and under inotropic stimulation. NO from iNOS contributes to this modification of metabolic phenotype.

Animals↗
PubMed2005

Interaction between inhibitors of inducible nitric oxide synthase and cyclooxygenase in Brewer's yeast induced pyrexia in mice: an isobolographic study.

We studied the interaction of S-methylisothiourea (a selective inducible nitric oxide synthase inhibitor) with rofecoxib (selective cyclooxygenase-2 inhibitor) and mefenamic acid (non-selective cyclooxygenase inhibitor) in Brewer's yeast-induced pyrexia in mice by isobolographic analysis. Each drug was effective in reducing pyrexia when used alone. Log-dose-response curves of all the three drugs did not show any significant departure from parallelism indicating thereby, a common mode of antipyretic action. However, rofecoxib exhibited significantly higher potency than S-methylisothiourea. Isobolographic analysis of combination of S-methylisothiourea with rofecoxib and mefenamic acid revealed additive interaction. Experimental ED(50) of the combinations was not significantly different from theoretical additive ED(50) of the corresponding drug combination, that substantiated the additive nature of interaction between inducible nitric oxide synthase and cyclooxygenase in Brewer's yeast-induced fever in mice. Results suggest involvement of a mediator that is subservient to both inducible nitric oxide synthase and cyclooxygenase-2 enzyme activities. For further investigation, peroxynitrite ion may be considered to be the putative mediator.

Animals↗
PubMed2006

Interaction between inhibitors of inducible nitric oxide synthase and cyclooxygenase in adjuvant-induced arthritis in female albino rats: an isobolographic study.

We studied the interaction of S-methylisothiourea (a selective inducible nitric oxide synthase inhibitor) with rofecoxib (a selective cyclooxygenase-2 inhibitor) and mefenamic acid (a non-selective cyclooxygenase inhibitor) in adjuvant-induced arthritis in female albino Wistar rats, applying the isobolographic analysis. Each drug was effective in reducing the progressive increase in paw volume less than 50% except rofecoxib, when used alone. Log dose-response curve was obtained for each drug along with the corresponding ED(25). Following isobolographic analysis, combination of S-methylisothiourea with rofecoxib and mefenamic acid revealed supra-additive or synergistic interaction. Experimental ED(25) of the combinations was significantly lower than the theoretical ED(25) of the corresponding drug combination which substantiated the synergistic type of interaction between inducible nitric oxide synthase and cyclooxygenase in adjuvant-induced arthritis in female albino rats. Results suggest that NO regulates the cyclooxygenase enzyme activity as the activity of cyclooxygenase enzymes in the LPS-stimulated leukocyte lysates was significantly low or hardly detectable in the presence of varying concentrations of S-methylisothiourea. Simultaneous inhibition of inducible nitric oxide synthase and cyclooxygenase appears to offer an alternative approach for ameliorating the progression of arthritis.

Animals↗
PubMed2005

Nitric oxide- and superoxide-dependent mitochondrial signaling in endotoxin-induced apoptosis in the rostral ventrolateral medulla of rats.

This study evaluated the hypothesis that the repertoire of cellular events that underlie circulatory fatality during endotoxemia may entail mitochondrial respiratory enzyme dysfunction, followed by the release of cytochrome c to the cytosol that triggers the activation of caspase cascades, leading to apoptotic cell death in the rostral ventrolateral medulla (RVLM) where sympathetic premotor neurons responsible for maintaining vasomotor tone are located. In adult Sprague-Dawley rats maintained under propofol anesthesia, nucleosomal DNA fragmentation was detected in the RVLM in a temporal profile that coincided positively with the progression of cardiovascular depression during experimental endotoxemia induced by Escherichia coli lipopolysaccharide (LPS). LPS also induced nitric oxide (NO) and superoxide (O(2)(-)) production, depressed mitochondrial Complex I and IV activity, promoted the release of cytochrome c from mitochondria to cytosol, upregulated the cytosolic expression of activated caspase-9 and -3, or increased caspase-3 enzyme activity in the RVLM. Microinjection bilaterally into the RVLM of an inducible nitric oxide synthase (iNOS) blocker, S-methylisothiourea, or a superoxide dismutase mimetic, Tempol, significantly blunted these apoptotic cellular events and antagonized the cardiovascular depression during endotoxemia. We conclude that caspase-dependent apoptotic cell death that results from NO- and O(2)(-)-associated mitochondrial signaling in the RVLM may underlie fatal cardiovascular depression during endotoxemia.

Animals↗
PubMed2005

Inhibition of iNOS with S-methylisothiourea was impaired in wound healing in caustic esophageal burn.

OBJECTIVE: Stricture formation is a late complication of caustic esophageal burn, which is a common problem in childhood. For this reason, this experimental study was designed to observe the possible effect of nitric oxide on healing and fibrosis formation in caustic esophageal burns. MATERIALS AND METHODS: The rats were divided into five groups. Group A (n=12) received sham burn and treatment with saline injection. Group B (n=34) received caustic burn. Rats in group C (n=31), were given water supplement with 10 g/L L-arginine that was started 24 h preoperatively and continued until postoperative day 4. In group D (n=21), S-methylisothiourea (SMT, specific inducible nitric oxide synthase (iNOS) inhibitor), was injected at a dose of 3 mg/kg i.p. at 30 min before caustic burn, and similar dose was reinjected immediately after caustic burn. SMT 6 mg/kg/day injections continued for 4 days long. In group E (n=22), Nomega-nitro-L-arginine (L-NNA, nonspecific nitric oxide synthase (NOS) inhibitor) was injected at a dose of 15 mg/kg i.p. at 30 min before caustic burn, and similar dose was reinjected immediately after caustic burn. L-NNA 30 mg/kg/day continues for 4 days. RESULTS: Dead rates were significantly higher in group E than in groups A-D. The mean hydroxyproline levels in esophageal tissue were significantly lower in groups A and B than in group D. Histopathologically, tissue damage scores in the esophageal tissue were higher in group D than in groups A-C. CONCLUSIONS: Inhibition of iNOS with SMT was impaired in wound healing due to caustic esophageal burn and provoked collagen accumulation at a later period. Those effects may due to inhibition of antioxidant, immunomodulatory and antifibrotic effects of NO.

Animals↗
PubMed2004

Involvement of inducible nitric oxide synthase in renal failure after mild hemorrhage.

The role of iNOS in rats after mild hemorrhaging was examined in this study. A mild hemorrhage (17% of total blood) induced a decrease of systemic blood pressure and heart rate, transiently followed by gradual recovery. The hemorrhage caused expression of renal iNOS mRNA and an increase in systemic NO products at 1 h after bleeding. Serum creatinine and serum urea nitrogen (UN) increased progressively up to 5 h after bleeding. Light microscopic findings showed that some inflammatory monocytes, mainly consisting of neutrophil, often existed in the glomerular capillaries, eosinophilic changes were observed in the cytoplasm at the proximal tubules, and urinary casts existed in the uriniferous space at 5 h after bleeding. The selective iNOS inhibitor, S-methylisothiourea (MTU), suppressed hemorrhagic expression of renal iNOS mRNA and systemic NO products, suppressed the increases of serum creatinine and UN, and improved renal histological aggravations induced by hemorrhaging. We speculated that MTU caused the negative circuit to suppress the renal failure through a decrease of NO generation. These results in the present study showed that iNOS expression induced by mild hemorrhaging at the early phase did participate in the development of renal failure.

Acute Kidney Injury↗
PubMed2004

Modulation of iNOS activity in age-related cardiac dysfunction.

Based on the role of inducible nitric oxide synthase (iNOS) in heart failure, we hypothesized that the elevated expression of iNOS compared to young mice in the myocardium contributes to the age-related decline of left ventricular (LV) function. Cardiac iNOS mRNA and protein expression was singularly identified in old, wild type (WT) male mice (I6-month) and not in young WT male mice (6-month). Characterized with in vivo pressure-volume loops analysis, an age-related LV dysfunction was found in the old WT mice. The LV dysfunction of the aged mice was modified to that of the younger mice by the specific iNOS inhibitors, aminoguanidine (AMG, 10 mg/Kg, i.v. or infusion, n = 15) and S-methyl-isothiourea (MITU, 3 mg/Kg, i.v. n = 7), and declined with L-arginine (10 mg/Kg, i.v. n = 7). All three drugs had no effects on the LV function of young WT mice or old iNOS knockout (KO) mice. The NOx and cGMP levels were significantly higher only in the old WT mice (n = 6) and cGMP levels decreased to normal with AMG administration. In conclusion, these results suggested that the iNOS/NO/cGMP pathway may contribute to ventricular dysfunction during the aging process and that inhibition of iNOS activity significantly improved heart function in aged mice.

Aging↗
PubMed2004

COX-2 and iNOS in opioid-induced delayed cardioprotection in the intact rat.

Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) have been previously implicated in the late phase of cardioprotection associated with opioid-induced and ischemic preconditioning (IPC) in conscious rabbits and COX-2 in isolated rat hearts pretreated with an exogenous delta opioid agonist. However, it is not know if both iNOS and COX-2 mediate the late phase of cardioprotection induced by opioids in the intact blood-perfused rat. Therefore, we investigated the role of COX-2 and iNOS in the delayed phase of protection mediated by delta opioid receptor activation. Rats were pretreated 24 hours prior to an occlusion/reperfusion protocol with the selective non-peptide delta opioid agonists, BW373U86 (BW) and SNC-121 (SNC). NS-398, a selective COX-2 inhibitor was administered after the 24-hour recovery period just prior to index ischemia. The selective iNOS inhibitors, S-methylthiourea (SMT) and aminoguanidine (AG), were administered in conjunction with opioid pretreatment or were also given 24 hours after opioid administration just prior to index ischemia. COX-2 inhibition by NS-398 given 24 hours after opioid administration attenuated the protective effects of both BW and SNC (46 +/- 6 vs. 13 +/- 3 and 51 +/- 5 vs. 29 +/- 2, p < 0.001, respectively). Similarly, inhibition of iNOS following 24 hours of treatment with opioids also attenuated the protective effects of BW and SNC. However, the delayed protective effects of the opioids were not attenuated by pretreatment with the iNOS inhibitors 24 hours prior to the infarct protocol. These results suggest that both COX-2 and iNOS are mediators of delayed protection induced by non-peptide delta opioid agonists. It appears that the trigger effect is not dependent on the activity of iNOS or COX-2 but the late phase of cardioprotection is dependent on the upregulation of these enzymes.

Analysis of Variance↗