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PubMed2002

Diagnosis and treatment of maple syrup disease: a study of 36 patients.

OBJECTIVE: To evaluate an approach to the diagnosis and treatment of maple syrup disease (MSD). METHODS: Family histories and molecular testing for the Y393N mutation of the E1alpha subunit of the branched-chain alpha-ketoacid dehydrogenase allow us to identify infants who were at high risk for MSD. Amino acid concentrations were measured in blood specimens from these at-risk infants between 12 and 24 hours of age. An additional 18 infants with MSD were diagnosed between 4 and 16 days of age because of metabolic illness. A treatment protocol for MSD was designed to 1) inhibit endogenous protein catabolism, 2) sustain protein synthesis, 3) prevent deficiencies of essential amino acids, and 4) maintain normal serum osmolarity. Our protocol emphasizes the enhancement of protein anabolism and dietary correction of imbalances in plasma amino acids rather than removal of leucine by dialysis or hemofiltration. During acute illnesses, the rate of decrease of the plasma leucine level was monitored as an index of net protein synthesis. The treatment protocol for acute illnesses included the use of mannitol, furosemide, and hypertonic saline to maintain or reestablish normal serum sodium and extracellular osmolarity and thereby prevent or reverse life-threatening cerebral edema. Similar principles were followed for both sick and well outpatient management, especially during the first year, when careful matching of branched-chain amino acid intake with rapidly changing growth rates was necessary. Branched-chain ketoacid excretion was monitored frequently at home and branched-chain amino acid levels were measured within the time of a routine clinic visit, allowing immediate diagnosis and treatment of metabolic derangements. RESULTS: 1) Eighteen neonates with MSD were identified in the high-risk group (n = 39) between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. The molar ratio of leucine to alanine in plasma ranged from 1.3 to 12.4, compared with a control range of 0.12 to 0.53. None of the infants identified before 3 days of age and managed by our treatment protocol became ill during the neonatal period, and 16 of the 18 were managed without hospitalization. 2) Using our treatment protocol, 18 additional infants who were biochemically intoxicated at the time of diagnosis recovered rapidly. In all infants, plasma leucine levels decreased to <400 micromol/L between 2 to 4 days after diagnosis. Rates of decrease of the plasma leucine level using a combination of enteral and parenteral nutrition were consistently higher than those reported for dialysis or hemoperfusion. Prevention of acute isoleucine, valine, and other plasma amino acid deficiencies by appropriate supplements allowed a sustained decrease of plasma leucine levels to the therapeutic range of 100 to 300 micromol/L, at which point dietary leucine was introduced. 3) Follow-up of the 36 infants over >219 patient years showed that, although common infections frequently cause loss of metabolic control, the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year of follow-up, and developmental outcomes were uniformly good. Four patients developed life-threatening cerebral edema as a consequence of metabolic intoxication induced by infection, but all recovered. These 4 patients each showed evidence that acutely decreased serum sodium concentration and decreased serum osmolarity were associated with rapid progression of cerebral edema during their acute illnesses. CONCLUSIONS: Classical MSD can be managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates. However, neurologic function may deteriorate rapidly at any age because of metabolic intoxication provoked by common infections and injuries. Effective management of the complex pathophysiology of this biochemical disorder requires integrated management of general medical care and nutrition, as well as control of several variables that influence endogenous protein anabolism and catabolism, plasma amino acid concentrations, and serum osmolarity.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed1996

Surface labelling of the type I methyltransferase M.EcoR124I reveals lysine residues critical for DNA binding.

The type IC methyltransferase M.EcoR124I consists of a specificity subunit (HsdS) and two methylation subunits (HsdM). Using chemical modifications, we have investigated the accessibility of lysine residues in the free enzyme and in the complex with its DNA recognition sequence. A total of 41 of the 109 lysine residues in the enzyme are susceptible to modification, of which 19 are located in the HsdS subunit and 11 in each of the two HsdM subunits. DNA binding results in extensive protection of lysine residues in the HsdS subunit, while those in the HsdM subunit are only protected weakly. The DNA binding activity of the methylase is abolished when a small fraction of the accessible lysine residues are modified. Peptide mapping and N-terminal sequencing has been used to locate the rapidly modified lysine residues in HsdS that are critical for DNA binding. Highly modified residues (K297, K261 and K327) are found in the C-terminal variable domain that is responsible for DNA recognition, but others (K196, K203 and K210) are found in the conserved regions that had not previously been implicated in DNA binding.

Amino Acid Sequence↗

PubMed2003

Solid-phase microextraction liquid chromatography/tandem mass spectrometry to determine postharvest fungicides in fruits.

A method to determine five postharvest fungicides (dichloran, flutriafol, o-phenylphenol, prochloraz, tolclofos methyl) in fruits (cherries, lemons, oranges, peaches) has been developed using solid-phase microextraction (SPME) coupled to liquid chromatography (LC) with photodiode array (DAD), mass spectrometry (MS), or tandem mass spectrometry (MS/MS) with ion trap detection. Extraction involved sample homogenization with an acetone/water solution (5:1), filtration, and acetone evaporation prior to fiber extraction. The pesticides were isolated with a fused-silica fiber coated with 50-microm Carbowax/template resin. The effects of pH, ion strength, sample volume, and extraction time were investigated, and their impact on the SPME-LC/MS was studied. Dynamic and static modes of desorption were compared and the variables affecting desorption processes in SPME-LC optimized. Static desorption provided the best recoveries and peak shapes. Recoveries at the limit of quantification (LOQ) levels were between 10% for prochloraz and 60% for o-phenylphenol, with relative standard deviations from 13.6% for prochloraz to 3.1% for o-phenylphenol. The versatility of the method was also exhibited by its excellent linearity in the concentration intervals between 0.0005 and 5 mg kg(-1) for dichloran and 0.01-10 mg kg(-1) for tolclofos methyl and prochloraz. LOQs ranged from 0.25 to 1 microg g(-1) using DAD, from 0.002 to 0.01 microg g(-1) using LC/MS, and from 0.0005 to 0.01 to microg g(-1) using LC/MS/MS. LOQs obtained in the present study using LC/MS and LC/MS/MS are lower than maximum residue limits established for all the fungicides in any matrix studied. The method enables to determine polar pesticides at low-microgram per gram levels in fruits.

Calibration↗

PubMed2005

Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) progressively affects the facial, shoulder, and upper arm muscles and is associated with contractions of the polymorphic D4Z4 repeat array in 4q35. Recently, we demonstrated that FSHD alleles are hypomethylated at D4Z4. To study potential relationships between D4Z4 hypomethylation and both residual repeat size and clinical severity, we compared the clinical severity score with D4Z4 methylation in unrelated FSHD patients. Correcting the clinical severity score for age at examination improves the parameter to define clinical severity and provides further support for hypomethylation of FSHD alleles. However, a linear relationship between repeat size and clinical severity of the disease cannot be established. Interestingly, FSHD can be separated in two clinical severity classes: patients with residual repeat sizes of 10 to 20 kb are severely affected and show pronounced D4Z4 hypomethylation. In contrast, patients with repeat sizes of 20 to 31kb show large interindividual variation in clinical severity and D4Z4 hypomethylation. Because the majority of familial FSHD cases are represented in this interval and considering the overt variation in clinical severity in these familial cases, it thus is imperative to develop comprehensive allele-specific assays monitoring total D4Z4 methylation to investigate whether interindividual variation in D4Z4 methylation can be translated into a prognostic factor for clinical severity.

Age Factors↗

PubMedDate not supplied

Trypsin modification by vinyl polymers with variable solubilities in response to external signals.

Trypsin was modified with various vinyl polymers by the graft polymerization of vinyl monomers using a trypsin derivative containing aliphatic azo groups as the initiator. The graft polymers were chosen to be sensitive to external signals, e.g., a redox-sensitive poly[3-carbamoyl-1-(p-vinylbenzyl)pyridinium chloride] and a pH-sensitive poly(methacrylic acid-co-methyl methacrylate). The trypsin modified with the redox-sensitive polymer became insoluble in water in the presence of Na2S2O4, and redissolved when H2O2 was added. However, the enzymatic activity of the homogeneous solution was not proportional to the concentration of the modified trypsin remaining in the solution. The trypsin modified with the pH-sensitive polymer was insoluble and soluble in acidic and neutral solutions, respectively. The enzymatic activity of the homogeneous solution changed reversibly with pH in proportion to the concentration of the modified trypsin remaining in the solution.

Azo Compounds↗

PubMed2002

Variable E-cadherin expression in a MNU-induced colon tumor model in rats which exposed with 50 Hz frequency sinusoidal magnetic field.

Inactivation of the E-cadherin system by multiple mechanisms, including both genetic and epigenetic events, plays a significant role in multistage carcinogenesis. We have investigated the effects of sinusoidal electromagnetic fields (SMF) on E-cadherin expression in an MNU (N-methyl-N-nitrosurea)-induced colon tumor model. Male wistar albino rats were used for the study. The rats were classified into four groups: I (MNU), II (SMF+MNU), III (SMF) and IV (control). After administered at MNU in 1st and 2nd groups, 2nd and 3rd groups were exposed to a sinusoidal magnetic field (SMF, 50 Hz, 5 mT) for 6 hours/day for 8 months. The expression of E-cadherin were examined in four groups of rat colon tissues by immunohistochemistry on paraffin sections. For immunohistochemical analysis, the labeled streptavidin biotin method was performed using a Vectastain Universal Quick Kit with microwave accentuation. Fisher's exact test was used for statistical analysis between proportions. Immunohistochemical studies of E-cadherin expression in this model demonstrated significant differences for cytoplasmic expression pattern. These results suggest that the electromagnetic fields result in significant alterations in cell adhesion mechanisms. This study has implications for understanding the role of fields in cell detachment in cancer metastasis. Further work is required to determine the relative effect of the magnetic fields on these phenomena.

Animals↗

PubMed1995

The effects of modulation of the L-arginine-nitric oxide pathway on myocardial stunning following repetitive coronary occlusion in dogs.

In order to determine the role of nitric oxide (NO) in myocardial stunning, the effects of both augmenting and inhibiting NO production on contractile function, following repetitive coronary occlusions, were evaluated in anesthetized dogs. The effect of the experimental protocol on endothelial function was also assessed. The increases in coronary blood flow in response to acetylcholine and nitroglycerin at 30 and 60 min after reperfusion were similar to those before coronary occlusions. Therefore, loss in vasodilator reserve was not observed following the multiple coronary occlusions used in this study. NG-nitro-L-arginine methyl ester (L-NAME) elevated blood pressure slightly, but did not change left ventricular end-diastolic pressure, left ventricular maximum positive dp/dt, and coronary blood flow. Although the degree of systolic bulging and collateral circulation during coronary occlusions was comparable to the control group, contractile function after reperfusion was significantly worse in the presence of L-NAME than in the control. The recovery of contractile function was also considerably delayed with administration of L-arginine. This deleterious effect on contractile function was not observed with its enantiomer D-arginine. Differences in collateral blood flow determined with microspheres and hemodynamic variables did not account for the effects of L-arginine. These results suggest that endogenous NO is important in limiting myocardial stunning following repetitive coronary occlusion. However, NO may be cytotoxic when present in substantial excess.

Acetylcholine↗

PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans II: Oral studies and bioavailability.

The pharmacokinetics of orally administered aqueous 3H-beta-methyldigoxin solutions were studied at two dose levels, 0.3 and 0.6 mg, in healthy human subjects. The drug and its metabolites were specifically assayed in biological fluids and compared with results after intravenous doses to the same subjects. No significant dose dependency was observed. The apparent half-life of absorption was 16+/-6 min (SEM). Digoxin was the only metabolite observed in the plasma and comprised 28.6+/-3.7% of the dose in the urine. 3H-beta-Methyldigoxin, renally excreted unchanged, comprised 25.7+/-1.7% (SEM). Water-soluble metabolites in the urine comprised 9.0+/-1.8%. Fecal and urinary excretion accounted for 85% of the dose at 144 hr. The oral absorption of unchanged 3H-beta-methyldigoxin from solution was 59+/-6% by area under the curve methods and 60+/-4% by renal excretion. A total of 73% of the dose in the solution was absorbed as beta-methyldigoxin and digoxin. First-pass metabolism prior to absorption was largely prehepatic and assignable to GI degradation; 21.9+/-2.8% was degraded with 12.8+/-4.0% to digoxin and 9.1+/-4.0% to water-soluble metabolites. From 14 to 18% of the administered oral dose did not reach the systemic circulation. Analog computer fitting of plasma and urine levels of drug and digoxin was consistent with the first-pass premise with a delayed absorption of GI-generated digoxin and other metabolites. There were no significant differences between the oral absorption of a tablet formulation and the solution. Orally administered beta-methyldigoxin solution delivered 97% cardioactivity as itself and digoxin with respect to an equivalent amount of intravenously administered digoxin. This value contrasts to the 140% delivered by intravenously administered beta-methyldigoxin on the premise of pharmacodynamic equivalence of systemically appearing digoxin and beta-methyl-digoxin. Literature reports on the oral bioavailability of solutions and solid dosage forms of digoxin were critically reviewed, but no reliable comparison of the extent and reproducibility of oral absorption of cardioactive agents from administered digoxin or beta-methyldigoxin could be made from the widely variable digoxin studies with nonspecific assays.

Administration, Oral↗

PubMed1995

Stereospecific sulfoxidation by toluene and naphthalene dioxygenases.

Studies on the sulfoxidation of aryl alkyl sulfides by purified toluene dioxygenase and naphthalene dioxygenase showed that naphthalene dioxygenase produces sulfoxides of (S) absolute configuration in high enantiomeric purity while those formed by toluene dioxygenase are of variable enantiomeric purity depending on the p-substituents on the benzene ring. Oxygen uptake experiments with naphthalene dioxygenase showed that the reaction rate and degree of oxygen incorporation are affected by both aryl and alkyl substituents. 18O2-Incorporation experiments showed that the oxygen atom of methyl phenyl sulfoxide formed by toluene dioxygenase and naphthalene dioxygenase is derived exclusively from O2. Accompanying studies showed that chloroperoxidase produces single (R)-sulfoxides (> 98% enantiomeric excess) from the aryl alkyl sulfides examined in the present study.

Chloride Peroxidase↗

PubMed2003

Diversity of selective environmental substrates for human cytochrome P450 2A6: alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine, and N-nitrosobenzylmethylamine.

Cytochrome P450 2A6 constitutes 5-10% of the total microsomal CYPs of human liver. Although CYP2A6 is the major coumarin 7-hydroxylase, other known substrates of CYP2A6 include many toxicants and precarcinogens. The chemical structure diversity of these substrates raises the question of their selectivity. Thus, kinetic parameters were determined for the hydroxylation of five substrates of diverse chemical structures known to be selective for cytochrome P450 2A6: methyl tert-butyl ether (MTBE), nicotine, coumarin, N-nitrosobenzylmethylamine (NBzMA), and N-nitrosodiethylamine (NDEA). Sources of enzymes were either human liver microsomes or heterologously expressed CYPs. Coumarin was shown to be the substrate with the highest affinity, followed by NDEA, nicotine, NBzMA, and MTBE. Variability of CYP2A6 catalytic activities in human liver was between 24-fold for MTBE to sevenfold for coumarin, while CYP2A6 content varied 68-fold in human liver microsomes. These five catalytic activities were highly significantly correlated between them and with hepatic CYP2A6 content. The most selective chemical inhibitor of these five substrates was shown to be 8-methoxypsoralen. Based upon chemical inhibition of the enzymatic activities of pure recombinant human CYPs, it cannot be totally excluded that P450s other than CYP2A6, especially CYP2E1, are involved, although to a lesser extent, in NDEA and NBzMA metabolism. In conclusion, the prototype probes for CYP2A6 phenotyping are coumarin and nicotine.

Adult↗

PubMed2001

Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist.

This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent lipophilicity to allow increased central nervous system penetration and pharmacological activity (gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over those analogues that could not form an intramolecular hydrogen bond.

Animals↗

PubMed2001

Microscopic origins of entropy, heat capacity and the glass transition in proteins.

Internal motion is central to protein folding, to protein stability through the resulting residual entropy, and to protein function. Despite its importance, the precise nature of the internal motions of protein macromolecules remains a mystery. Here we report a survey of the temperature dependence of the fast dynamics of methyl-bearing side chains in a calmodulin-peptide complex using site-specific deuterium NMR relaxation methods. The amplitudes of motion had a markedly heterogeneous spectrum and segregated into three largely distinct classes. Other proteins studied at single temperatures tend to segregate similarly. Furthermore, a large variability in the degree of thermal activation of the dynamics in the calmodulin complex indicates a heterogeneous distribution of residual entropy and hence reveals the microscopic origins of heat capacity in proteins. These observations also point to an unexpected explanation for the low-temperature 'glass transition' of proteins. It is this transition that has been ascribed to the creation of protein motional modes that are responsible for biological activity.

Binding Sites↗

PubMed1978

Nucleotide sequence of the recognition site for the restriction-modification enzyme of Escherichia coli B.

The nucleotide sequence of the recognition site for the restriction-modification enzyme of Escherichia coli B (SB site) has been determined. The recognition site is a 15-nucleotide sequence consisting of the trimer 5'TGA3', followed by an 8-nucleotide domain of variable sequence, which in turn is followed by tetramer 5'TGCT3'. The sequence has no 2-fold rotational symmetry. Single base changes in the constant nucleotide domains result in the loss of sensitivity to both restriction and modification. Our data are also consistent with modification occurring by methylation of two adenine residues per SB site: one on the adenine of the trimer 5'TGA3' and the other on the complementary strand on the adenine complementary to the first thymine of the tetramer 5'TGCT3'. All nine independently isolated spontaneous mutants at the SB1 site of bacteriophage f1 are caused by a G-to-T transversion. Mutations at the SB2 site are caused by various single base changes.

Adenine↗

PubMed2004

Response of first attack of inflammatory bowel disease requiring hospital admission to steroid therapy.

INTRODUCTION: Corticoid administration is the usual treatment of Crohńs disease (CD) and ulcerative colitis (UC) attacks. However, information available on response rates and their predictive factors is scarce. OBJECTIVE: To establish response to steroidal treatment in an homogeneous group of patients with CD or UC during their first admission to hospital. METHODS: Restrospective analysis of 86 patients who received systemic steroidal treatment for a severe flare-up during their first hospital admission between 1995 and 2000. Patients were treated per protocol with fluid therapy, absolute diet, IV 6-methyl-prednisolone 1 mg/kg/day, and enoxaparin at prophylactic doses. Clinical response at 30 days was considered good in case of complete remission, and poor in case of partial or absent remission. Univariate and multivariate analyses according to non-parametric statistics were performed for sociodemographic and biologic variables. RESULTS: 45 patients with CD and 41 with UC were included. Good response rates were 64.4% for CD and 60.9% for UC. The univariate analysis showed that patients with good response have shorter evolution times and fewer previous flare-ups (p < 0.05) regarding CD. However, the multivariate analysis showed that none of the analyzed variables had predictive value. CONCLUSION: The response rate of severe inflammatory bowel disease attacks to corticoids is around 60% in CD and UC. Data resulting from the current study cannot predict which patients will ultimately respond to therapy.

Adult↗

PubMedDate not supplied

Isolation and gas chromatographic determination of chlorsulfuron in milk.

A method for the isolation and gas chromatographic determination of chlorsulfuron in milk is presented. Blank or chlorsulfuron-spiked milk samples were blended into C-18 (octadecylsilyl derivatized silica, ODS) packing material. A column made from the C-18/milk matrix was washed with hexane after which chlorsulfuron was eluted with dichloromethane (DCM). The DCM eluate contained chlorsulfuron which was free from interfering co-extractants when analyzed by gas chromatography utilizing a nitrogen/phosphorus detector. Chlorsulfuron was found to undergo a thermally induced decomposition to give 2-amino-4-methoxy-6-methyl-1,3,5-triazine, which was detected and quantitated by this method. Standard curves for these analyses were linear (r = 0.992 +/- 0.004, n = 5), with an average percentage recovery of 91.6 +/- 10.8%, over the concentration range examined (62.5-2000 ng/mL). The inter- and intra-assay variabilities were 11.6 +/- 7.5% and 6.2%, respectively.

Animals↗

PubMed1986

Double-blind placebo-controlled study of the efficacy and tolerability of suprofen suppositories in patients with osteoarthritic pain.

In a placebo-controlled double-blind trial analgesic effectiveness and tolerability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 300 mg suppositories were evaluated for 45 informed patients suffering from chronic pain due to osteoarthritis; the subjects were treated rectally, t.i.d., for 10 days. Suprofen proved to be statistically significantly superior to placebo in all the variables considered for evaluation of the analgesic effect, i.e., pain intensity and relief scores, sum of pain intensity differences (SPID), total pain relief (TOTPAR), global assessments by investigator and patient. In particular, the efficacy of suprofen was judged by the physician good or very good in 86.3% of the patients. Similar frequencies of rectal side-effects were observed in both treatment groups, with slightly but not significantly higher incidence in the group treated with suprofen. Haematologic and clinical chemistry laboratory tests showed no statistically significant alterations due to the treatment.

Adult↗

PubMed1986

The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice.

The effects of different dosing paradigms for the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were investigated in C57-black and CF-W albino mice. Several groups of mice received a total dose of 80 mg/kg of MPTP administered at different doses per injection and/or at different time intervals. In C57-black mice, the effects of MPTP administration on the neostriatal content of dopamine ranged from a 91% depletion (4 injections of 20 mg/kg per injection at 1 h intervals) to a non-significant effect (4 injections of 10 mg/kg per injection at 2 h intervals on each of 2 successive days). There was also considerable influence of the MPTP dose per injection and the dosing interval in CF-W mice, although the extent of neostriatal dopamine depletion in CF-W mice was not as great as that observed in C57-black mice. In addition, MPTP produced variable effects on neostriatal dopamine levels in different strains of mice as well as in Swiss-Webster mice obtained from different sources. Some of the strains were affected to a great extent while others were only marginally affected.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1994

The roles of nitric oxide and hydrogen peroxide production in lipopolysaccharide-induced intestinal damage.

The importance of gastrointestinal injury in endotoxin-induced shock and multiple organ failure is of great interest. In this paper we describe a method to assess the degree of intravascular congestion and bleeding into the wall of the intestine by determining the hemoglobin content of the tissue. After validating this method, we used it to study the mechanism of jejunal injury induced by intravenous injection of Escherichia coli lipopolysaccharide (LPS, 50 mg/kg bw), the role of nitric oxide release in maintaining the integrity of endothelial cells, and the participation of H2O2 production in the LPS-induced intestinal damage in rats. Our results show that after the administration of LPS at the dose of 50 mg/kg intravenously, the hemoglobin content of the jejunum (17.8 mg/100 mg tissue) increased 7.7-fold over that of control animals (2.3 mg/100 mg), reflecting a serious degree of congestion, bleeding, and damage in the gastrointestinal tract. Administration of nitro-L-arginine methyl ester (L-NAME) not only enhanced this injury, but also markedly decreased the dose of LPS necessary to induce intestinal damage. Infusion of L-arginine (300 mg/kg bolus plus infusion 600 mg/kg.h intravenously) protected the intestine against LPS or LPS plus L-NAME. Inhibition of basal nitric oxide release by L-NAME produced significant changes in cardiovascular variables, but failed to induce a significant bleeding damage. However, when inhibition of NO release was combined with enhanced H2O2 production by a small dose of LPS, a serious bleeding damage was observed. This was accompanied by a marked decrease in mesenteric blood flow and cardiac output. High dose of LPS induced the above effects, and thus could be responsible for the bleeding damage, while low dose of LPS that fails to inhibit nitric oxide, did not induce any intestinal bleeding. It seems that inhibition of NO release and stimulation of H2O2 production are both involved in the LPS-induced bleeding damage.

Animals↗