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At least 19 recordsLinked to original sources
PubMed1989

Variations in the distribution of methylguanidine with the progression of renal failure after methylguanidine loading.

Methylguanidine (MG) was intraperitoneally administered to both normal rats and those given adenine, and MG levels in the serum, liver, kidney, muscle, brain and urine were compared. The accumulation of MG in the body increased with the progression of renal failure, whereas the rate of urinary excretion of MG in rats given adenine for 30 days was lower than the corresponding values in rats given adenine for 10 and 20 days. The velocity of MG elimination from serum and tissues became lower as the period of adenine administration lengthened. In particular, the rate of MG elimination from muscle was markedly low in comparison with that from the serum, liver, kidney or brain, and a high concentration of MG was still present 24 h after MG loading. In addition, the amount of MG obtained by subtracting the total amounts detected in the serum, liver, kidney, muscle, brain and urine from the dose decreased gradually as the period of adenine administration lengthened. The MG-scavenging effect is diminished according to the progress of renal failure.

Adenine↗
PubMed1975

Factors affecting the metabolic production of methylguanidine.

1. Methylguanidine administered orally to normal volunteers was almost completely recovered in the urine, indicating that it is absorbed in the gastrointestinal tract and is not converted into other compounds. In normal persons at least, its urinary output therefore corresponds to its metabolic production rate plus the amount ingested. 2. In normal persons, diets based on foods not containing methylguanidine (e.g. vegetarian, protein-free and milk-egg) caused a fall in the urinary output of methylguanidine as compared with the output of the same subjects on a free diet. Conversely, higher amounts of methylguanidine were excreted on a diet rich in broth and in boiled beef, which contain large amounts of methylguanidine formed from the oxidation of creatinine, caused by boiling. 3. Oral administration of creatinine to normal volunteers induced an immediate and marked increase in urinary excretion of methylguanidine, and the ingestion of [methyl-14-C]creatinine by uraemic patients was followed by the urinary excretion of labelled methylguanidine. These findings indicate that creatinine is partly converted into methylguanidine in both normal and uraemic subjects and accounts for the high metabolic production of methylguanidine in patients with renal failure, in whom the body pool of creatinine is high. 4. Creatinine, incubated at 38 degrees C for 24 h in Krebs bicarbonate solution (pH 7-38) through which was bubbled oxygen with 15% carbon dioxide, was partially oxidized to methylguanidine. This raises the possibility that even in vivo such a conversion may occur "non-enzymatically".

Animals↗
PubMed1998

Biosynthesis of methylguanidine in the hepatic peroxisomes and the effect of the induction of peroxisomal enzymes by clofibrate.

A state of peroxidation is one of the factors contributing to uremia. For example, we have reported that certain species of reactive oxygen, particularly the hydroxyl radical, play an important role in the biosynthesis of methylguanidine which contributes to toxicity in patients with uremia. However, it is uncertain which enzymes are involved in the synthesis of methylguanidine from creatinine. In this study, we attempt to show methylguanidine synthesis in the presence of peroxisomal enzymes that catalyze the beta-oxidation of fatty acids. In addition, we investigate the effect of clofibrate, which induces peroxisomal enzymes or glutathione peroxidase activity, on methylguanidine synthesis in the peroxisomal fraction. Male Wistar rats were fed with the chow containing 0.5% clofibrate to induce peroxisomal enzymes and control rats were fed with ordinary laboratory chow. Peroxisomal fractions were obtained from liver homogenates by centrifugation, and incubated with creatinine in 0.1 M potassium phosphate buffer pH 7.4 at 37 degrees C. Results show that methylguanidine is synthesized from creatinine concomitant with the synthesis of hydrogen peroxide from endogenous substrates in the peroxisomal fraction. This methylguanidine synthesis is inhibited by the addition of dimethylsulfoxide, glutathione, or sodium azide (p < 0.01). The rate of methylguanidine synthesis in clofibrate-treated rats was significantly less than that in control rats (p < 0.02). These results suggest that methylguanidine is synthesized in the peroxisomal fraction, and reactive oxygen species which are generated through this enzymatic reaction, participate in methylguanidine synthesis. Moreover, the induction of a scavenger system, especially glutathione peroxidase takes precedent over the generation of reactive oxygen species in peroxisomes treated with clofibrate.

Animals↗
PubMed1978

A selective method for determination of methylguanidine in biological fluids. Its application in normal subjects and uremic patients.

A selective analytical method for the determination of methylguanidine in plasma in biological fluids has been developed. Methylguanidine is extracted in a column to dichloromethane as an ion pair with hexanitrodiphenylamine (dipicrylamine). It is isolated from coextracted compounds by partition chromatography as the picrate ion-pair. The methylguanidine fraction is collected and after reextraction to a buffer solution the methylguanidine content is quantitatively determined photometrically as picrate. An absolute recovery of 95 +/- 5% was obtained in the concentration range 1.5-10 microgram/ml plasma. The concentration of methylguanidine in plasma was higher in uremic patients, (44.4 +/- 5.71 mumol/l in conservatively-treated and 42.4 +/- 7.87 mumol/l in dialysis-treated patients) than in normal subjects, (4.0 mumol/l), but still lower than reported by other investigators using non-specific methods and also lower than the concentrations found to be toxic in experimental animals. There was a significant correlation between methylguanidine and creatinine concentration but no correlation between methylguanidine and urea concentration in plasma. No obvious relation was found between plasma methylguanidine concentration and various uremic symptoms, mode of treatment or protein intake.

Creatinine↗
PubMed1993

Relationship between serum levels of methylguanidine and glycemic control in IDDM children.

OBJECTIVE: To examine the serum levels of methylguanidine in IDDM children and compare them with markers for glycemic control. Reports have indicated that active oxygen, which damages various tissues, increases in diabetes mellitus. The increase of active oxygen is one of the risk factors for diabetic complications. The synthesis of methylguanidine, a metabolic product of guanidine, is mainly regulated by active oxygen. RESEARCH DESIGN AND METHODS: Forty-eight children with IDDM (mean age 13.3 yr) and 17 age-matched nondiabetic control subjects were studied. Diabetic children were divided into a well-controlled group (HbA1c < 8%, n = 24) and a poorly controlled group (HbA1c > 8%, n = 24). Serum concentrations of methylguanidine were measured by enzymatic assay. RESULTS: Levels of methylguanidine in the poorly controlled group (1.31 +/- 0.08 microM) were significantly higher than those in both the well-controlled group (0.85 +/- 0.08 microM) and the control group (0.59 +/- 0.11 microM), respectively (P < 0.01). Methylguanidine levels showed a positive correlation with the levels of HbA1c (P < 0.01) or fructosamine (P < 0.01). No significant correlations were noted between methylguanidine levels and age, sex, duration of diabetes, or insulin dose. CONCLUSIONS: Our data indicate that the levels of methylguanidine in IDDM children might be affected by glycemic control and that the determination of serum methylguanidine levels could be a useful test for evaluating the state of diabetic control.

Biomarkers↗
PubMed1998

Comparison of antioxidant activities of aminoguanidine, methylguanidine and guanidine by luminol-enhanced chemiluminescence.

1. The objective of this study was to investigate the ability of aminoguanidine, methylguanidine and guanidine to inhibit free radicals or metabolites generated by either stimulated human leucocytes or cell-free systems using luminol-enhanced chemiluminescence (CL). 2. Aminoguanidine (0.1 microM-10 mM), methylguanidine (10 microM-10 mM) and guanidine (10 microM-10 mM) produced concentration-dependent inhibition (96+/-0.1%, n=7, 59+/-1.3%, n=6, and 62+/-3%, n=6, P<0.05 at 10 mM, respectively) in FMLP-stimulated leucocytes CL. 3. In cell-free experiments, hydrogen peroxide (H2O2), hypochlorous acid (HOCl), hydroxyl radical and peroxynitrite-induced CL responses were initiated by hydrogen peroxide (3.5 mM), NaOCl (50 microM), FeSO4 (40 nM) and peroxynitrite (20 nM), respectively. Aminoguanidine, methylguanidine and guanidine produced concentration-dependent inhibition in H2O2-(69+/-0.7%, n=7, 26+/-1%, n=6, and 15+/-0.5%, n=6, at 1 mM, respectively) and HOCl-(84+/-0.3%, n=6, 50+/-1%, n=6, and 29+/-1%, n=7, at 1 mM, respectively) induced luminol CL. Peroxynitrite-induced CL was markedly attenuated in a concentration-dependent manner by aminoguanidine (99+/-0.1%, n=6, at 10 mM), methylguanidine (5+/-0.2%, n=6, at 10 mM) and guanidine (27+/-0.4%, n=7, at 10 mM). However, inhibition with aminoguanidine was found to be more marked than with methylguanidine and guanidine. Aminoguanidine (95+/-0.5%, n=6, at 1 mM) and methylguanidine (25+/-1%, n=6, at 1 mM), but not guanidine (2+/-1%, n=6, at 1 mM), significantly decreased ferrous iron-induced CL. 4. Collectively, these data suggest that aminoguanidine and a high concentration (> or = 0.1 mM) of methylguanidine have direct scavenging activities against H2O2, HOCl, hydroxyl radical and peroxynitrite. Guanidine, at a high concentration (> or = 0.1 mM), scavenges H2O2, HOCl and peroxynitrite, but not the hydroxyl radical. These direct scavenging properties may contribute to inhibitory effects of these compounds on human leucocyte CL.

Antioxidants↗
PubMed1985

Biosynthesis of methylguanidine in isolated rat hepatocytes and in vivo.

To clarify the organ in which methylguanidine is synthesized, high doses of creatinine, which is known to stimulate the synthesis of methylguanidine, were administered to male Wistar rats intraperitoneally. Various tissues of the rats were frozen by a freeze clamp method before and 1, 2 and 3 h after injection, and methylguanidine was determined by high-pressure liquid chromatography using 9,10-phenanthrenequinone for fluorometric determination. We found evidence that the liver, kidney, lung, muscle, red blood cells and gut flora synthesize methylguanidine. In addition, we measured the synthesis of methylguanidine in isolated hepatocytes prepared from normal rats following the addition of creatinine, arginine and guanidinoacetic acid to the incubation medium. Synthesis of methylguanidine was observed only in those incubations which contained creatinine, and was dependent on the concentration of creatinine in the media and on the incubation period. Isolated rat hepatocytes also synthesized guanidine in the presence of guanidinoacetic acid. These results indicate that the liver is one of the organs which synthesize methylguanidine and also that creatinine is the precursor.

Animals↗
PubMed1989

Production of methylguanidine in dogs with acute and chronic renal failure.

1. Methylguanidine is a suspected uraemic toxin that accumulates in renal failure. 2. We measured methylguanidine in the plasma of dogs with acute ischaemic-induced renal failure and in the plasma and urine of dogs with spontaneous chronic renal insufficiency, using a highly sensitive method involving solid-phase extraction followed by h.p.l.c. with post-column fluorescence detection. 3. Constriction of the remaining renal artery of four uninephrectomized dogs for 90 min resulted in a significant (P less than 0.01) increase in plasma creatinine concentration after 24 h (from 113 +/- 3 to 303 +/- 50 mumol/l; mean +/- SEM). Over the next 14 days, plasma creatinine fell towards baseline concentrations. Plasma methylguanidine also increased significantly (P less than 0.05) 24 h after renal occlusion (from 0.16 +/- 0.04 to 0.86 +/- 0.32 mumol/l) and showed a similar pattern to the plasma creatinine concentration. 4. In a further four dogs, administration of mannitol (2 g/kg) at the time of reperfusion significantly attenuated these responses. 5. Dogs with chronic renal failure demonstrated increased plasma concentrations and urinary excretion of methylguanidine, and the levels appeared to be related to the severity of renal insufficiency. Thus, the dogs with the highest plasma creatinine concentrations and lowest creatinine clearances had the highest plasma methylguanidine concentrations. The clearance of methylguanidine exceeded that of creatinine, indicating that the toxin undergoes renal tubular secretion.

Acute Kidney Injury↗
PubMed1981

Tissue and blood cell concentration of methylguanidine in rats and patients with chronic renal failure.

Methylguanidine concentration in blood cell of nondialysed patients with chronic renal failure was quantitatively determined by the method of the present authors. We also determined tissue methylguanidine concentrations in the liver, blood cell, kidney, colon, muscle and brain of uremic rat experimentally produced by Platt's method. Methylguanidine concentrations in blood cell and tissues except the brain of the uremic rats and in blood cell of the uremic patients were 5--7 times higher than those in their serums. An increased methylguanidine concentration in the liver of the uremic rat receiving 40% protein diet was observed. These results imply that methylguanidine acts as one of the important uremic toxins in the intracellular space except for the brain, and suggest that the liver specifically affects the formation of methylguanidine.

Animals↗
PubMed1990

Determination of methylguanidine in plasma and urine by high-performance liquid chromatography with fluorescence detection following postcolumn derivatization.

A high-performance liquid chromatographic method was developed for the determination of methylguanidine in biological fluids. Methylguanidine and the internal standard were isolated from plasma by cation-exchange solid-phase extraction prior to chromatographic analysis. Urine samples were diluted and injected directly onto the analytical column. Chromatographic separation was carried out on an Ultrasil cation-exchange column using a mixture of methanol and monochloroacetate (15/85, v/v) as the mobile phase. Postcolumn derivatization of methylguanidine was carried out using alkaline ninhydrin reagent and the resulting fluorescent product was detected on-line. The method was specific, sensitive, reproducible, and linear over a wide a range of concentrations. The lower limit of detection for methylguanidine in plasma and urine was 1 and 100 ng/ml, respectively. The method was successfully employed for quantification of the levels of methylguanidine in normal and uremic human subjects, normal dogs, and dogs with ischemic-induced acute or spontaneous chronic renal failure.

Animals↗
PubMed1983

Hepatic microsomal cytochrome p-450-dependent N-demethylation of methylguanidine.

Cytochrome P-450-dependent N-demethylation of methylguanidine, a uremia toxin, was investigated. Methylguanidine was stoichiometrically converted into equal amounts of guanidine and formaldehyde by aerobic incubation with phenobarbital-induced microsomes and NADPH. The guanidine formation in the incubation mixture followed Michaelis-Menten kinetics and required the presence of molecular oxygen and NADPH. Methimazole, a non-formaldehyde-producing substrate specific for FAD-containing monooxygenase, did not inhibit significantly formaldehyde formation, suggesting that microsomal FAD-containing monooxygenase does not play a significant role in N-demethylation of methylguanidine. The direct involvement of cytochrome P-450 in the N-demethylation is supported by the observations that addition of methylguanidine to purified cytochrome P-450 preparation caused a type I spectral change and that inhibitors of cytochrome P-450, such as carbon monoxide and metyrapone, markedly decreased the rate of demethylation. Neither superoxide anion nor hydrogen peroxide was directly involved in the demethylation reaction. In addition, guanidine formation was observed in the reconstituted system containing purified cytochrome P-450. Thus, these findings indicate that the hepatic microsomal mixed function oxidase system catalyzes N-demethylation of methylguanidine to guanidine.

Animals↗
PubMed1991

Inhibitory effect of methylguanidine on insulin binding to its receptor. Mechanism underlying insulin resistance in uremia.

To elucidate the mechanism responsible for the decreased insulin binding to erythrocytes in uremic patients, the effects of incubation with sera obtained from uremic patients or with methylguanidine, respectively, on insulin binding were examined. Insulin binding to erythrocytes from uremic patients was lower than that from normal subjects (3.1 +/- 0.19% vs 6.6 +/- 0.33%, Mean +/- SEM, P less than .005), being due mainly to decreased binding affinity (58% of control). Incubation of erythrocytes with 1:5 diluted sera of uremic patients resulted in decreased insulin binding (65 +/- 5% of control) and this decrease was restored to the level of 78 +/- 3% of the controls after incubation with buffer for 12 h. Methylguanidine inhibited insulin binding to erythrocytes in a dose-dependent manner. Post-dialyzed serum with 100 ng/ml of methylguanidine (as seen in pre-dialyzed uremic patients) inhibited insulin binding to erythrocytes as much as pre-dialyzed serum (54.3 +/- 3% vs 47 +/- 1% of control). Incubation of IM-9 lymphocytes with 100 ng/ml of methylguanidine did not alter the insulin receptor mRNA level. These results suggest that methylguanidine inhibits insulin binding to its receptor, resulting in decreased insulin binding to erythrocytes.

Erythrocytes↗
PubMed2004

Effect of methylguanidine in carrageenan-induced acute inflammation in the rats.

In vitro and in vivo studies have demonstrated that methylguanidine, an inhibitor of nitric oxide synthase (NOS), is also able to reduce tumour necrosis factor-alpha (TNF-alpha) release. In the present study, we evaluated the anti-inflammatory potential of methylguanidine treatment in two models of acute inflammation (carrageenan-induced paw edema and pleurisy) where oxyradical, nitric oxide (NO) and prostaglandins play a crucial role in the inflammatory processes. Our data show that methylguanidine, given intraperitoneally at the dose of 30 mg/kg, inhibits the inflammatory response reducing significantly (P<0.05) paw swelling, pleural exudates formation, mononuclear cell infiltration and histological injury. Furthermore, our data suggests that there is a significant (P<0.05) reduction in the activity and expression both of the inducible NOS (iNOS) and of cyclooxygenase-2 in lung tissue of pleurisy model. Methylguanidine is also able to reduce the appearance of nitrotyrosine and of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) synthase immunoreactivity in the inflamed lung tissues. Treatment with aminoguanidine, the reference drug, significantly reduced all the evaluated pro-inflammatory parameters in carrageenan-treated rats. Taken together, the present results demonstrate that methylguanidine exerts potent anti-inflammatory effects that could be, in part, related to an inhibition of the expression/activity of the iNOS and cyclooxygenase-2 and, another part, may be related to a reduction of TNF-alpha release.

Acute Disease↗
PubMed1997

Effect of methylguanidine, guanidine and structurally related compounds on constitutive and inducible nitric oxide synthase activity.

The inhibitory activity of methylguanidine, guanidine and their precursors, creatine and creatinine, on both the neuronal constitutive and lung inducible isoforms of nitric oxide synthase were examined in this study. Methylguanidine and guanidine (0.01-3 mM) significantly (P<0.01) inhibited in a concentration-dependent manner both isoforms of the enzyme. Furthermore analysis of the inhibition curves by ANOVA revealed that methylguanidine and guanidine act as non selective inhibitors of both nitric oxide synthases (P>0.4 for both methylguanidine and guanidine). In contrast, creatine and creatinine, although containing guanidine group, were totally ineffective on either enzyme even at concentration up to 3 mM. The results obtained for tested compounds also suggest a role for the lateral chain of guanidine group in the enzyme inhibition. The lack of selectivity of methylguanidine and guanidine in inhibiting both the nitric oxide synthase enzymes could account for some pathological manifestations like neurological disorders, host defense impairment and probably hypertension, that often occur in patients with uremia or chronic renal failure.

Animals↗
PubMed1994

Effect of recombinant human erythropoietin on synthesis of methylguanidine in uraemic patients on haemodialysis or continuous ambulatory peritoneal dialysis.

The effect of recombinant human erythropoietin (rHuEPO) on synthesis of methylguanidine was studied in 6 uraemic patients on haemodialysis and 5 uraemic patients on continuous ambulatory peritoneal dialysis (CAPD). The two groups of patients were started on a 24-week course of thrice weekly 1500 IU of rHuEPO by the intravenous route. Serum methylguanidine level and methylguanidine/creatinine ratio were comparable in these groups. In the two groups no significant differences were observed in these measurements comparing the pretreatment values with those 4, 8, 12 or 24 weeks after starting rHuEPO administration. During rHuEPO therapy, serum methylguanidine levels and methylguanidine/creatinine ratio showed no considerable difference between the two groups. These findings suggest that administration of rHuEPO does not alter methylguanidine synthesis in uraemic patients on haemodialysis and CAPD.

Adult↗
PubMed1997

Synthesis and pharmacological evaluation of N-(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methylguanidines as N-methyl-D-aspartate receptor ion-channel blockers.

In the mammalian central nervous system, the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors may play an important role in brain diseases such as stroke, brain or spinal cord trauma, epilepsy, and certain neurodegenerative diseases. Compounds which specifically antagonize the actions of the neurotransmitter glutamate at the NMDA receptor ion-channel site offer a novel approach to treating these disorders. CERESTAT (4, aptiganel CNS 1102) is currently undergoing clinical trial for the treatment of traumatic brain injury and stroke. Previously, we reported that analogues of N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (4) bound to the NMDA receptor ion-channel site with high potency and selectivity. Recently, molecules active at both sigma receptors and NMDA receptor sites were investigated. A series of substituted diphenylguanidines 6 which are structurally related to N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine was prepared. Compounds containing appropriate substitution pattern in one of the phenyl rings of diphenylguanidines displayed high affinity. For example, N-(2,5-dibromophenyl)-N'-(3-ethylphenyl)-N'- methylguanidine (27b, R2 = R5 = Br, R3 = C2H5) exhibited potency at both sigma receptors and NMDA receptor sites; 27b also showed high efficacy in vivo in a neonatal rat excitotoxicity model. Further studies indicated that substituent effects were important in this compound series, and 2,5-disubstituted phenyl was the preferred substitution pattern for high-affinity binding at NMDA receptor sites. Bromo and methylthio were the optimal substituents for the R2 and R5 positions of the 2,5-disubstituted phenyl group, respectively. N-(2-Bromo-5-(methylthio)phenyl)-N'- (3-ethylphenyl)-N'-methylguanidine (34b, R2 = Br, R5 = SMe, R3 = C2H5) was highly active at NMDA receptor sites. We found that the binding affinity of guanidines of type 6 could be further enhanced with the appropriate substitution at R3. Optimal activity in this series are afforded by 43b and 44b (R2 = Cl or Br, R5 = R3 = SCH3). Both 43b and 44b bound to NMDA receptor sites with high potency and selectivity (Ki vs [3H]MK-801: 1.87 and 1.65 nM, respectively); these compounds are active in vivo in various animal models of neuroprotection. The structure--activity relationships for these compounds at the NMDA receptor ion-channel site are discussed.

Animals↗