Tissue and Blood Cell Concentration of Methylguanidine in Rats and Patients with Chronic Renal Failure

Background: Rats with chronic renal failure have a low nitric oxide (NO) production and a diminished NO excretion. The supplementation of L-arginine has an inhibitory effect on the progression of renal insufficiency. Methods: The present study was designed to determine whether chronic renal failure patients have a low NO production. Plasma and urine nitrate (NO₃) and nitrite (NO₂), stable metabolites of NO, were measured in 83 consecutive patients with chronic renal failure. The 83 chronic renal failure patients were divided into three groups: group 1, mild renal failure (creatinine clearance >60 ml/min/1.73 m²); group 2, moderate renal failure (creatinine clearance >30 <60 ml/min/1.73 m²), and group 3, severe renal failure (creatinine clearance <30 ml/min/1.73 m²). Thirty-three healthy volunteers served as controls. Results: The daily urinary NO excretion was significantly lower in patients with moderate and severe renal failure as compared with those with mild renal failure and normal controls. The lowest values were found in the severe renal failure group. When the 24-hour urinary NO excretion or NO per milligram creatinine and the NO clearance were correlated with the renal function in all patients as a group, these parameters were directly correlated with the creatinine clearance and inversely correlated with the serum creatinine level. The plasma NO concentration was not different between the three chronic renal failure groups, but higher than in the controls. Plasma NO in renal failure patients was not correlated with the creatinine clearance or serum creatinine levels. Conclusions: Chronic renal failure is a state of NO deficiency. Treatment strategies to increase NO production (L-arginine supplementation or other NO compounds) may prove to be useful in maintaining the renal function and slow the progression of renal disease.

Section: Discussionmentioning

confidence: 99%

Low Nitric Oxide Production in Patients with Chronic Renal Failure

Blum

Yachnin

Wollman

et al. 1998

“…With regard to the synthesizing organ, gut flora [4], liver [9,10] and muscle [10] are considered possibilities. However, these studies were long-term experiments in which creatinine or other possible precursors were ad ministered chronically or animals with chronic renal fai lure were used.…”

Section: Discussionmentioning

confidence: 99%

“…In this study creatinine was administered to normal rats as a precursor of MG synthesis because it is known to stimulate MG synthesis. It has been reported that the concentrations of MG in blood cells and other tissues except the brain of uremic rats are higher than that in plasma [2,9]. Because of the possibility that, in a long-term experiment, MG synthesized in some other organ might enter another organ via plasma, various tissues, i.e.…”

Section: Discussionmentioning

confidence: 99%

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Biosynthesis of Methylguanidine in Isolated Rat Hepatocytes and in vivo

Nagase

Aoyagi

Narita

et al. 1985

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.

“…Whereas nearly 100 different guanidino compounds have been found in the natural world, those found in the serum and urine of patients with renal failure include guanidine, guanidinosuccinic acid, guanidinopropionic acid, guanidinoacetic acid, arginine, creatinine (Cr), creatine, and methylguanidine (MG). Among these compounds, MG has been studied from various aspects in relation to its toxicity [9, 10], quantification [11], precursor [12, 13, 14], organs where it is produced [15, 16, 17], production pathways [18, 19, 20, 21, 22], factors influencing its production [23, 24, 25], etc. However, few studies have examined the specific location of MG production in the kidney and the factors involved in its production.…”

Section: Introductionmentioning

confidence: 99%

Site of Methylguanidine Production and Factors That Influence Production Levels

Yokozawa

Muto

Wakaki

et al. 2002

The site of methylguanidine (MG) production in the kidney was investigated using animal models of renal disease and cultured renal epithelial cells. In rats with proximal tubular injury induced by adenine, the blood and urinary levels of MG increased as the severity of injury increased. In contrast, in cases of glomerular injury, there were no such changes in MG levels. Thus, it was apparent that proximal tubular injury served to promote MG production. In addition, a marked increase was observed in the intensities of bands attributable to 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-OH in the electron spin resonance spectrum of the kidney in the rats given adenine. In these rats, the activity of the radical-scavenging enzymes superoxide dismutase, catalase, and glutathione peroxidase was decreased. This suggests that the formation of excessive radicals and deterioration of defense mechanisms that contribute to the development of oxidative stress underlie the enhanced MG production. The experiments using cultured cells revealed that an oxide of adenine, 2,8-dihydroxyadenine (DHOA), directly induced renal tubular injury. These findings indicate that the accumulation of creatinine due to DHOA, combined with oxidative stress, resulted in increased MG production.