Guanidino compounds in the sera of uremic patients and in the sera and brain of experimental uremic rabbits

Matsumoto, Masuo; Kishikawa, Hidemi; Mori, Akitane

doi:10.1016/0006-2944(76)90002-8

Cited by 53 publications

(22 citation statements)

References 7 publications

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“…24) A variety of endogenous substances are found to accumulate in uremic blood. 25) These include among others creatinine, urea, indolic derivatives, 26,27) guanidino derivatives, 28,29) and amino acids. [30][31][32] To investigate the endogenous substances responsible for inhibiting the losartan metabolism, 9 kinds of uremic toxins were selected: indolic derivatives; IS, IA and Trp, guanidino derivatives; MG and GSA, amino acids; Cst and BAIBA, others; Cr and HA.…”

Section: Discussionmentioning

confidence: 99%

Effect of Experimental Renal Failure on the Pharmacokinetics of Losartan in Rats.

Yoshitani

Yagi

Inotsume

et al. 2002

Biological & Pharmaceutical Bulletin

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Losartan is a potent, orally active, angiotensin II receptor antagonist and is used as an antihypertensive agent.1) Losartan binds selectively and specifically to the AT 1 subtype of angiotensin receptor. In contrast to angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists directly abolish the actions of angiotensin II in the body.Losartan is metabolized to EXP3174, 2-n-butyl-4-chloro-1-[(2Ј-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole-5-carboxylic acid, which contributes to the overall in vivo activity of losartan in rats 2) and humans.3) EXP3174 has a longer half-life than losartan. The conversion of losartan to EXP3174 is catalyzed by two cytochrome P450 subfamilies: CYP2C9 and CYP3A4. 4) In normal volunteers, renal clearance accounts for about 12 and 55% of the systemic clearance of losartan and EXP3174, respectively. 5)Progressive renal insufficiency is commonly accompanied by hypertension, which frequently results in the use of antihypertensive agents to reduce blood pressure or, secondarily, to provide renoprotection 6) ; accordingly, it is necessary to investigate the effect of renal failure on the pharmacokinetics of antihypertensive drugs to establish when dosage adjustment is necessary. Very limited information is available on the pharmacokinetics of losartan in humans with renal dysfunction. Sica et al. reported that the steady-state areas under the curve (AUC) of losartan and EXP3174 were not significantly changed with renal impairment. 7) On the other hand, Saruta et al. reported that the maximum serum concentration (C max ) and AUC 0-24 in patients with renal impairment were higher than those in patient with normal renal function. 8)Renal failure is commonly thought to have its sole effect on the renal elimination of drugs.9) However, in fact, renal failure has a variety of influences on drug kinetics: it reduces nonrenal drug elimination (which includes renal as well as hepatic drug metabolism), and influences protein binding and alters the volume of distribution of some drugs.10-12) Renal failure reduces the bioavailability of some drugs and increases that of others. Even for drugs which are not renally eliminated, renal failure can lead to the accumulation of toxic metabolites.9)The purpose of this investigation was to determine the effects of experimental renal failure on the pharmacokinetics of losartan in rats. Animals Male Wistar rats (8 weeks) weighting 250-302 g, were purchased from SLC Japan (Hamamatsu). Before the experiments, the rats were housed in a temperature-and humidity-controlled room with free access to water and standard rat chow. The animal experiments were performed in accordance with The Guidelines for Animal Experiments of Tokyo Medical and Dental University. MATERIALS AND METHODS MaterialsInduction of Acute Renal Failure To produce experimental acute renal failure (ARF), rats received a subcutaneous injection of uranyl nitrate, 10 mg/kg as a 1% solution in normal saline, about 72 h before the experiment. 13) Control animals received an injecti...

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Section: Discussionmentioning

confidence: 99%

Effect of Experimental Renal Failure on the Pharmacokinetics of Losartan in Rats.

Yoshitani

Yagi

Inotsume

et al. 2002

Biological & Pharmaceutical Bulletin

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“…The lactone can be detected in concentrated extracts from the seeds of y-hydroxyargininecontaining Vicia, but lactonization may occur during or after extraction . a-N-acetylarginine (19) has been isolated from cattle brain and found in normal human urine (Terheggen et al, 1972) and serum (Matsumoto et al, 1976a). In hyperargininemia, elevated values occur in urine (Terheggen et al, 1972) and serum (Marescau et al, 1982).…”

Section: Nh2mentioning

confidence: 99%

Natural Guanidino Compounds

Robin¹,

Marescau

1985

Guanidines

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“…[4] In parallel with the progressive structural deterioration of the remaining kidney, a picture of chronic renal failure (CRF) develops with accumulation of urea, creatinine, and other guanidine compounds in blood. [5] Limited availability of the substrate L-arginine due to decreased production after renal mass reduction (RMR) may reduce NO synthesis, and there is some evidence that superoxide production may be increased. [6] Abnormalities in NO synthetic pathway like decreased synthesis, increased degradation due to oxidative stress, and reduced sensitivity to NO are among the common responsible mechanisms mediating the complex hemodynamic and homeostatic disorders associated with the progression of renal disease.…”

Section: Introductionmentioning

confidence: 99%

Multiple Antioxidants and L-Arginine Modulate Inflammation and Dyslipidemia in Chronic Renal Failure Rats

Korish

2010

Renal Failure

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The kidney is an important source of L-arginine, the endogenous precursor of nitric oxide (NO). Surgical problems requiring extensive renal mass reduction (RMR) decrease renal NO production, leading to multiple hemodynamic and homeostatic disorders manifested by hypertension, oxidative stress, and increased inflammatory cytokines. Using the RMR model of chronic renal failure (CRF), we assessed the effects of twelve weeks' administration of L-arginine and/or a mixture of antioxidants (L-carnitine, catechin, vitamins E and C) on plasma cytokines, soluble intercellular adhesion molecule-1 (sICAM-1), nitrate and nitrites (NO 2 /NO 3 ), lipid profile, blood pressure, and renal function. CRF rats showed increased plasma IL-1a, IL1-b, IL-6, TNF-a, and sICAM-1 levels and decreased anti-inflammatory cytokines IL-4 and 10 levels, hypertension, and dyslipidemia. L-arginine treatment improved kidney functions, decreased systolic blood pressure, and decreased inflammatory cytokines levels. Antioxidants administration decreased inflammatory cytokines and sICAM-1 levels and increased IL-4 levels. Combined use of both L-arginine and the antioxidant mixture were very effective in their tendency to recover normal values of kidney functions, plasma cytokines, sICAM-1, blood pressure, NO 2 /NO 3 , cholesterol, and triglycerides concentrations. Indeed, the effects of L-arginine and the antioxidants on the reduction of proinflammatory cytokines may open new perspectives in the treatment of uremia.

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Guanidino compounds in the sera of uremic patients and in the sera and brain of experimental uremic rabbits

Cited by 53 publications

References 7 publications

Effect of Experimental Renal Failure on the Pharmacokinetics of Losartan in Rats.

Effect of Experimental Renal Failure on the Pharmacokinetics of Losartan in Rats.

Natural Guanidino Compounds

Multiple Antioxidants and L-Arginine Modulate Inflammation and Dyslipidemia in Chronic Renal Failure Rats

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