Structure-activity relationships of arginine analogues on nitric oxide synthase activity in the rat brain

Yokoi, Isao; Kabuto, Hideaki; Habu, Hiroshi; Inada, Kazunori; Toma, Junji; Mori, Akitane

doi:10.1016/0028-3908(94)90025-6

Cited by 22 publications

(18 citation statements)

References 19 publications

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“…In apparent contradiction to these findings, agmatine was shown to inhibit NOS 66,67. However, others using highly purified enzyme preparations have demonstrated that agmatine itself is neither a substrate for, nor inhibitor of, NOS 68–71. We have demonstrated that the inhibitory effects of agmatine on iNOS generation of NO is primarily by the aldehyde metabolite of agmatine, rather than agmatine itself 72.…”

Section: Agmatinecontrasting

confidence: 71%

“…66,67 However, others using highly purified enzyme preparations have demonstrated that agmatine itself is neither a substrate for, nor inhibitor of, NOS. [68][69][70][71] We have demonstrated that the inhibitory effects of agmatine on iNOS generation of NO is primarily by the aldehyde metabolite of agmatine, rather than agmatine itself. 72 Although this point at first glance may seem trivial, it would explain the aforementioned contradictory effects on NO generation, and is fundamental for the model system we will propose (FIG.…”

Section: Agmatinementioning

confidence: 99%

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Agmatine: At the Crossroads of the Arginine Pathways

Satriano

2003

Annals of the New York Academy of Sciences

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In acute inflammatory responses, such as wound healing and glomerulonephritis, arginine is the precursor for production of the cytostatic molecule nitric oxide (NO) and the pro-proliferative polyamines. NO is an early phase response whereas increased generation of polyamines is requisite for the later, repair phase response. The temporal switch of arginine as a substrate for the inducible nitric oxide synthase (iNOS)/NO axis to arginase/ornithine decarboxylase (ODC)/polyamine axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Herein we describe the capacity of another arginine pathway, the metabolism of arginine to agmatine by arginine decarboxylase (ADC), to aid in this interregulation. Agmatine is an antiproliferative molecule due to its suppressive effects on intracellular polyamine levels, whereas the aldehyde metabolite of agmatine is a potent inhibitor of iNOS. We propose that the catabolism of agmatine to its aldehyde metabolite may act as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Thus, agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in inflammation.

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Section: Agmatinecontrasting

confidence: 71%

Section: Agmatinementioning

confidence: 99%

Agmatine: At the Crossroads of the Arginine Pathways

Satriano

2003

Annals of the New York Academy of Sciences

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“…Of the tested diverse amino acids, L-NIO was approximately four times more potent than L-ornithine and twice as potent as L-arginine, while the closely related vinyl-L-NIO displayed a Luzzi & Marletta (2005) and Southan & Szabo( 1996). b Reported as a weak NOS substrate (Yokoi et al, 1994). c Taken from Proskuryakov et al (2005) and Southan & Szabo( 1996).…”

Section: Resultsmentioning

confidence: 99%

Known regulators of nitric oxide synthase and arginase are agonists at the human G‐protein‐coupled receptor GPRC6A

Wellendorph

Bräuner‐Osborne

2006

British J Pharmacology

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1 GPRC6A is a novel family C G-protein-coupled receptor (GPCR) with so far unknown physiological function. It was the aim of our study to further characterize the ligand preferences of the receptor and elucidate structural requirements for activity. 2 We have previously generated a functional chimeric receptor construct, h6A/5.24, containing the ligand-binding amino-terminal domain of the human GPRC6A and the seven-transmembrane domain and carboxy terminus of the homologous goldfish receptor 5.24. Based on knowledge that this chimera prefers basic L-a-amino acids such as arginine, lysine and ornithine, we searched for commercially available analogues of these and other L-a-amino acids, and tested them for activity in a fluorescence-based calcium assay. The majority of the tested compounds are involved in the regulation of nitric oxide synthase (NOS) and arginase enzymes. Altogether we profiled 30 different analogues. 3 We found that a structurally wide range of L-a-amino-acid analogues of both arginine, lysine, and ornithine are agonists at h6A/5.24, whereas no antagonists were identified. From the profiling it is concluded that L-a-amino acids containing a highly basic side chain confer the highest activity, although the most potent compound was only twice as potent as L-arginine, which has a EC 50 value of 23.5 mM. 4 The reported agonism of NOS-and arginase-active compounds at GPRC6A has obvious implications in interpretation of experiments involving the NOS and arginase systems, and interfering effects at GPRC6A should be regarded of relevance, especially as the physiological function of the receptor is not yet understood.

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“…1A), isolated periodic sharp waves Nitric oxide, synthesized from ARG by the action of NOS (1), suppresses the occurrence of convulsive seizures (6,22). Manipulation of the neocortical quantity of NO by inhibition of NOS may be accomplished by administration of NOS-substrate binders (19,23,24). One such inhibitor of NOS, GGA, is found in small quantities in cerebral cortex.…”

Section: Resultsmentioning

confidence: 99%

Seizures induced by α‐guanidinoglutaric acid, a nitric oxide synthase inhibitor, are controlled by l‐arginine

et al. 1996

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We evaluated the effect of manipulation of nitric oxide (NO) synthesis on epileptiform discharges recorded from immobilized rats during intracerebroventricular injection of c~-guanidinoglutaric acid (GGA), an endogenous convulsant and a NO synthase (NOS) inhibitor, alone or in combined with a NOS substrate, 1~ arginine (ARG). GGA alone, or combined with SO mM ARG, resulted in prolonged electrographical seizures while co-injection of either 100 or 200 mM of ARG with GGA caused significantly protection. These data show that ARG inhibited epileptiform discharges in a dose-dependent fashion, suggesting that the discharges initiated by inhibition of NOS with the intrinsic convulsant GGA are abated by increasing the concentration of the NOS substrate ARG.

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Structure-activity relationships of arginine analogues on nitric oxide synthase activity in the rat brain

Cited by 22 publications

References 19 publications

Agmatine: At the Crossroads of the Arginine Pathways

Agmatine: At the Crossroads of the Arginine Pathways

Known regulators of nitric oxide synthase and arginase are agonists at the human G‐protein‐coupled receptor GPRC6A

Seizures induced by α‐guanidinoglutaric acid, a nitric oxide synthase inhibitor, are controlled by l‐arginine

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