N-nitro-L-arginine methyl esters

L-NAME (N-nitro-L-arginine methyl ester), like L-NMMA, is a structural analogue of L-arginine and competes with L-arginine for NO-synthase, which uses L-arginine as a substrate for the formation of NO. L-NMMA and L-NAME are very effective NO-synthesis inhibitors, both in vitro and in vivo. 

N-Nitro-L-arginine methyl ester (L-NAME) is an inhibitor of NOS L-NAME reportedly reduces the volume of cortical and striatal infarct after middle cerebral artery occlusion in the rat. This protection can be reversed by co-injection of L-arginine. L-NAME also reduced the excitotoxic damage induced by NMDA injection. Finally, the authors showed that L-NAME reduced glutamate efflux produced by ischaemic injury in rats. The authors concluded that NOS induced by NMDA receptor overstimulation is a key event in the neuronal injury cascade (Buisson eta/., 1993). 

S. Gumuslu, M. Serteser, T. Ozben, S. Balkan, and E. Balkan, Inhibitory Role of N -nitro-L-Arginine Methyl Ester (L-NAME), a Potent Nitric Oxide Synthase Inhibitor on Brain Malondialdehyde and Conjugated Diene Levels During Focal Cerebral Ischemia in Rats. Clinica ChimicaActa 267(2) (1997) 213-223. 

Vargas F, Osuna A, Fernandez-Rivas A Vascular reactivity and flow-pressure curve in isolated kidneys from rats with N-nitro-L-arginine methyl ester-induced hypertension. J Hypertens 14 373-9,1996... 

Buxton, I. L. O., Cheek, D. J., Eckman, D., Westfall, D. P., Sanders, K. M., and Keef, K. D. (1993). N -nitro-L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists. Circ. Res. 72, 387-395. 

Reports dealing with mechanistic studies of NOS indicate that the enzyme can transfer electrons from NADPH to molecular oxygen via FAD or FMN to form superoxide anion and H2O2 in the presence of calcium or calmodulin (Mayer et al., 1990 Pou etal., 1992). One of these studies also demonstrated the concentration-dependent diminution of superoxide anion generation in the presence of N -nitro-L-arginine methyl ester (l-NAME). NOS has also been shown to donate electrons to acceptors, including nitro-blue tetrazolium (NBT) (Dawson et al., 1991) and cytochrome c (Klatt et al., 1992). These studies have used L-citrulhne rather than NO determination to detect NOS activity. 

Wink et al. (1993b) demonstrated that NO (and/or reactive species formed from -NO autoxidation) inhibits CYP activity in both reversible and irreversible manners. Khatsenko et al. (1993) reported that the decrease in total microsomal CYP caused by endotoxin injection in rats is inhibited by coadministration of N°-nitro-L-arginine methyl ester (l-NAME), an inhibitor of NO synthase (NOS), indicating that the decrease in drug-metabolizing activity under inflammatory conditions is a result of endogenous -NO synthesis. Stadler etal. (1994) demonstrated a decrease in CYP activity and protein expression in vitro in isolated hepatocytes as a result of -NO synthesis. 

Other studies have discounted a prejunctional effect of NO on NE release from sympathetic nerve endings. In this context neither NO, supplied as acidified nitrite to the transmurally stimulated guinea pig pulmonary artery (Cederqvist and Gustafsson, 1994) or endogenously released by acetylcholine in the mesenteric artery of the dog (Toda et al., 1990), nor the prevention of NO synthesis with NNA and N -nitro-L-arginine methyl ester in the rabbit pulmonary artery (Schinozuka et al., 1992) and the rat tail artery (Thorin and Atkinson, 1994), nor its destruction with hemoglobin in the coronary vessels of the isolated rabbit heart (Wennmalm et al., 1989) were found to affect NE release. 

Bagetia, G., lannanone, M., Scorsa. A. M., and Ni.stico. G. (1992). Tacrine-Induced seizure.s and brtun damage in LiCl-trcated rats can be prevented by N-nitro-L-arginine methyl ester, tar. I Pharmacol. 213, 301-304. 

Administration of an aqueous extract of yohimbe at doses of 1 to 1000 ng/kg elicited a dose-dependent increase in mean blood pressure and an increase in medullary blood flow. Both the pressor action and renal medullary vasodilation were blocked by endothelin A and B receptor antagonists in combination. N -nitro-L-arginine methyl ester also inhibited the increase in medullary blood flow induced by yohimbe. The authors of the study concluded that preliminary observations indicate that, in addition to the a-adrenergic antagonist actions that characterize yohimbine, yohimbe possesses endothelin-like actions and affects nitric oxide production in the renal circulation (Ajayi et al. 2003). 

Capasso, R, N. Mascolo, A.A. Izzo, and T.S. GagineUa. 1994. Dissociation of castor oil-induced diarrhoea and intestinal mucosal injury in rat Effect of N -nitro-L-arginine methyl ester. Br. /. Pharmacol. 113(4) 1127. 

For quantification of basal vascular nitric oxide ( NO) production from isolated vessels, Kleschyov et al. (2000) incubated rabbit aortic or venous strips with 250 (iM colloid Fe/diethyldithiocarbamate, which resulted in a linear increase in tissue-associated NO-Fe/diethyldithiocarbamate electron paramagnetic resonance signal during 1 h. Removal of endothelium or addition of 3 mM N -nitro-L-arginine methyl ester inhibited the signal. 

In the guinea pig, pre-treatment with the NOS inhibitor, N -nitro-L-arginine methyl ester (100 mM) administered by s.c. osmotic minipump for 50 h re-... 

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