N®-Nitro-L-arginine

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). 

Jansson, L., and Sandler, S. (1991). The nitric oxide synthase II inhibitor N -nitro-L-arginine stimulates pancreatic islet insulin release in vitro, but not in the perfused pancrease. Endocrinology (Baltimore) 128, 3081-3085. 

We have recently analysed the effects of an oral dose of quercetin, the most abundant dietary flavonoid, on the hypertension, oxidant status and renal, cardiac and vascular alterations induced in rats by chronic inhibition of NO synthesis with N-nitro L-arginine methylester (L-NAME). Administration of this NO synthase inhibitor to rats for six weeks induced a progressive increase in systolic blood pressure, but concomitant administration of an oral daily dose of quercetin (10 mg Kg 1) inhibited the development of hypertension induced by L-NAME (Duarte et al, 1999, Meth. Find. Exp. Clin. Pharmacol. 21 (suppl. A), 40). Moreover, when... 

Fig. (7). Effects of quercetin (50 mg Kg 1 per day) in the established phase of N-nitro L-arginine methylester (L-NAME)-induced hypertension in rats. L-NAME groups ( ) L-NAME plus quercetin ( ).

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... 

L-arginine analog NOS inhibitors also show some limited isoform selectivity N°-cyclopropyl-L-arginine, N°-nitro-L-arginine (l-NA), and its methyl ester,... 

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. 

FIGURE 4 Densitometric analysis of Northern blots showing the effects of nitric oxide (NO) on the expression of monocyte chemoattractant protein (MCP-1) mRNA. Cultured human umbilical vein endothelial cells were incubated for 12 hr with solvent (control), the NO synthase inhibitor N°-nitro-L-arginine (L-NAG), or the NO donor SIN-1. Data were obtained using five different cell preparations. P < 0.01. 

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. 

Carreau, A., Duval, D., Poignet, H., Scatton, B., Vige, X., andNowicki, J.-P. (1994). Neuropro-tective efficacy of N"-nitro-L-arginine after focal cerebral ischemia in the mouse and inhibition of cortical nitric oxide synthase. Eur. J. Pharmacol. 256, 241-249. 

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. 

Yamamoto, R., Wada, A., Asada, Y., Niina, H., and Sumiyoshi, A. (1993). N -Nitro-L-arginine, an inhibitor of nitric oxide synthesis, decreases noradrenaline outflow in rat isolated perfused mesenteric vasculature. Naunyn-Schmiedeberg s Arch. Pharmacol. 347, 238-240. 

Gordon, J. B., and Todd, M. L. (1993). Effects of N-nitro-L-arginine on total and segmental vascular resistances in developing lamb lungs. J. Appl. Physiol. 75, 76-85. 

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. 

---