Back

Nitric Oxide Stimulation Research

• Luiking YC, Engelen MPKJ, Deutz NEP. Regulation of nitric oxide production in health and disease. Curr Opin Clin Nutr Metab Care 2010; 13(1): 97-104.

  Increasing the arginine availability by arginine therapy or arginase inhibition was therefore proposed as a potential therapy to treat hypertension.

  Recent studies in septic patients and transgenic mice models found that inadequate de novo arginine production from citrulline reduces NO2 production.

  Citrulline supplementation may therefore be a novel therapeutic approach in conditions of arginine deficiency.

  Abnormalities in vascular NO2 production and transport result in endothelial dysfunction with various cardiovascular pathologies like hypertension, atherosclerosis and angiogenesis-associated disorders.

  Interestingly, NOS3 can generate superoxide when the concentrations of either L-arginine or BH4 are low. This "uncoupling" of NOS3 occurs in several pathologies, like diabetes, hypercholesterolaemia and hypertension.

  NO2 production was also suggested as a major inherited factor of insulin sensitivity, with diet-induced oxidative scavenging of NO as a first hit towards insulin resistance.

  Arginase has been proposed as an attractive therapy in modifying the arterial response to injury and may offer therapeutic interventions in the treatment of vascular disease.

• Ali EMM, Hamdy SM, Mohamed TM. Nitric oxide synthase and oxidative stress: regulation of nitric oxide synthase.

  Thus, arginase has recently been emerged as a critical regulator of NO2 synthesis that may contribute to the development of numerous pathologies, including vascular disease. The release of NO2 by endothelial NOS (eNOS) plays a crucial role in preserving vascular homeostasis.

L-Arginine Research

• Lekakis JP et al. Oral l-arginine improves endothelial dysfunction in patients with essential hypertension. Int J of Cardiology 2002; 86: 317-323.

  L-Arginine resulted in a significant improvement of flow-mediated dilatation while placebo did not significantly change this parameter

  Long-term oral administration of L-arginine induces a sustained improvement in NO activity that is associated with down regulation of endothelial adherence to monocytes and inhibition of monocyte accumulation to vessel wall

• Lucotti, Pietro, Emanuela Setola, Lucilla D. Monti, Elena Galluccio, Sabrina Costa, Emilia P. Sandoli, Isabella Fermo, Giovanni Rabaiotti, Roberto Gatti, and PierMarco Piatti. Beneficial effects of a long-term oral L-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin resistant type 2 diabetic patients. Am J Physiol Endocrinol Metab 2006; 291: E906 –E912.

  Long-term oral L-arginine treatment resulted in an additive effect compared with a diet and exercise training program alone on glucose metabolism and insulin sensitivity.

  Furthermore, it improved endothelial function, oxidative stress, and adipokine release in obese type 2 diabetic patients with insulin resistance.

  Oral L-arginine supplementation improved endothelial-dependent vasodilation in patients with chronic heart failure with an additional effect compared with exercise alone.

  Although in the present study endothelial-dependent vasodilation was not measured, the measurement of circulating NO2 end metabolites (i.e., NOx) and the NO2 second messenger (i.e., cGMP) levels during ergometric walking test confirmed the positive effect of L-arginine supplementation on endothelial function.

  Associated with an improvement in nitric oxide-induced endothelial function there was a significant decrement in basal and postexercise endothelin-1 levels as previously found after acute and chronic L-arginine therapy

• Chou SY, Hsu CS, Hsu MY, Liang SJ, Yeh CL, Yeh SL. Effects of different arginine concentrations on angiogenic protein production induced by HeLa cells. Nutrition 2010; 26: 818-822.

  The findings of this study suggest that Arg administration at levels similar to or higher than physiologic concentrations enhance the production of angiogenic protein and iNO2 may partly play a role in promoting angiogenesis in the presence of HeLa cells.

  Supplemental Arg has been demonstrated to improve the immunologic response. The clinical relevance of the effects has been documented in several animal experiments and human studies

• Dong JY et al. Effect of oral l-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials.

  Several mechanisms may be responsible for the beneficial effect of L-arginine on BP. As a substrate for NO2 synthase, L-arginine may exhibit antihypertensive activities by augmenting the production of NO2 in endothelium and improving its bioavailability in vascular smooth muscle cells, which are essential to maintain vascular homeostasis.

  A recent meta-analysis suggests that oral L-arginine supplementation is effective at improving endothelial cell function in individuals with endothelial dysfunction. In addition, L-arginine has been shown to improve insulin resistance.

• Lucotti P et al. Oral l-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass. Metabolism Clinical and Experimental 2009; 58: 1270-1276.

  Compared with placebo, L-arginine decreased asymmetric dimethylarginine levels (P b .01), indices of endothelial dysfunction, and increased cyclic guanosine monophosphate (P b .01), L-arginine to asymmetric dimethylarginine ratio (P b .0001), and reactive hyperemia (P b .05).

  Finally, L-arginine increased insulin sensitivity index (P b .05) and adiponectin (P b .01) and decreased interleukin-6 and monocyte chemoattractant protein–1 levels.

  In conclusion, insulin resistance, endothelial dysfunction, and inflammation are important cardiovascular risk factors in coronary artery disease patients; and L-arginine seems to have anti-inflammatory and metabolic advantages in these patients.

  To support a role of L-arginine on endothelial function, L-arginine supplementation was able to determine a significant increment of reactive hyperemia, marker of endothelial- mediated vasodilation, and c-GMP levels, second messenger of NO.

  In fact, reactive hyperemia increased by 31% and c-GMP levels increased by 54%.

• Ochiai M et al. Short-term effects of l-citrulline supplementation on arterial stiffness in middle-aged men. International Journal of Cardiology 2012; 155: 257-261.

  The serum nitrogen oxide (NOx, the sum of nitrite plus nitrate) and NO metabolic products were significantly increased only in the L-citrulline group.

  Plasma citrulline, arginine and the ratio of arginine/asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO2 synthase (arginine/ADMA ratio) were significantly increased in the L-citrulline group compared with the placebo group.

  Moreover, there was a correlation between the increase of plasma arginine and the reduction of baPWV (9% decrease).

  We evaluated the mechanism of this effect based on the hypothesis that L-citrulline increases NO2 bioavailability by increasing L-arginine via the L-citrulline/L-arginine pathway.

  Here, we used baPWV as a promising parameter for assessing arterial stiffness. The stiffness of the central arteries is a predictor of a cardiovascular disease.