The Physiological Impact of Oral Arginine Supplements in Male Sprague Dawley and Zucker Diabetic Fatty Rats

Abstract

Oral arginine supplements have become popular in recent years due to their proposed vasodilatory effect via the nitric oxide synthase pathway. L-arginine, however, is also a substrate for three other enzymes – arginase, arginine decarboxylase, and arginine:glycine amidinotransferase producing urea, agmatine, and creatine, respectively. Interestingly, both L- and D-arginine have also been found to be effective in vitro scavengers of the toxic glucose and fructose metabolite methylglyoxal. Yet, despite the widespread use of oral arginine supplements, the impact of L- and D-arginine on arginine metabolic pathways and basal methylglyoxal production remains unclear. We thus sought to investigate the effect of L-arginine and D-arginine, each at 500 mg/kg/day in drinking water administered for 4 weeks and 1000 mg/kg/day for 16 weeks to separate groups of 9-week-old male Sprague Dawley (SD) rats. As arginine supplements have been shown to be more effective in a disease state, we also supplemented Zucker lean and Zucker Diabetic Fatty (ZDF) rats with 1000 mg/kg/day of oral L- or D-arginine for 12 weeks. We then quantified the expression of arginine related enzymes and their metabolites in the plasma, urine and various organs/tissues. Additionally, we assessed the effect on basal methylglyoxal levels and its degradation by the glyoxalase pathway, relevant cardiovascular parameters, and oral glucose tolerance. L-arginine significantly decreased cationic amino transporter 1 expression in the ileum of both SD and ZDF rats. L-arginine also significantly increased eNOS expression in the aorta and kidney of SD and ZDF rats but only decreased mean arterial pressure in ZDF rats. Arginase expression was decreased in the ileum of SD rats by L-arginine but increased in ZDF rats. Interestingly, L-arginine decreased arginase activity in the ileum of ZDF rats. Plasma creatine levels were unaffected by either L-or D-arginine in the plasma of SD rats. Oddly, D-arginine, which is thought to be inert, was able to alter the expression/activity of enzymes and metabolites of all four arginine metabolic pathways. L-arginine generally maintained or decreased methylglyoxal (MG) levels in both SD and ZDF rats. In ZDF, but not SD rats, L-arginine decreased levels of methylglyoxal in the plasma. Oppositely, D-arginine generally increased MG levels except for in the ileum and lungs of SD rats. Finally, neither isomer proved beneficial in ameliorating impaired glucose tolerance of ZDF rats. In conclusion, both L- and D-arginine significantly affected enzymes and metabolites in several pathways that use arginine as a substrate. As a vasodilator, L-arginine appears to be more effective in a pathological rather than physiological model. Finally, the efficacy of L- and D-arginine as in vivo scavengers of MG will require further investigation.