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  • l Arginine supplementation was reported to be efficient

    2024-05-15

    l-Arginine supplementation was reported to be efficient, inefficient or toxic in aged patients. The present study does not support our hypothesis that increased tissue arginase activity may account for the ineffectiveness and even the toxicity of l-arginine supplementation in ageing. Indeed, except in the lung, tissues did not respond to l-arginine supplementation by an increase in arginase activity. Notably, this supplementation was even found to decrease arginase activity in aorta, thus again supporting a differential regulation of arginase pathway between Ro 48-8071 sale and other tissues. Of interest, our results demonstrated the effectiveness of l-arginine supplementation to improve endothelial function and to decrease SBP in aged rats, suggesting that l-arginine supplementation enhanced endothelial NO production in aorta from aged rats as previously observed (Stathopulos et al., 2001) and that substrate depletion is likely the primary mechanism by which arginase reduced NOS activity (Elms et al., 2013). Furthermore, l-arginine-induced changes in arginase pathway were also tissue-dependent as l-arginine selectively increased Arg2 expression in the brain. Such increase would enhance polyamines synthesis which is altered in age-related neurodegenerative diseases (Yi et al., 2009). More detailed analyses at specific brain structures will however be essential to confirm a potential relevance of this effect. The present study only investigated one of the numerous pathways involved in l-arginine metabolism. Further studies investigating changes in argininosuccinate lyase, arginine:glycine amidinotransferase, arginine decarboxylase, endothelial NOS, inducible NOS or l-arginine transporters would be necessary to get an integrated view as regards the effect of l-arginine supplementation on l-arginine metabolism in case of ageing (Morris, 2007). In clinical settings, the plasma l-arginine/l-ornithine ratio is commonly used as an indicator of arginase activity (Baranyi et al., 2015, Havlinovà et al., 2014), a low ratio being considered as a reflection of high arginase activity (Sourij et al., 2011). In the present study, this ratio was decreased by ageing despite evidence of decrease (in liver and kidney) but also no difference (in other tissues) in arginase activity between aged and young rats, thus questioning the significance of this ratio in ageing. Surprisingly, while a decrease in plasma l-ornithine levels was expected from l-arginine deficiency, we found that plasma l-ornithine levels were not decreased but on the contrary tended to be elevated in aged rats. Such elevated plasma l-ornithine levels in aging rats might result, in theory, from either enhancement of de novo synthesis by arginase and/or ornithine aminotransferase (OAT), and/or lower catabolism by ornithine decarboxylase (ODC) and/or ornithine transcarbamylase (OTC) (Morris, 2007). Our results refute an increase in tissue arginase activity as a culprit for the high plasma l-ornithine levels. However the contribution of red blood cells (RBC) arginase cannot be excluded. Indeed RBC express Arg1 (Yang et al., 2013) than can be released into plasma after RBC lysis (Morris, 2012). Thus an additional hypothesis that might explain the high plasma l-ornithine levels is that aged-induced RBC lysis induces a plasma release of Arg1 which subsequently converts plasma l-arginine to l-ornithine. However, this latter hypothesis seems unlikely since previous data did not report an increase but a 30% decrease in RBC arginase activity in aged rats (Gupta et al., 2004). As regards OAT, no study has been performed in ageing. Likewise, data on the relationship between ageing and l-ornithine-catabolizing enzymes (i.e. ODC and OTC) are conflicting or lacking. ODC activity and/or expression have been found increased in the kidney (Ferioli and Comolli, 1975) and spinal cord (Virgili et al., 2001), and decreased in the liver (Beyer et al., 1992), ovaries (Tao and Liu, 2013), heart, lung and cerebral cortex (Das and Kanungo, 1982). Therefore, further studies are needed to understand the complex interplay between ageing and l-ornithine metabolism.