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Cardiovascular Research 1998 37(3):560-563; doi:10.1016/S0008-6363(97)00294-0
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Dietary arginine and the prevention of cardiovascular diseases

Michel de Lorgeril*

Laboratoire de Physiologie-GIP Exercice, Explorations Fonctionnelles Cardiorespiratoires, CHU Nord de Saint-Étienne, Niveau 6, 42055 Saint-Étienne, France

* Tel.: +33 (4) 77828300; fax: +33 (4) 77828447; e-mail: lorgeril@univ-st-etienne.fr

Received 2 September 1997; accepted 24 September 1997

Endothelium plays a primary role in local regulation of vascular activity by synthesis and release of vasoactive substances, including the endothelium-derived relaxing factor, now identified with nitric oxide (NO), a labile substance derived from L-arginine. From its discovery [1, 2], NO has been recognized as a major intercellular, and perhaps intracellular, mediator [1, 2]. NO has potent biological properties as a vasoactive, platelet-regulatory, neurotransmitter and also cytotoxic agent [3]. Disorders of the endothelial NO synthase pathway might play a role in cardiovascular disorders including systemic and pulmonary hypertension [4–8], hypercholesterolaemia [9]and atherosclerosis [10, 11]although it is still unclear whether the decrease in endothelium-dependent vasorelaxation observed in hyperlipidaemia results from an increase in NO inactivation [12, 13]or a decreased formation of this compound [14, 15].

Investigators used arginine, the substrate of NO synthase, and antagonists of NO synthase as pharmacological means to manipulate the pathway. Only recently the idea emerged that arginine is not only a substrate for the enzyme which converts it to NO and citrulline but also a nutrient whose intake is highly variable among individuals and among populations. Although arginine was recently presented as a new possible pharmacological agent for atherosclerosis [16], the hypothesis that chronic high or low intake of arginine may play a role in coronary heart disease (CHD) has not been documented yet.

In the present issue of Cardiovascular Research, Bode-Böger et al. report that dietary arginine interferes with the metabolism of eicosanoids in a rabbit model of hypercholesterolaemia [17]. The cholesterol-induced increase of thromboxane A2, a potent vasoconstrictor and activator of platelet function derived from arachidonic acid, was significantly attenuated by arginine, the formation of atherosclerotic-type lesions and platelet function were partly inhibited and the vasoconstrictor effect of serotonin on isolated aortic rings was normalized. Arginine supplementation had no effect on blood cholesterol and cholesterol feeding did not affect plasma arginine. Arginine supplementation corresponded to a 6-fold increase in daily arginine intake and resulted in a 3-fold increase in plasma levels.

Although the NO- and eicosanoid-producing pathways have been studied extensively, little is known about potential interactions between the 2 pathways [18]. Few studies have suggested that NO may increase the production of eicosanoids through activation of prostaglandin H synthase [19, 20]. An additional interest of the study of Bode-Böger is thus to depict the in vivo time course of NO and eicosanoid production during the development of hypercholesterolaemia and atherosclerotic-type arterial lesions.

The a priori limitation of this study is that the hypercholesterolaemic rabbit model has little in common with the human condition. For instance, in the study of Bode-Böger, cholesterol feeding resulted in a considerable increase of blood cholesterol, from 0.70 to almost 21 µmol/l, whereas in man, dietary cholesterol by itself has usually little or no effect on blood cholesterol.

In addition, atherosclerotic human lesions are much more complex than those observed in the hypercholesterolaemic rabbit. Nonetheless, recent human data indicate that the effects of arginine were actually similar as those shown by Bode-Böger. For instance, dietary arginine (at doses ranging from 8 to 21 g per day) was reported to improve endothelium-dependent relaxation [21]and to normalize platelet aggregation [22]in hypercholesterolaemic humans.

The main question which is arising for nutritionists and cardiologists is the relevance of these new data for the long-term prevention of CHD by manipulating dietary arginine and/or proteins from foods. This idea has been proposed by Cooke in 1993 [23]following the publication of a report about a possible protective effect of nut consumption on the risk of CHD [24]. It was argued that nuts are extremely rich in arginine (see Table 1). In subjects with normal kidney function, arginine plasma level is mainly dependent of dietary intake of arginine whereas it is unclear whether plasma arginine regulates NO synthase [25]. Also, Mediterranean populations known to be protected from CHD [26]use to consume nuts daily and in a recent secondary prevention dietary trial, in which a 50% reduction of CHD risk was demonstrated, dieters were firmly encouraged to eat nuts every day and they did so [27]. However, a major source of arginine in the western diet is meat (Table 1). Considering the dietary recommendations given by most physicians to their CHD patients, which usually include low and rare consumption of meat, it is to be feared that such patients are in fact rather low consumers of arginine and consequently relatively deficient. So far, no epidemiological data are available regarding this specific point. On the other hand, high meat consumption has been consistently associated with high CHD risk [24, 26]. The saturated fatty acids present in meat are usually considered responsible for its effect on CHD risk through effects on blood cholesterol and haemostasis [26]. Fish is also a major potential source of arginine and there is now a consensus to admit that fish consumption, in moderate amount, reduces the risk of CHD [28]. For most investigators, however, the benefits due to fish consumption are linked to their content in omega-3 fatty acids rather than in arginine. Interestingly, omega-3 fatty acids have been shown to stimulate, through an unknown mechanism, systemic NO synthesis [29]which suggests another possible interplay between NO and eicosanoids.


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  		Table 1 Arginine, methionine and folic acid in foods (per 100 g of food)

 
How to reconcile these apparently confusing data?

First, it should be pointed out that patients following a low fat prudent diet can partly compensate their low intake of arginine from animal foods by consuming whole cereals, legumes and fish (Table 1). Second, reported associations between CHD events and dietary factors are usually based on the assumption that nutrients (and not foods) are the active agents. While this undoubtedly has some validity, the nutrient emphasis ignores the possibility that the biologic activity of one nutrient may depend on the presence or absence of other substances in a given food. For instance, if nuts are rich in arginine, they are also rich in alpha linolenic acid, the main vegetable omega-3 fatty acid, whose cardioprotective properties have been reported [30]. Also the potential protective effect of a given amount of dietary arginine is of course not the same when it is associated with either the protective omega-3 fatty acids present in fish or the toxic saturated fatty acids found in meat. Finally, while the intake of arginine from proteins of legumes and cereals is quite lower than that from meat, the intake of methionine, the precursor of the very toxic homocysteine [31], is considerably lower (5 to 10 times lower) when vegetables and cereals are the source of proteins (see Table 1). High plasma homocysteine levels are undoubtedly associated with increased risk of various cardiovascular diseases including CHD [31]. Similar reasoning can apply to the intake of folic acid (see Table 1) which is the main co-factor of homocysteine metabolism. The amount of folic acid in cereals and vegetables is actually at least 2-fold higher than in meat. Thus, the ratio dietary methionine/folic acid, the major determinant of plasma homocysteine level, is much more favorable in cereals and vegetables than in meat. Plasma concentrations of folic acid, methionine and homocysteine are actually related to food intake in human subjects [32]and oral methionine loading has been used to unmask dysfunctional enzymes of the homocysteine degradation pathway. Regarding the arginine–NO question, studies have shown that the adverse vascular properties of homocysteine (and also of hypercholesterolaemia) are partly modulated by NO and related oxidised compounds [33–35]. Thus, in humans, the vascular effects of arginine–NO and methionine–homocysteine are interrelated and this is a crucial point when thinking about preventive intervention.

As written above, degradation of homocysteine requires well functioning enzymes (partly depending on genetic polymorphism) and adequate amounts of major vitamin co-factors, the most important being folic acid which is contained in natural foods (Table 1). It is likely that dietary advice to improve the methionine/folic acid ratio may be helpful and probably sufficient in most subjects whereas folate supplementation and food fortification have been proposed for patients with severe deficiency or high risk of CHD [36].

An important point, to come back to the work of Bode-Böger et al. on dietary arginine, is whether similar conclusions (the usefulness of arginine supplementation) could be drawn from our present knowledge. Certainly, clinical studies (including observation studies and trials) should be urgently performed.

However, from a more general point of view, when considering the number of nutrients that would be desirable to give as supplements to prevent CHD (antioxidants, various fatty acids and amino acids, several vitamins of the B group, fibers and so on), the task seems to be unrealistic. In our affluent societies, the first thing to do is probably to reduce the consumption of many pernicious nutrients (which means decreasing the consumption of foods such as meat, dairy products, polyunsaturated fats, etc.) rather than increasing the antidotes. Recent successful dietary trials have shown that a comprehensive combination of moderate decrease and increase of the intakes of certain foods can actually, safely and at very low cost reduce the risk of CHD [37].


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