Effect of Oral L-arginine Supplementation on Blood Pressure

A Meta-analysis of Randomized, Double-blind, Placebo-controlled Trials

Jia-Yi Dong, BSc; Li-Qiang Qin, MD, PhD; Zengli Zhang, MD, PhD; Youyou Zhao, PhD; Junkuan Wang, PhD; Fabrizio Arigoni, PhD; Weiguo Zhang, MD, PhD

Disclosures

Am Heart J. 2011;162(6):959-965. 

In This Article

Discussion

This meta-analysis of randomized, double-blind, placebo-controlled trials brought evidence that oral L-arginine supplementation, compared with placebo, significantly lowered systolic BP by 5.39 mm Hg (95% CI −8.54 to −2.25) and diastolic BP by 2.66 mm Hg (95% CI −3.77 to −1.54).

The magnitudes of the BP reductions in response to L-arginine supplementation in this meta-analysis are moderate but detectable. It should be noted that most participants included in these studies were normotensive, a category in which there may be less room for improving. In fact, one trial 20 that performed separate analysis according to hypertension status showed greater BP reductions in hypertensive participants than in normotensive ones (systolic BP: −5.6 vs −1.8 mm Hg, diastolic BP: −3.8 vs −1.8 mm Hg). It would be useful to perform stratified analysis by hypertension status, but the small number of trials conducted in hypertensive subjects[18,20,22] precluded such analysis. Yet our meta-regression analysis suggested an inverse, although not significant (P = .13), relation between baseline systolic BP and net change in systolic BP. It is therefore possible that L-arginine supplementation could exert larger BP-lowering effect in those with high BP. Given the inherent limitations of meta-regression analysis, this finding should be regarded as hypothesis-generating and need to be verified in future studies.

The observed heterogeneity among trials of L-arginine on systolic BP appeared to be due to 2 trials[14,17] that showed large BP reductions. After exclusion of these two trials, heterogeneity disappeared, and the combined effect size did not substantially change and remained significant. In one trial,[17] both treatment and control groups were submitted to a low-caloric diet and exercise training program, and L-arginine supplementation combined with lifestyle modification and dietary therapy may have led to the pronounced BP reductions. For another trial,[14] the disparate results were likely due to chance as the sample size was rather small (n = 12). In addition, all the participants enrolled in these 2 trials[14,17] were type 2 diabetic patients.

Several mechanisms may be responsible for the beneficial effect of L-arginine on BP. As a substrate for NO synthase, L-arginine may exhibit antihypertensive activities by augmenting the production of NO in endothelium and improving its bioavailability in vascular smooth muscle cells, which are essential to maintain vascular homeostasis.[23,24] A recent meta-analysis[25] 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,[14,26] which plays an important role in the etiology of hypertension associated with metabolic syndrome.[27,28]

It is also worth mentioning the "L-arginine paradox" that exogenous L-arginine supplementation improves NO-mediated biological effects despite high endogenous concentration of L-arginine.[29] One possible explanation may be related to asymmetric dimethylarginine (ADMA). ADMA is an endogenous inhibitor of NO synthase and has been shown to reduce the sensitivity of NO synthase to L-arginine.[23,24,30] There is also considerable evidence that ADMA modulates endothelial NO synthase activity within the concentration range found in patients with vascular disease.[23,24,29] Overcoming the inhibition of NO synthase by ADMA may therefore underlie the beneficial effects of L-arginine supplementation on BP.[31]

Our study had stringent inclusion and exclusion criteria. All included studies were randomized, double-blind, placebo-controlled trials, which minimized biases and suggested a high internal validity. We excluded studies[32,33] using L-arginine supplementation as part of intervention, and hence the BP-lowering effect was mainly attributable to L-arginine supplementation. We were able to detect the potential sources of heterogeneity among studies with the use of sensitivity analyses. In addition, results of sensitivity analyses supported the robustness of the findings.

However, the results of this meta-analysis should be interpreted with caution because of several limitations. First, the sample sizes of individual trials were relatively small, which limited the capacity of randomization to minimize the potential influences of confounding factors. For example, in one trial[22] more participants in the placebo group used antihypertensive medication than those in the L-arginine group (45% vs 24%), and this imbalance may have obscured the effect of L-arginine on BP. Nevertheless, restricting analysis to trials in absence of antihypertensive medication use did not change the overall BP estimates. Second, the validity of our meta-analysis depended upon the quality of the individual studies. Although all studies were randomized and double-blind, allocation concealment, quality of randomization, and details of withdrawals were not always reported. In addition, information on the adverse effects of L-arginine supplementation was available in a few studies. Third, the included studies had a short duration, with the majority shorter than 3 months. Therefore, the effect of L-arginine supplementation on BP as well as its safety in long term is uncertain. Fourth, only 11 studies were eligible for this meta-analysis. Most of them were conducted in patients with specific diseases and disorders, such as gestational hypertension, type 2 diabetes, and hypercholesterolemia, which may have limited the generalization of the findings. Finally, as with any meta-analyses, publication bias may affect the results. Although formal statistical tests[10,11] did not detect evidence of this bias in our meta-analysis, the power of these tests were limited due to the small number of studies.

In conclusion, this meta-analysis of randomized, double-blind, placebo-controlled trials provides evidence that oral L-arginine supplementation significantly lowers both systolic and diastolic BP. Large-scale, long-term randomized controlled trials are warranted to confirm the BP-lowering effect of L-arginine supplementation, in particular among the hypertensive populations. While it is premature to recommend L-arginine supplementation to treat and control hypertension, adopting a healthy diet that contains L-arginine–rich foods such as fish, soy, whole grains, beans, and nuts may contribute to hypertension prevention.

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