Sex May Modulate the Effects of Combined Polyphenol Extract and L-citrulline Supplementation on Ambulatory Blood Pressure in Adults with Prehypertension: A Randomized Controlled Trial

Abstract

Increased blood pressure (BP), vascular dysfunction and inflammation are involved in the etiology of cardiovascular disease (CVD). Although several dietary components such as polyphenols and L-citrulline may help to control BP, their combined impact on ambulatory BP in individuals at risk of CVD remains unknown. The objective of this research was to investigate the short-term impact of supplementation with a combination of polyphenol extract and L-citrulline on ambulatory BP, endothelial function and inflammation. In a randomized double-blind parallel trial, 73 men and women with prehypertension were supplemented with a placebo (cellulose, n = 34, Plac) or 548 mg/day of polyphenols and 2 g/day of L-citrulline (n = 35, Suppl) for 6 weeks. The primary outcome of this study was the difference between groups in 24-h ambulatory diastolic BP (DBP) at week six. Secondary outcomes were a difference between groups at week six in ambulatory systolic BP (SBP), casual BP, serum lipids and high-sensitivity C-reactive protein (hs-CRP) concentrations and skin advanced glycation end products (AGEs). Potential interaction of treatment with sex was examined. Suppl had no impact on mean ambulatory SBP and DBP (p > 0.10 vs. placebo). Daytime and 24-h SBP were reduced with Suppl in women (p ≤ 0.01), but not in men (p ≥ 0.27). A non-significant reduction in AGEs was observed after Suppl compared to Plac among all participants (p = 0.07) and there was no difference in the concentrations of blood lipids (p > 0.20) or CRP (p = 0.36) between treatments at week six. Therefore, supplementation with polyphenol extract and L-citrulline for 6 weeks has no impact on ambulatory BP, blood lipids and CRP in adults with prehypertension. However, the polyphenol extract/L-citrulline supplement may reduce ambulatory SBP in women, but not in men. These preliminary results need further research efforts towards further documenting this sex-dependent BP response to supplementation with polyphenols and L-citrulline.

Metabolic effects of L‐citrulline in type 2 diabetes

“…Because Cit metabolism shows species differences, extrapolation of these findings to humans needs caution. Second, Cit metabolism is different between males and females; for example, the blood pressure‐lowering effects of Cit are more significant in women than men 102,103 ; these findings highlight the importance of considering sex differences on the impact of Cit when carbohydrate metabolism is evaluated. Third, most reported animal and human studies on the metabolic effects of Cit are from short‐term studies, with concerns remaining about their long‐term potential adverse effects 112 .…”

“…89 In addition, compared to men, women have lower Cit plasma flux, lower Arg/Cit, higher Cit/nitrite ratios in RBC and serum, 100 higher NOS-dependent NO production, 100 and higher wholebody NO biosynthesis. 101 Furthermore, the systolic and diastolic blood pressure-lowering effect of Cit is higher in women, 102,103 which is partially explained by the higher activity of the enzymatic machinery involved in Cit metabolism. In men, following administration of Cit (2-15 g), it is distributed in a volume of 15.2-17.2 L, and its plasma concentration rapidly (T max = 38-56 min) reaches a maximum level (C max = 515-3849 μM).…”

Sexual dimorphism in the context of nutrition and health

“…Additionally, a cross-sectional analysis of a Korean population reported an inverse association between flavonoid intake and obesity in women, whilst for men a positive association was determined for some subclasses (namely, flavonols, flavanones and anthocyanidins) (101) . In a randomised double-blind parallel trial, a combination of 548 mg daily of polyphenols and 2 g daily of L-citrulline reduced ambulatory systolic blood pressure in women, but not in men (102) . Furthermore, a systematic review and meta-analysis described an inverse association between (poly)phenol consumption and gastric cancer.…”

Phytochemicals and Vitamin D for a Healthy Life and Prevention of Diseases

“…Table 2 shows the clinical trials related to grape polyphenols. In addition to cardiovascular disorders, a recently conducted variety of randomised controlled trials for metabolic syndrome related disorders including dementia, gut microbiota related research, periodontal diseases, allergic diseases, and cancer have revealed intriguing findings [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. These clinical trials have confirmed the benefits of the consumption of polyphenol phytochemicals for their risk-reducing effects in a variety of disorders.…”