Combined Citrulline and Glutathione Supplementation Improves Endothelial Function and Blood Pressure Reactivity in Postmenopausal Women

Arturo Figueroa, Arun Maharaj, Yejin Kang, Katherine N Dillon, Mauricio A Martinez, Masahiko Morita, Dai Nogimura, Stephen M Fischer, Arturo Figueroa, Arun Maharaj, Yejin Kang, Katherine N Dillon, Mauricio A Martinez, Masahiko Morita, Dai Nogimura, Stephen M Fischer

Abstract

Postmenopausal women (PMW) may experience endothelial dysfunction associated with arginine (ARG) deficiency relative to asymmetric dimethylarginine (ADMA) caused by oxidative stress. Endothelial dysfunction contributes to increased blood pressure (BP) responsiveness to sympathoexcitation induced by the cold pressor test (CPT). We investigated the effects of citrulline alone (CIT) and combined with the antioxidant glutathione (CIT+GSH) on vascular function. Forty-four healthy PMW were randomized to CIT (6 g), CIT+GSH (2 g + 200 mg: Setria®) or placebo (PL) for 4 weeks. Brachial artery flow-mediated dilation (FMD), aortic stiffness (pulse wave velocity, PWV), brachial and aortic BP reactivity to CPT, and serum fasting blood glucose (FBG), ARG, and ARG/ADMA ratio were measured. Baseline FBG was higher in CIT+GSH vs. PL. FMD increased after CIT+GSH vs. PL (p < 0.05). CIT and CIT+GSH increased ARG/ADMA (p < 0.05), but did not affect aortic PWV. CIT+GSH attenuated the brachial and aortic systolic BP and mean arterial pressure (MAP) responses to CPT vs. PL and CIT (p < 0.05). The improvements in FMD were related to baseline FMD (r = -0.39, p < 0.05) and aortic MAP response to CPT (r = -0.33, p < 0.05). This study showed that CIT+GSH improved FMD and attenuated systolic BP and MAP reactivity in PMW. Although CIT increased ARG/ADMA, it did not improve FMD in healthy PMW.

Keywords: arginine/ADMA ratio; blood pressure responsiveness; citrulline; endothelial function; glutathione.

Conflict of interest statement

M.M. and D.N. are employees of Kirin Holdings Co., Ltd. M.M., D.N. and Kirin had no influence on participant handling, data collection, analysis or interpretation, and manuscript writing. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CONSORT flow chart of participants through the study. CIT, citrulline, CIT+GSH, and CIT+glutathione.
Figure 2
Figure 2
Changes (Δ) in brachial artery flow-mediated dilation (ΔFMD%) from 0 to 4 weeks. Abbreviations: CIT, citrulline; CIT+GSH, CIT+glutathione. * p < 0.05 vs. placebo.
Figure 3
Figure 3
Relationship between changes (Δ) in the brachial artery flow-mediated dilation (ΔFMD%) from 0 to 4 weeks and baseline (0 week) FMD%. Abbreviations: CIT, citrulline; CIT+GSH, CIT+glutathione.
Figure 4
Figure 4
Changes (Δ) in (A) the brachial systolic blood pressure SBP (SBP), (B) brachial mean arterial pressure (MAP), (C) aortic SBP, and (D) aortic MAP to the cold pressor test before and after supplementations. Abbreviations: CIT, citrulline; CIT+GSH, CIT+glutathione. * p < 0.05 before vs. after, †p < 0.05 vs. placebo and CIT, ‡p < 0.05 vs. placebo.
Figure 5
Figure 5
Changes (Δ) in serum levels of arginine (A), ornithine (B), and the arginine/ADMA ratio (C) from 0–4 weeks in the three groups. Values are the mean ± SE. Abbreviations: ARG, arginine; ADMA, asymmetric dimethylarginine; CIT, citrulline; CIT+GSH, CIT+glutathione. * p < 0.05 vs. placebo and CIT+GSH; †p < 0.05 vs. CIT+GSH.

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