L-Citrulline supplementation attenuates aortic pressure and pressure waves during metaboreflex activation in postmenopausal women.

Postmenopausal women have augmented pressure wave responses to low-intensity isometric handgrip exercise (IHG) due to an overactive metaboreflex (postexercise muscle ischaemia, PEMI), contributing to increased aortic systolic blood pressure (SBP). Menopause-associated endothelial dysfunction via arginine (ARG) and nitric oxide deficiency may contribute to exaggerated exercise SBP responses. L-Citrulline supplementation (CIT) is an ARG precursor that decreases SBP, pulse pressure (PP) and pressure wave responses to cold exposure in older adults. We investigated the effects of CIT on aortic SBP, PP, and pressure of forward (Pf) and backward (Pb) waves during IHG and PEMI in twenty-two postmenopausal women. Participants were randomised to CIT (10 g/d) or placebo (PL) for 4 weeks. Aortic haemodynamics were assessed via applanation tonometry at rest, 2 min of IHG at 30 % of maximal strength, and 3 min of PEMI. Responses were analysed as change (Δ) from rest to IHG and PEMI at 0 and 4 weeks. CIT attenuated ΔSBP (−9 ± 2 v. −1 ± 1 mmHg, P = 0·006), ΔPP (−5 ± 2 v. 0 ± 1 mmHg, P = 0·03), ΔPf (−6 ± 2 v. −1 ± 1 mmHg, P = 0·01) and ΔPb (−3 ± 1 v. 0 ± 1 mmHg, P = 0·02) responses to PEMI v. PL. The ΔPP during PEMI was correlated with ΔPf (r = 0·743, P < 0·001) and ΔPb (r = 0·724, P < 0·001). Citrulline supplementation attenuates the increase in aortic pulsatile load induced by muscle metaboreflex activation via reductions in forward and backward pressure wave amplitudes in postmenopausal women.

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

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.

Effects of L-Citrulline Supplementation on Endothelial Function and Blood Pressure in Hypertensive Postmenopausal Women.

Aging and menopause are associated with decreased nitric oxide bioavailability due to reduced L-arginine (L-ARG) levels contributing to endothelial dysfunction (ED). ED precedes arterial stiffness and hypertension development, a major risk factor for cardiovascular disease. This study investigated the effects of L-citrulline (L-CIT) on endothelial function, aortic stiffness, and resting brachial and aortic blood pressures (BP) in hypertensive postmenopausal women. Twenty-five postmenopausal women were randomized to 4 weeks of L-CIT (10 g) or placebo (PL). Serum L-ARG, brachial artery flow-mediated dilation (FMD), aortic stiffness (carotid-femoral pulse wave velocity, cfPWV), and resting brachial and aortic BP were assessed at 0 and 4 weeks. L-CIT supplementation increased L-ARG levels (Δ13 ± 2 vs. Δ−2 ± 2 µmol/L, p < 0.01) and FMD (Δ1.4 ± 2.0% vs. Δ−0.5 ± 1.7%, p = 0.03) compared to PL. Resting aortic diastolic BP (Δ−2 ± 4 vs. Δ2 ± 5 mmHg, p = 0.01) and mean arterial pressure (Δ−2 ± 4 vs. Δ2 ± 6 mmHg, p = 0.04) were significantly decreased after 4 weeks of L-CIT compared to PL. Although not statistically significant (p = 0.07), cfPWV decreased after L-CIT supplementation by ~0.66 m/s. These findings suggest that L-CIT supplementation improves endothelial function and aortic BP via increased L-ARG availability.

Acute Citrulline Blunts Aortic Systolic Pressure during Exercise and Sympathoactivation in Hypertensive Postmenopausal Women.

PURPOSE: Hypertensive postmenopausal women (PMW) have exaggerated exercise systolic blood pressure (SBP) due to impaired functional sympatholysis. l-Citrulline (CIT) supplementation attenuates aortic SBP responses to cold pressor test (CPT)-induced vasoconstriction in young men. We hypothesized that acute CIT ingestion would attenuate aortic SBP and leg hemodynamic responses during exercise and CPT (EX + CPT). METHODS: Fifteen hypertensive PMW (61 ± 7 yr) were randomly assigned to consume either 6 g of CIT or placebo (PL) separated by a minimum 3-d washout phase. Brachial and aortic blood pressure, femoral artery blood flow (FBF), and vascular conductance (FVC) were measured at rest and during 5 min of unilateral plantarflexion exercise with a CPT applied during minutes 4 and 5. RESULTS: No differences between conditions were found in FBF, FVC, and brachial and aortic blood pressure at rest and during exercise alone. Changes in brachial SBP (CIT vs PL, 29 ± 12 vs 40 ± 10 mm Hg) and mean arterial pressure (CIT vs PL, 21 ± 10 vs 33 ± 11 mm Hg), and aortic SBP (CIT vs PL, 27 ± 11 vs 38 ± 9 mm Hg) and mean arterial pressure (CIT vs PL, 23 ± 9 vs 33 ± 11 mm Hg) to EX + CPT were lower in the CIT versus PL condition (P < 0.05). FBF, FVC, and functional sympatholysis (%ΔFVC) were not significantly different between conditions. CONCLUSIONS: Acute CIT ingestion attenuated aortic SBP response to exercise and cold-induced sympathetic activation that may prevent left ventricle overload in hypertensive PMW.

L-Citrulline supplementation attenuates aortic pulse pressure and wave reflection responses to cold stress in older adults.

BACKGROUND AND AIMS: Augmented aortic systolic blood pressure (SBP) and wave reflection via sympathetic-mediated vasoconstriction elevates the risk for adverse cardiovascular events in older adults. L-citrulline (L-CIT) supplementation has shown to reduce aortic SBP and pulse pressure (PP) responses to cold pressor test (CPT) induced sympathoactivation in young men. The aim of this study was to elucidate the efficacy of L-CIT supplementation to attenuate aortic hemodynamic responses to CPT in older adults. METHODS AND RESULTS: Sixteen older adults were randomly assigned to placebo or L-CIT (6 g/day) for 14-days in a crossover, double-blind, placebo-controlled design. Brachial SBP and aortic SBP, PP, augmented pressure (AP), augmentation index standardized at 75 bpm (AIx@75), and pressure of the forward (Pf) and reflected (Pb) waves were evaluated at rest and during CPT pre- and post-intervention. Although no hemodynamic changes at rest, brachial SBP (Δ-12 ± 18 vs. Δ4 ± 14 mmHg; P = 0.008) and aortic SBP (Δ-10 ± 14 vs. Δ4 ± 12 mmHg; P = 0.005), PP (Δ-10 ± 12 vs. Δ4 ± 11 mmHg; P = 0.002), AP (Δ-4 ± 4 vs. Δ2 ± 7 mmHg; P = 0.004), AIx@75 (Δ-3.2 ± 7.2 vs. Δ2.2 ± 6.9%; P = 0.038), Pf (Δ-6 ± 10 vs. Δ3 ± 9 mmHg; P = 0.019), and Pb (Δ-4 ± 6 vs. Δ2 ± 6 mmHg; P = 0.008) responses to the CPT were significantly attenuated following L-CIT supplementation vs. placebo. CONCLUSIONS: L-CIT supplementation attenuated aortic pulsatile pressure and pressure wave reflection responses to CPT in older adults, providing possible cardioprotection during cold-induced sympathoactivation in older adults.

Combined L-Citrulline Supplementation and Slow Velocity Low-Intensity Resistance Training Improves Leg Endothelial Function, Lean Mass, and Strength in Hypertensive Postmenopausal Women.

Hypertension is highly prevalent in postmenopausal women. Endothelial dysfunction is associated with hypertension and the age-related decreases in muscle mass and strength. L-citrulline supplementation (CIT) and slow velocity low-intensity resistance training (SVLIRT) have improved vascular function, but their effect on muscle mass is unclear. We investigated whether combined CIT and SVLIRT (CIT + SVLIRT) would have additional benefits on leg endothelial function (superficial femoral artery flow-mediated dilation (sfemFMD)), lean mass (LM), and strength in hypertensive postmenopausal women. Participants were randomized to CIT (10 g/day, n = 13) or placebo (PL, n = 11) alone for 4 weeks and CIT + SVLIRT or PL + SVLIRT for another 4 weeks. sfemFMD, leg LM and muscle strength were measured at 0, 4, and 8 weeks. CIT increased sfemFMD after 4 weeks (CIT: Δ1.8 ± 0.3% vs. PL: Δ−0.2 ± 0.5%, p < 0.05) and 8 weeks (CIT + SVLIRT: Δ2.7 ± 0.5% vs. PL + SVLIRT: Δ−0.02 ± 0.5, p = 0.003). Leg LM improved after CIT + SVLIRT compared to PL + SVLIRT (Δ0.49 ± 0.15 kg vs. Δ0.07 ± 0.12 kg, p < 0.05). Leg curl strength increased greater with CIT + SVLIRT compared to PL + SVLIRT (Δ6.9 ± 0.9 kg vs. Δ4.0 ± 1.0 kg, p < 0.05). CIT supplementation alone improved leg endothelial function and when combined with SVLIRT has additive benefits on leg LM and curl strength in hypertensive postmenopausal women.