Endothelial and exercise vasodilation are reduced in postmenopausal females with obesity versus lean and overweight.

BACKGROUND: Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight (OW) and OB categories. METHODS: Participants were grouped by body mass index (BMI) into LN (BMI 18.5-24.9 kg/m2; n = 11), OW (BMI 25.0-29.9 kg/m2; n = 15), and OB (BMI 30.0-39.9 kg/m2; n = 13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises. RESULTS: Significantly lower FA-FMD (P < 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P < 0.001) compared to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were correlated to FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -0.386, P = 0.015, FA-VC: r = -0.456, P = 0.004). CONCLUSION: Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished leg endothelial function, BF and VC during exercise in postmenopausal females.

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.

Endothelial dysfunction influences augmented aortic hemodynamic responses to metaboreflex activation in postmenopausal women.

PURPOSE: Postmenopausal women experience augmented aortic hemodynamic responses to isometric handgrip (IHG) exercise and metaboreflex activation post-exercise muscle ischemia (PEMI). Relationships between endothelial function brachial artery flow-mediated dilation (FMD) and aortic stiffness carotid-femoral pulse wave velocity (cfPWV) with aortic pulsatile hemodynamics during IHG and PEMI have not been determined. The relationships between aortic hemodynamic responses to PEMI were evaluated. METHODS: Aortic blood pressure (BP), wave reflection, and pressure of forward (Pf) and backward (Pb) waves were measured using arterial tonometry at rest, IHG at 30% maximal force, and PEMI in 30 (15/group) postmenopausal women with low (≤ 4.5%) and normal (≥ 5.5%) FMD. Hemodynamic responses were analyzed as the change (Δ) from rest to the last minute of IHG and PEMI. RESULTS: Brachial and aortic systolic BP (SBP) responses to IHG were higher in the low vs normal FMD group (P < 0.05). Aortic SBP (Δ20 ± 8 vs Δ11 ± 7 mmHg), pulse pressure (PP) (Δ12 ± 8 vs Δ6 ± 4 mmHg), augmented pressure (AP) (Δ5 ± 3 vs Δ2 ± 2 mmHg), and Pb (Δ6 ± 4 vs Δ3 ± 2 mmHg) responses to PEMI were greater (P < 0.05) in women with low vs. normal FMD. FMD was negatively correlated with aortic SBP, PP, AP, and Pb (P < 0.05) responses to PEMI. cfPWV was not correlated with responses to PEMI. CONCLUSION: Endothelial dysfunction relates to augmented aortic pulsatile load during metaboreflex activation, which may increase cardiovascular risk in postmenopausal women.

Alcohol Drinking and Blood Alcohol Concentration Revisited.

BACKGROUND: It is widely assumed that the amount of alcohol in the blood reflects the amount of alcohol consumed. However, several factors in addition to amount of alcohol consumed can influence blood alcohol concentration (BAC). This study examines the effect of alcohol dose, concentration, and volume on BAC in rats with a high-alcohol-drinking (HAD) phenotype. METHODS: Study 1 examined the relationship between the amount of alcohol consumed and BAC. Alcohol-naïve, male, HAD rats (N = 7) were given access to alcohol for 2 h/d for 9 consecutive days with food and water ad libitum. Alcohol intake and BAC were measured at 30, 60, and 90 minutes after onset of access. Study 2 examined the effects of altering alcohol dose, concentration, and volume on BAC (as measured by area under the curve). Alcohol-naïve, male, HAD rats (N = 39) were infused, via an intragastric cannulus, with 1.16, 2.44, or 3.38 g alcohol/kg body weight (BW), produced by varying alcohol volume while holding concentration constant or by holding volume constant while varying concentration. Other rats were infused with 10, 15, or 20% v/v alcohol solutions while holding dose constant. RESULTS: BAC was more strongly correlated with the ratio of alcohol intake (g/kg BW) to total fluid intake (mls) (R = 0.85 to 0.97, p < 0.05 to p < 0.001) than it was with the amount of alcohol consumed (g/kg BW) (R = 0.70 to 0.81, p < 0.05). No effect of alcohol dose was seen during the first hour following the onset of an alcohol infusion regardless of whether dose was achieved by altering alcohol volume or concentration. After 1 hour, higher alcohol doses were predictive of greater BACs. CONCLUSIONS: The fact that a 3-fold difference in alcohol dose did not result in significant differences in BACs during the first 30 minutes after ingestion of alcohol has potentially important implications for interpretation of studies that measure alcohol-sensitive end points during this time.

A Combination of Naltrexone + Varenicline Retards the Expression of a Genetic Predisposition Toward High Alcohol Drinking.

BACKGROUND: This study examined whether naltrexone (NTX) or varenicline (VAR), alone or in combination, can retard the phenotypic expression of a genetic predisposition toward high alcohol drinking in rats selectively bred for high alcohol intake when drug treatment is initiated prior to, or concomitantly with, the onset of alcohol drinking. METHODS: Alcohol-naïve P rats were treated daily with NTX (15.0 mg/kg BW), VAR (1.0 mg/kg BW), a combination of NTX (15.0 mg/kg BW) + VAR (1.0 mg/kg BW), or vehicle (VEH) for 2 weeks prior to, or concomitantly with, their first opportunity to drink alcohol and throughout 21 days of daily 2-hour alcohol access. Drug treatment was then discontinued for 3 weeks followed by reinstatement of drug treatment for an additional 3 weeks. RESULTS: When P rats were pretreated with drug for 2 weeks prior to onset of alcohol access, only NTX + VAR in combination blocked the acquisition of alcohol drinking in alcohol-naïve P rats. When drug treatment was initiated concomitantly with the first opportunity to drink alcohol, NTX alone, VAR alone, and NTX + VAR blocked the acquisition of alcohol drinking. Following termination of drug treatment, NTX + VAR and VAR alone continued to reduce alcohol drinking but by the end of 3 weeks without drug treatment, alcohol intake in all groups was comparable to that seen in the vehicle-treated group as the expression of a genetic predisposition toward high alcohol drinking emerged in the drug-free P rats. After 3 weeks without drug treatment, reinstatement of NTX + VAR treatment again reduced alcohol intake. CONCLUSIONS: A combination of NTX + VAR, when administered prior to, or concomitantly with, the first opportunity to drink alcohol, blocks the acquisition of alcohol drinking during both initial access to alcohol and during a later period of alcohol access in P rats with a genetic predisposition toward high alcohol intake. The results suggest that NTX + VAR may be effective in curtailing alcohol drinking in individuals at high genetic risk of developing alcoholism.

Combining Varenicline (Chantix) with Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in a Rodent Model of Alcoholism.

BACKGROUND: This study examined whether varenicline (VAR), or naltrexone (NTX), alone or in combination, reduces alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake. METHODS: Alcohol-experienced P rats that had been drinking alcohol (15% v/v) for 2 h/d for 4 weeks were fed either vehicle (VEH), VAR alone (0.5, 1.0, or 2.0 mg/kg body weight [BW]), NTX alone (10.0, 15.0, or 20.0 mg/kg BW), or VAR + NTX in 1 of 4 dose combinations (0.5 VAR + 10.0 NTX, 0.5 VAR + 15.0 NTX, 1.0 VAR + 10.0 NTX, or 1.0 VAR + 15.0 NTX) at 1 hour prior to alcohol access for 10 consecutive days, and the effects on alcohol intake were assessed. RESULTS: When administered alone, VAR in doses of 0.5 or 1.0 mg/kg BW did not alter alcohol intake but a dose of 2.0 mg/kg BW decreased alcohol intake. This effect disappeared when drug treatment was terminated. NTX in doses of 10.0 and 15.0 mg/kg BW did not alter alcohol intake but a dose of 20.0 mg/kg BW decreased alcohol intake. Combining low doses of VAR and NTX into a single medication reduced alcohol intake as well as did high doses of each drug alone. Reduced alcohol intake occurred immediately after onset of treatment with the combined medication and continued throughout prolonged treatment. CONCLUSIONS: Low doses of VAR and NTX, when combined in a single medication, reduce alcohol intake in a rodent model of alcoholism. This approach has the advantage of reducing potential side effects associated with each drug. Lowering the dose of NTX and VAR in a combined treatment approach that maintains efficacy while reducing the incidence of negative side effects may increase patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake.

L-Citrulline Supplementation Improves Arterial Blood Flow and Muscle Oxygenation during Handgrip Exercise in Hypertensive Postmenopausal Women.

Endothelial dysfunction decreases exercise limb blood flow (BF) and muscle oxygenation. Acute L-Citrulline supplementation (CIT) improves muscle tissue oxygen saturation index (TSI) and deoxygenated hemoglobin (HHb) during exercise. Although CIT improves endothelial function (flow-mediated dilation [FMD]) in hypertensive women, the impact of CIT on exercise BF and muscle oxygenation (TSI) and extraction (HHb) are unknown. We examined the effects of CIT (10 g/day) and a placebo for 4 weeks on blood pressure (BP), arterial vasodilation (FMD, BF, and vascular conductance [VC]), and forearm muscle oxygenation (TSI and HHb) at rest and during exercise in 22 hypertensive postmenopausal women. Compared to the placebo, CIT significantly (p < 0.05) increased FMD (Δ-0.7 ± 0.6% vs. Δ1.6 ± 0.7%) and reduced aortic systolic BP (Δ3 ± 5 vs. Δ-4 ± 6 mmHg) at rest and improved exercise BF (Δ17 ± 12 vs. Δ48 ± 16 mL/min), VC (Δ-21 ± 9 vs. Δ41 ± 14 mL/mmHg/min), TSI (Δ-0.84 ± 0.58% vs. Δ1.61 ± 0.46%), and HHb (Δ1.03 ± 0.69 vs. Δ-2.76 ± 0.77 µM). Exercise BF and VC were positively correlated with improved FMD and TSI during exercise (all p < 0.05). CIT improved exercise artery vasodilation and muscle oxygenation via increased endothelial function in hypertensive postmenopausal women.

Increased risk for alcohol- and other substance-exposed pregnancies among women who smoke tobacco: A secondary analysis of a primary care-based intervention.

INTRODUCTION: Among women at risk for alcohol-exposed pregnancies (AEP), smoking tobacco may be associated with increased severity of alcohol use, and risk for tobacco-exposed and other substance-exposed pregnancies (TEPs/SEPs). Our secondary data analysis of the 'CHOICES Plus' intervention trial explored AEP and SEP risk by smoking status. METHODS: Eligible women (N=261) were recruited from 12 primary care clinics in a public healthcare system, not pregnant, aged 18-44 years, drinking >3 drinks/day or >7 drinks/week, sexually active, and not using effective contraception. We compared women who did and did not smoke tobacco on alcohol and drug severity, and psychological distress (e.g. anxiety) at baseline. RESULTS: Participants were primarily Hispanic (47.1%) or non-Hispanic Black (41.8%) and reported incomes <$20000/year (69.3%). Tobacco smoking prevalence was 45.2%. Compared to non-smokers, those who smoked drank more days/week (mean=3.3, SD=2.0 vs mean=2.7, SD=1.8, p<0.01), had higher alcohol use disorders identification test (AUDIT) scores (mean=12.1, SD=7.6 vs mean=9.8, SD=7.1, p<0.05), were more likely to report current drug use (66.1% vs 48.3%, p<0.01), and had a greater number of (lifetime) drugs used (mean=3.0, SD=2.0 vs mean=2.0, SD=1.5 days, p<0.0001). Also, those who smoked reported greater levels of anxiety (mean=5.9, SD=5.6 vs mean=4.5, SD=4.9, p<0.05), lower confidence to not drink (mean=2.8, SD=0.8 vs mean=3.1, SD=1.0, p<0.01), lower confidence to reduce risky drinking (mean=6.3, SD=3.1 vs mean=7.3, SD=2.8, p<0.0001), greater drinking temptations (mean=3.0, SD=0.9 vs mean=2.6, SD=0.9, p<0.01), and, yet greater readiness to reduce alcohol use (mean=6.2, SD=3.0 vs mean=5.2, SD=3.0, p<0.05). CONCLUSIONS: Women who drink and smoke may have the highest AEP, TEP, and other SEP risk. Primary care providers should screen for alcohol and tobacco co-use and provide brief intervention and/or treatment referral. CLINICAL TRIAL REGISTRATION: The study was registered on the official website of ClinicalTrials.gov. IDENTIFIER: ID NCT01032772.

Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake.

BACKGROUND: This study examined whether prazosin reduces alcohol drinking over the course of prolonged treatment and whether it blocks the initiation of alcohol drinking in rats with a genetic predisposition toward high alcohol drinking, that is alcohol-preferring (P) rats. METHODS: In study one, alcohol-experienced P rats that had been drinking alcohol for 2 h/d for several months were treated daily with prazosin (0, 0.5, 1.0, or 2.0 mg/kg body weight [BW]) for 7 weeks. In study two, alcohol-naïve P rats were treated daily with prazosin (0, 1.0, or 2.0 mg/kg BW) for 2 weeks prior to, or concomitantly with, the initiation of alcohol access and throughout 3 weeks of alcohol availability. Prazosin treatment and alcohol access were then discontinued for 2 weeks followed by reinstatement of alcohol access without prazosin treatment for 4 weeks, followed by resumption of daily prazosin treatment (2.0 mg/kg BW) for 3 weeks. RESULTS: Prazosin reduced alcohol drinking throughout 7 weeks of treatment in P rats accustomed to drinking alcohol. Following termination of prazosin treatment, alcohol drinking slowly returned to pretreatment baseline. Reduced alcohol intake was accompanied by increased water intake. In alcohol-naïve P rats, prazosin administration prior to the first opportunity to drink alcohol and throughout 3 weeks of alcohol access retarded acquisition of alcohol drinking and reduced the amount of alcohol consumed. When prazosin was administered concomitantly with the first opportunity to drink alcohol, it abolished acquisition of alcohol drinking. Discontinuation of prazosin treatment allowed expression of a genetic predisposition toward high alcohol drinking to gradually emerge. Prazosin retained the ability to reduce alcohol intake with repeated treatments. CONCLUSIONS: Prazosin decreased alcohol drinking during prolonged treatment and may be useful for treating alcoholism and alcohol-use disorders. Prazosin may also be useful for deterring the initiation of drinking in individuals with a family history of alcoholism.

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.

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.

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.

Menopause influences aortic pulse pressure and pressure wave responses to metaboreflex activation in women.

OBJECTIVE: Postmenopausal women (post-MW) have greater risk of heart failure due to aortic pulsatile overload on the left ventricle associated with increased backward wave pressure (Pb). Post-MW have exaggerated peripheral blood pressure (BP) response to exercise mediated by metaboreflex (postexercise muscle ischemia [PEMI]) overactivation. Increased forward wave pressure (Pf) and Pb are determinants of aortic pulse pressure (PP) during isometric handgrip exercis (IHG) in young adults. We hypothesized that aortic PP and pressure wave responses to PEMI are augmented in nonhypertensive post-MW compared with premenopausal women (pre-MW). METHODS: Aortic BP, Pf, Pb, and reflection magnitude were assessed at rest and during IHG and PEMI by applanation tonometry in 15 pre-MW and 16 post-MW. RESULTS: Aortic systolic BP during PEMI similarly increased in both groups. The increase in diastolic BP was lower in post-MW (post-MW Δ6 ± 2 vs pre-MW Δ11 ± 2 mm Hg, P < 0.05). Aortic PP (post-MW Δ8 ± 2 vs pre-MW Δ3 ± 2), Pf (post-MW Δ6 ± 1 vs pre-MW Δ0 ± 1), and Pb (post-MW Δ5 ± 1 vs pre-MW Δ2 ± 1) augmented during PEMI in post-MW ( P < 0.05 for all), but not in pre-MW. Reflection magnitude increased during PEMI only in pre-MW (pre-MW Δ7 ± 2 vs post-MW Δ-1 ± 2, P < 0.05) due to concurrent increases in Pf and Pb in post-MW. CONCLUSIONS: Even in nonhypertensive postmenopausal women, increases in Pf and Pb and decrease in aortic DBP are important factors that contribute to the augmented aortic PP response to PEMI.

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.

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.

Creation of a Multispecialty Clinic for Patients with Central Sensitization-Based Chronic Pain Conditions.

OBJECTIVE: To design and evaluate, through a human-centered design approach, a multispeciality clinic for patients with central sensitization syndromes that combined virtual previsit consultations, traditional face-to-face appointments, and technology-enabled educational programming. PATIENTS AND METHODS: Patients with suspected fibromyalgia and chronic abdominal pain were seen in a multispecialty practice, and the performance of the clinic was evaluated against a contemporary cohort. Quantitative and qualitative evaluation measures included team estimates of time spent on care-related tasks, physician rank of alignment of patient need with clinic design, major appointment changes, and nonvisit care tasks. Members of the care team also evaluated strengths, weaknesses, opportunities, and threats to the success of the clinic. RESULTS: The pilot clinic was operated from April 1, 2020, to April 30, 2021, and included 34 patients with suspected fibromyalgia/chronic abdominal pain. During the pilot period, physicians ranked the value of the virtual previsit consultations in providing care as 7.5 on a scale of 0 to 10 and reported an average of 50 minutes in preparation for the appointment, execution of the appointment, and postvisit documentation. We did not observe substantial differences in the number of added appointments or messages received within the patient portal when compared with a comparison cohort. Patients who participated in the combination nurse educator-led and digital education program provided positive feedback about their experience. CONCLUSION: Our clinic model provides a framework for the treatment of patients with debilitating centrally sensitized conditions and future expansion of virtual care delivery models to better meet patient care and educational needs.

Impaired pulse pressure amplification, augmentation index, and arterial stiffness are associated with reduced limb lean mass in overweight and obese postmenopausal women.

BACKGROUND: The age-related muscle mass loss has been associated with increased arterial stiffness (brachial-ankle pulse wave velocity, baPWV) and wave reflection (augmentation index, AIx). In healthy individuals, pulse pressure (PP) is lower in the aorta compared to the brachial artery (PP amplification, PPA). Postmenopausal women experience elevated aortic stiffness leading to increased AIx and aortic PP causing reduced PPA, an independent predictor of cardiovascular mortality. It is unknown whether appendicular skeletal muscle index (ASMI), arm (ArmLM) or leg lean mass (LegLM) are negatively associated with PPA. The purpose of this study was to investigate the associations between vascular function (PPA, AIx, and baPWV) and lean mass (ASMI, ArmLM, and LegLM) in postmenopausal women. METHODS: The study was performed in 93 postmenopausal women (48-71 years; BMI: 30 ± 7 kg/m2). PPA (brachial/aortic PP), aortic AIx, and baPWV were measured. ArmLM and LegLM were measured by dual-energy X-ray absorptiometry. ASMI was calculated as (ArmLM+LegLM)/Ht2. Associations between vascular and lean mass measures were analyzed by multiple linear regression. RESULTS: PPA was associated with ASMI (ß = 0.29, p = .016) and LegLM (ß = 0.25, p = .028) after adjustment for age, height, systolic pressure, strength, and heart rate. AIx was associated with ASMI (ß = -0.27, p = .011), ArmLM (ß = -0.25, p = .023), and LegLM (ß = -0.22, p = .026), while baPWV was associated with reduced ASMI (ß = -0.23, p = .043) and ArmLM (ß = -0.23, p = .045), but not with LegLM (ß = -0.19, p = .074) after full adjustment. CONCLUSIONS: Our findings indicate that impaired pulsatile hemodynamics (PPA and AIx) are negatively associated with ASMI and LegLM, while arterial stiffness is negatively associated with ASMI and ArmLM. Thus, vascular dysfunction may be implicated in muscle mass loss in overweight and obese postmenopausal women.

The Effects of Mat Pilates Training on Vascular Function and Body Fatness in Obese Young Women With Elevated Blood Pressure.

BACKGROUND: Effective nonpharmacological interventions targeting the enhancement of vascular function and decline of body fatness (BF) in obese individuals are indispensable for the prevention of hypertension and cardiovascular events in young adults. Mat Pilates training (MPT) has gained significant popularity worldwide, yet its effects on vascular function and body composition are understudied. We examined the effects of MPT on vascular function and BF in young obese women with elevated blood pressure (BP). METHODS: Twenty-eight young obese women with elevated BP were randomized to an MPT (n = 14) or a nonexercising control (CON, n = 14) group for 12 weeks. Systemic arterial stiffness (brachial-ankle pulse wave velocity (baPWV)), brachial and aortic BP, wave reflection (augmentation index (AIx)), plasma nitric oxide (NO) levels, and BF percentage (BF%) were assessed before and after 12 weeks. RESULTS: MPT significantly reduced (P ˂ 0.05) baPWV (-0.7 ± 0.2 m/s), AIx (-4 ± 1%), brachial systolic BP (-5 ± 1 mm Hg), aortic systolic BP (-6 ± 1 mm Hg), and BF% (-2 ± 1%), while significantly increasing plasma NO (6 ± 2 µM) (P ˂ 0.05) compared with CON. MPT improved systemic arterial stiffness, aortic BP, wave reflection, circulating plasma NO, and BF% in young obese women with elevated BP. CONCLUSIONS: MPT may be an effective intervention for the improvement of vascular function and BF in young obese women with elevated BP, a population at risk for hypertension and early vascular complications. CLINICAL TRIALS REGISTRATION: Trial Number NCT03907384.

Response of exercise-onset vasodilator kinetics to L-citrulline supplementation during different phases of the menstrual cycle.

The purpose of this study was to determine whether L-citrulline (CIT) supplementation during the follicular and luteal phases of the menstrual cycle would present differential effects on vasodilator kinetics in dynamically contracting muscle. Twenty-four women were studied during the follicular (day 15 after onset of menses, n = 13) or the luteal phase (day 25 after onset of menses, n = 11). Supplementation with CIT (6g/day) or placebo occurred 7-days prior to testing in a crossover design across two menstrual cycles. Forearm vascular conductance (FVC) was calculated from blood flow and mean arterial pressure measured continuously during handgrip exercise performed at 10% maximal grip strength. FVC was calculated for each duty cycle (contract:relax, 1:2s) and expressed as a change from baseline (ΔFVC) before being fit with a monoexponential model. Amplitude of the ΔFVC response and the number of duty cycles for ΔFVC to reach 63% of steady-state amplitude (τΔFVC) were derived from the model. Analysis of variance showed no difference in the amplitude of ΔFVC between CIT and placebo (p = .45) or between menstrual cycle phases (p = .11). Additionally, τΔFVC was not different (p = .35) between CIT and placebo in women tested during the follicular (6 ± 3 versus 5 ± 3 duty cycles) or luteal phase (9 ± 1 versus 8 ± 1 duty cycles) although τΔFVC was found to be slower for women tested during the luteal as compared to the follicular phase (8 ± 4 versus 5 ± 3 duty cycles, p = .02). These results indicate that exercise-onset vasodilator kinetics is unaltered with CIT supplementation in young healthy women irrespective of menstrual cycle phase.

Attenuated aortic blood pressure responses to metaboreflex activation in older adults with dynapenia.

BACKGROUND: Low muscle strength (dynapenia) is a primary characteristic of sarcopenia, the age-related loss of muscle mass and strength or low walking speed. New evidence suggests that muscle strength positively affects blood pressure (BP) responses to exercise. As older adults with lowest handgrip strength also have lowest BP at rest, those with dynapenia may experience attenuated BP responses during physical activity. The purpose of this study was to test the hypothesis that dynapenic older adults would exhibit lower BP response to post-exercise muscle ischemia (PEMI). METHODS: Brachial and aortic systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) were measured in older adults (age, 80 ± 5 y) with dynapenia (n = 16) and non-dynapenia (n = 9) at rest and during PEMI following 2 min of isometric handgrip exercise at 30% maximal voluntary contraction. Walking speed was assessed by an 8-foot (2.44 m) walk course. RESULTS: Increases in aortic SBP (11 ± 2 vs. 23 ± 6 mm Hg, p = .03), DBP (6 ± 2 vs.14 ± 4 mm Hg, p = .04), and MAP (8 ± 1 vs. 17 ± 5 mm Hg, p = .02) were lower in dynapenic compared to non-dynapenic adults. Aortic MAP (r = 0.52, p < .05) response to PEMI was correlated with MVC in dynapenic adults. Gait speed was correlated with aortic DBP response to PEMI (r = 0.698, p = .05) in non-dynapenic adults. CONCLUSIONS: Our findings indicate that aortic DBP response to muscle metaboreflex activation is attenuated in older adults with dynapenia. Normal aortic DBP response during metaboreflex activation may positively affect walking performance in non-dynapenic older adults.