Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure

Alsop, Paige; Hauton, David

doi:10.1007/s00421-016-3418-7

Cited by 37Cardiovascular Health and Disease PreventionNitric Oxide and Endothelin EffectsCardiovascular and exercise physiology

Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure

Open access

Alsop, Paige, Hauton, David·2016·European Journal of Applied Physiology

DOI 10.1007/s00421-016-3418-7PMC PMC4983290

Open this paper in CoChat — free account Open PDF

Abstract

PURPOSE: Both inorganic nitrate and citrulline are known to alter the arginine-nitric oxide-nitrate system to increase the bioavailability of nitric oxide with potential benefits in the treatment of heart failure. However, their effects on cardiac electrical activity, vascular compliance and peripheral conductance are less well understood. This study examined the effect of nitrate and citrulline on cardiac electrical activity and blood flow. METHODS: Young adult subjects (n = 12) were recruited to investigate the effects of acute oral nitrate consumption (8 mg/kg) and chronic citrulline consumption (3 g/day) on cardiac electrical activity measured by ECG recording and blood pressure. Blood flow and vascular compliance were measured by IR-plethysmography at the thumb and the hallux. RESULTS: Nitrate (p < 0.05) and citrulline (p < 0.01) consumption both decreased diastolic blood pressure but had no effect on either pulse pressure or rate-pressure product (NS for both). Citrulline also decreased systolic pressure (p < 0.01). Nitrate and citrulline both decreased vascular compliance (p < 0.05 for both) prior to isometric grip exercise, but this was increased for nitrate following exercise (NS). Citrulline decreased R-R interval 9 % (p < 0.05) at rest and increased heart rate (p < 0.05) in addition to significantly decreasing pulse transit duration (6 %; p < 0.05). QRS duration was also decreased by 5 % for citrulline (p < 0.05) with the reduction in R-R interval. CONCLUSION: Both nitrate and citrulline supplementation decreased vascular tone at rest but citrulline also altered sympathovagal balance to increase sympathetic tone. We suggest that both oral nitrate and citrulline may be suitable adjuvants for patients with heart failure to improve peripheral tissue oxygenation.

AI snapshot

Written from the paper’s full text.

TL;DR

In 12 healthy young adults, acute oral nitrate (8 mg/kg) and 7-day citrulline (3 g/day) both lowered blood pressure and increased peripheral vascular conductance without changing rate-pressure product. Citrulline also modestly increased sympathetic tone and heart rate, but the authors suggest both supplements may be suitable adjuvants for heart failure to improve peripheral tissue oxygenation.

Key findings

Acute nitrate reduced diastolic blood pressure 6% (p < 0.05) and mean arterial pressure 5% (p < 0.05); systolic pressure fell 3% but was not significant, and rate-pressure product was unchanged.
Citrulline reduced systolic pressure 6%, diastolic pressure 14%, and mean arterial pressure 10% (p < 0.01 for all), increased heart rate 9% (p < 0.05), decreased R–R interval (p < 0.05), decreased QRS duration 5% (p < 0.05), and decreased maximum voluntary contraction 7% (p < 0.05).
Both supplements increased peripheral flow estimates: hallux pulse interval decreased 30% with nitrate and 35% with citrulline at rest (p < 0.05), and after isometric grip exercise decreased further by 35% and 55%, respectively (p < 0.05 and p < 0.01). Pulse amplitude ratio fell at rest by 15% with nitrate and ~30% with citrulline (p < 0.05 for both).
Citrulline increased the LF/HF ratio by one-third (p < 0.05) at rest and during exercise, whereas nitrate had no effect on sympathovagal balance; breath-hold increased LF/HF 4-fold in all conditions (p < 0.001). Citrulline halved exercise-induced heart-rate augmentation (2.7 ± 1.7 vs 6.6 ± 1.7 bpm, p < 0.05).

Methods

Twelve young adult non-smokers (mean age 22.8 ± 2.0 years; 4 male/8 female) completed both nitrate and citrulline arms; exclusion criteria included existing cardiac or kidney disease, diabetes, hypertension, and Raynaud’s disease.
Subjects attended two sessions at least 1 week apart. Measurements included ECG, blood pressure, and IR-plethysmography at thumb and hallux during rest, 30 s breath-hold, and 30% MVC isometric grip. Acute nitrate (8 mg/kg in sugar-free cordial) was tested after 2 h; citrulline (3 g/day) was taken for 7 days before repeat testing.
Data are mean ± SEM; Student’s t test compared nitrate or citrulline effects, and ANOVA with Bonferroni post hoc accounted for multiple comparisons.

Limitations

Stated by the authors: no estimates of dietary nitrate intake were made, and subjects were assumed to maintain equivalent intake; plasma nitrate or citrulline concentrations were not measured; gender and menstrual-cycle stage were not accounted for; citrulline’s short plasma half-life (0.9 h) versus nitrate (5–8 h) may make sampling timing critical.
Evident from the text: the sample was small (n = 12) and composed of healthy young adults, not heart failure patients, so the proposed adjuvant benefit for heart failure remains speculative. The nitrate-associated fall in haemoglobin oxygen saturation is attributed to possible methaemoglobin formation, but methaemoglobin was not directly measured.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00421-016-3418-7

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 69 cited sources checked · 0 supported · 0 flagged

Findingown data
In young adults at rest, nitrate treatment had no significant effect on sympathovagal balance.
“For subjects at rest, nitrate treatment had no effect on sympathovagal balance (NS; Fig. 5)”
Quote in the paperNot a substantial claim
Findingown data
In young adults, the domain-averaged durations of cardiac events P, P-R, Q-T, Q-Tc, T, R-T, J-T and S-T were unchanged by breath-hold, isometric grip exercise, nitrate or citrulline.
“Estimation of the domain-averaged durations for the cardiac events P, P-R, Q-T, Q-Tc, T, R-T, J-T and S-T was unchanged by either physiological intervention—breath-hold or ISGE—or by supplement—nitrate of citrulline (NS for all; data not shown).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, chronic citrulline supplementation (3 g/day) decreased diastolic blood pressure.
“citrulline decreased DP 14 % (p < 0.01; Table 2)”
Quote in the paperSubstantial claim
Findingown data
In young adults, citrulline supplementation had no significant effect on pulse amplitude ratio during isometric grip exercise relative to untreated controls.
“on the initiation of isometric grip exercise at 30 % ISGE PAR increased relative to untreated, such that it was not significantly different from the untreated controls (NS; Fig. 4b).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation approximately halved the increase in heart rate during isometric exercise (2.7 ± 1.7 bpm vs 6.6 ± 1.7 bpm; p < 0.05).
“the increase in HR during exercise was 2.7 ± 1.7 bpm for citrulline-treated subjects and hence the augmentation in response to exercise was approximately halved by citrulline (p < 0.05; Fig. 6).”
Quote in the paperNot a substantial claim

Findingown data
In young adults, citrulline supplementation decreased pulse amplitude ratio (PAR) by approximately 30 % during rest (p < 0.05).
“citrulline supplementation significantly decreased PAR ~30 % during the rest period (p < 0.05; Fig. 4b)”
Quote in the paperNot a substantial claim
Findingown data
In young adults, following isometric grip exercise, citrulline supplementation further decreased mean pulse interval at the hallux by 55 % (p < 0.01).
“mean pulse interval at the hallux was further decreased 35 % by nitrate (p < 0.05; Fig. 3b) and 55 % by citrulline (p < 0.01; Fig. 3b).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation decreased mean arterial pressure by 5 % (p < 0.05).
“mean arterial pressure (MAP) was decreased 5 % by nitrate treatment (p < 0.05; Table 2)”
Quote in the paperSubstantial claim
Findingown data
In young adults at rest, citrulline treatment increased the LF/HF ratio by one-third (p < 0.05).
“citrulline treatment increased LF/HF by one-third, implying an increase in contribution from sympathetic nervous system (p < 0.05; Fig. 5).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation had no significant effect on mean pulse interval measured at the thumb following isometric grip exercise.
“Following ISGE, both nitrate and citrulline had no effect mean pulse interval measured at the thumb (NS for both; Fig. 3a) compared with untreated controls.”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation decreased pulse interval measured at the thumb by 15 % at rest (p < 0.05).
“both nitrate and citrulline decreased pulse interval measured at the thumb 15 %, for nitrate treatment this did not reach statistical significance (NS; Fig. 3a), whereas for citrulline this was significantly different from untreated subjects (p < 0.05; Fig. 3a).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation decreased mean pulse interval measured at the hallux by 35 % at rest (p < 0.05).
“For the hallux mean pulse interval was decreased 30 % by nitrate (p < 0.05; Fig. 3b) and decreased 35 % by citrulline (p < 0.05; Fig. 3b).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation had no significant effect on heart rate during breath-hold and isometric grip exercise.
“during both breath-hold and ISGE both HR (NS; Fig. 2a) and R–R interval (NS; Fig. 2b) were unchanged by citrulline supplementation.”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation had no significant effect on mean pulse interval measured at the thumb following isometric grip exercise.
“Following ISGE, both nitrate and citrulline had no effect mean pulse interval measured at the thumb (NS for both; Fig. 3a) compared with untreated controls.”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation had no significant effect on rate-pressure product.
“Rate-pressure product (RPP) was unaffected by either nitrate or citrulline treatment (NS for both; Table 2).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation decreased pulse amplitude ratio during recovery after isometric grip exercise (p < 0.05).
“During the subsequent recovery period, PAR declined following citrulline treatment and the significant difference from untreated subjects was restored (p < 0.05; Fig. 4b).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation had no significant effect on QRS interval.
“QRS interval was unchanged following nitrate supplementation (NS; Fig. 2c).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation decreased pulse amplitude ratio (PAR) by 15 % at rest (p < 0.05).
“Following nitrate supplementation, PAR decreased 15 % (p < 0.05; Fig. 4a) at rest (Time t = 0 to t = 10 min).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation had no significant effect on pulse pressure.
“Nitrate (p < 0.05) and citrulline (p < 0.01) consumption both decreased diastolic blood pressure but had no effect on either pulse pressure or rate-pressure product (NS for both).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, following isometric grip exercise, nitrate supplementation further decreased mean pulse interval at the hallux by 35 % (p < 0.05).
“mean pulse interval at the hallux was further decreased 35 % by nitrate (p < 0.05; Fig. 3b) and 55 % by citrulline (p < 0.01; Fig. 3b).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, breath-hold increased the LF/HF ratio fourfold (p < 0.001 for all).
“Irrespective of treatment, breath-hold increased sympathetic tone, measured as LF/HF ratio 4-fold (p < 0.001 for all; Fig. 5)”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation had no significant effect on pulse pressure.
“Nitrate (p < 0.05) and citrulline (p < 0.01) consumption both decreased diastolic blood pressure but had no effect on either pulse pressure or rate-pressure product (NS for both).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation decreased mean pulse interval measured at the hallux by 30 % at rest (p < 0.05).
“For the hallux mean pulse interval was decreased 30 % by nitrate (p < 0.05; Fig. 3b) and decreased 35 % by citrulline (p < 0.05; Fig. 3b).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, the one-third increase in LF/HF noted for citrulline compared with untreated subjects was preserved during isometric grip exercise (p < 0.05).
“the one-third increase noted for citrulline compared with untreated subjects was preserved (p < 0.05; Fig. 5).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation decreased haemoglobin oxygen saturation by 2 % (p < 0.001).
“Haemoglobin % oxygen saturation, measured by pulse oximetry, was unaffected by citrulline but was decreased 2 % by nitrate supplementation (p < 0.001; Table 2).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation decreased systolic pressure by 6 % (p < 0.01).
“citrulline decreased SP 6 % (p < 0.01; Table 2)”
Quote in the paperSubstantial claim
Findingown data
In young adults, citrulline treatment decreased maximum voluntary contraction by 7 % compared with untreated controls (p < 0.05).
“Citrulline treatment decreased MVC by 7 % compared with untreated controls (p < 0.05; Table 2).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation increased heart rate by 9 % at rest (p < 0.05).
“Citrulline increased HR 9 % (p < 0.05; Fig. 2a) and decreased R–R interval significantly (p < 0.05; Fig. 2b) for subjects at rest.”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation decreased R-R interval by 9 % at rest (p < 0.05).
“Citrulline decreased R–R interval 9 % (p < 0.05) at rest”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation decreased mean arterial pressure by 10 % (p < 0.01).
“citrulline reduced MAP 10 % (p < 0.01; Table 2)”
Quote in the paperSubstantial claim
Findingown data
In young adults, citrulline supplementation decreased QRS interval by 5 % at rest (p < 0.05).
“for subjects at rest, citrulline decreased QRS interval 5 % (p < 0.05; Fig. 2c)”
Quote in the paperNot a substantial claim
Findingown data
In untreated young adults, isometric grip exercise increased heart rate by 6.6 ± 1.7 bpm.
“ISGE increased heart rate 6.6 ± 1.7 bpm for untreated subjects (Fig. 6).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, neither nitrate nor citrulline had any additional effect on heart rate variability estimates during breath-hold.
“neither nitrate nor citrulline had any additional effect on HRV estimates (NS; Fig. 5).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation had no significant effect on rate-pressure product.
“Rate-pressure product (RPP) was unaffected by either nitrate or citrulline treatment (NS for both; Table 2).”
Quote in the paperNot a substantial claim
Findingown data
In young adults, citrulline supplementation had no significant effect on R-R interval during breath-hold and isometric grip exercise.
“during both breath-hold and ISGE both HR (NS; Fig. 2a) and R–R interval (NS; Fig. 2b) were unchanged by citrulline supplementation.”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation had no effect on heart rate augmentation during isometric exercise.
“For nitrate-supplemented subjects, this increase was preserved, nitrate having no effect on HR augmentation during exercise.”
Quote in the paperNot a substantial claim
Findingown data
In young adults, isometric grip exercise at 30 % MVC did not increase measures of sympathovagal balance compared with corresponding controls.
“ISGE at 30 % MVC did not increase measures of sympathovagal balance compared with the corresponding controls”
Quote in the paperNot a substantial claim
Findingown data
In young adults, nitrate supplementation did not significantly change systolic pressure.
“Nitrate supplementation decreased systolic pressure 3 %, but this was not significantly different from untreated subjects (NS; Table 1).”
Quote in the paperNot a substantial claim
Findingown data
In untreated young adults, isometric grip exercise decreased R-R interval (p < 0.05).
“This was accompanied by corresponding decreases in R–R interval following ISGE (p < 0.05; Fig. 2b).”
Quote in the paperNot a substantial claim
Findingown data
In untreated young adults, pulse amplitude ratio was unchanged by 30 % MVC isometric grip exercise.
“For untreated subjects, PAR was unchanged as a result of 30 % MVC-ISGE (NS; Fig. 4a).”
Quote in the paperNot a substantial claim
Findingreasoning
When the apparent reduction in R-R interval is taken into account, the QRS interval is preserved across all interventions.
“when the apparent reduction in R–R interval is taken into account the QRS interval is preserved across all interventions”
Quote in the paperNot a substantial claim
Findingreasoning
Estimates of blood velocity in the peripheral circulation measured from the pulse interval indicate that both exogenous nitrate and citrulline increase the flow velocity measured at both hand and foot.
“Estimates of blood velocity in the peripheral circulation measured from the pulse interval indicate that both exogenous nitrate and citrulline increase the flow velocity measured at both hand and foot.”
Quote in the paperNot a substantial claim
Findingreasoning
On relaxation, the PAR failed to return to pre-exercise levels.
“On relaxation, the PAR failed to return to pre-exercise levels”
Quote in the paperNot a substantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
Findingcitation
Nitrate consumption decreased diastolic pressure, as shown by ourselves and others.
“Evidence in support of this was the decreased diastolic pressure following nitrate consumption shown by ourselves and others (Levitt et al. 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Levitt et al. 2015 source
  Not checked in the free run.
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
Findingcitation
Nitrate decreased the PAR at rest.
“Nitrate decreased the PAR at rest”
Quote in the paperSubstantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
Findingown data
Examination of heart rate variability (HRV) LF/HF ratio suggests that nitrate had no effect on the sympathovagal balance in young adults.
“Examination of the heart rate variability (HRV) to quantify the balance between sympathetic and parasympathetic tone, indicated by the LF/HF ratio, suggests that nitrate had no effect on the sympathovagal balance in young adults.”
Quote in the paperNot a substantial claim
Findingnone given
These effects occur without altering cardiac electrical activity.
“These effects occur without altering cardiac electrical activity”
Quote in the paperSubstantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
Findingown data
The impact on sympathetic tone was modest as a breath-hold challenge had no effect on the sympathovagal balance when compared with untreated subjects.
“the impact on sympathetic tone was modest as a challenge to strongly stimulate the sympathetic NS (a breath-hold) had no effect on the sympathovagal balance when compared with untreated subjects.”
Quote in the paperNot a substantial claim
Findingown data
Citrulline increased the level of sympathetic tone modestly at both rest and during exercise.
“citrulline increased the level of sympathetic tone modestly at both rest and during exercise.”
Quote in the paperNot a substantial claim
Findingnone given
Citrulline modestly alters sympathovagal balance to increase sympathetic tone.
“Citrulline modestly alters sympathovagal balance to increase sympathetic tone”
Quote in the paperNot a substantial claim
Findingnone given
This does not alter the vascular response to either citrulline or nitrate.
“but this does not alter the vascular response to either citrulline or nitrate.”
Quote in the paperNot a substantial claim
Premisecitation
Inorganic nitrate found in certain fruit and vegetable juices has the potential to reduce blood pressure.
“inorganic nitrate found in certain fruit and vegetable juices has shown the potential to reduce blood pressure (Siervo et al. 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Siervo et al. 2013 source
  Not checked in the free run.
Premisecitation
Citrulline has the potential to increase plasma nitrate and nitric oxide availability.
“Citrulline, the end product of arginine-mediated nitric oxide production, has shown the potential to increase plasma nitrate and NO availability (Schwedhelm et al. 2007; Morita et al. 2014).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Schwedhelm et al. 2007 source
  Not checked in the free run.
- cites Morita et al. 2014 source
  Not checked in the free run.
Interpretationreasoning
For citrulline, the fall in blood pressure was of sufficient magnitude to induce tachycardia to preserve rate-pressure product.
“For citrulline, the fall in blood pressure was of sufficient magnitude to induce tachycardia to preserve RPP.”
Quote in the paperNot a substantial claim
Interpretationown data
Citrulline altered sympathovagal balance to increase sympathetic tone.
“Both nitrate and citrulline supplementation decreased vascular tone at rest but citrulline also altered sympathovagal balance to increase sympathetic tone.”
Quote in the paperSubstantial claim
Interpretationown data
Despite apparent hypotension, unchanged rate-pressure product suggests that cardiac work was unchanged.
“Despite the apparent hypotension, cardiac rate-pressure product (RPP) was unchanged suggesting that cardiac work was unchanged.”
Quote in the paperSubstantial claim
Premisecitation
The efficacy of organic nitrates gradually attenuates.
“One shortcoming of such therapies is a gradual attenuation of the efficacy of organic nitrates (Leier et al. 1983).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Leier et al. 1983 source
  Not checked in the free run.
Premisecitation
Citrulline attenuated the systolic pressure increase in response to the cold pressor test.
“Citrulline also attenuated the systolic pressure (SP) increase in response to the cold pressor test (Figueroa et al. 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Figueroa et al. 2010 source
  Not checked in the free run.
Premisecitation
Inorganic nitrate has the potential to improve cardiovascular parameters including vascular compliance.
“and for the improvement in cardiovascular parameters including vascular compliance (Lidder and Webb 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Lidder and Webb 2012 source
  Not checked in the free run.
Premisecitation
In human subjects, citrulline decreased arterial stiffness in middle-aged men.
“In human subjects, citrulline decreased arterial stiffness in middle-aged men (Ochiai et al. 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Ochiai et al. 2012 source
  Not checked in the free run.
Premisecitation
Dietary nitrate decreased diastolic pressure in as little as 3 days.
“Dietary nitrate decreased DP in as little as 3 days (Larsen et al. 2006)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Larsen et al. 2006 source
  Not checked in the free run.
Premisecitation
Arteriolar and venular components of the cardiovascular system have differing sensitivities to glyceryl trinitrate.
“arteriolar and venular components of the cardiovascular system have differing sensitivities to GTN, with venous distension maximal at very low nitrate concentrations whilst arterial resistance shows lower sensitivities to GTN (Imhof et al. 1980).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Imhof et al. 1980 source
  Not checked in the free run.
Premisecitation
Previous experiments demonstrated increased nitric oxide production in vivo.
“and increased nitric oxide production in vivo (Churchward-Venne et al. 2014; Schwedhelm et al. 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Churchward-Venne et al. 2014
  Not checked in the free run.
- cites Schwedhelm et al. 2007 source
  Not checked in the free run.
Premisecitation
Citrulline supplementation in human subjects increased plasma arginine.
“supplementation of citrulline in human subjects increased plasma arginine (Moinard et al. 2008, 2015)”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Moinard et al. 2008
  Not checked in the free run.
- cites Moinard et al. 2015
  Not checked in the free run.
Interpretationcitation
Citrulline may yield a modest increase in cardiac oxygen consumption.
“indicates that citrulline may yield a modest increase in cardiac oxygen consumption.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Hauton et al. 2015 source
  Not checked in the free run.
Interpretationreasoning
Despite a decrease in R-R interval and modest tachycardia noted for citrulline, the overall burden in cardiac mechanical performance was unchanged.
“despite a decrease in R–R interval and the modest tachycardia noted for citrulline, the overall burden in cardiac mechanical performance was unchanged.”
Quote in the paperSubstantial claim
Premisecitation
Citrulline supplementation decreased both systolic and diastolic blood pressure in humans following 14 days of supplementation.
“humans decreased both SP and DP blood pressure following 14-days supplementation (Sanchez-Gonzalez et al. 2012; Figueroa et al. 2010).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Sanchez-Gonzalez et al. 2012
  Not checked in the free run.
- cites Figueroa et al. 2010 source
  Not checked in the free run.
Interpretationown data
The observations on QRS interval were a direct result of the modest tachycardia caused by citrulline.
“suggesting that our observations were a direct result of the modest tachycardia caused by citrulline.”
Quote in the paperNot a substantial claim
Premisecitation
Citrulline supplementation in human subjects enhanced the bioavailability of nitric oxide.
“enhanced the bioavailability of nitric oxide (Morita et al. 2014)”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Morita et al. 2014 source
  Not checked in the free run.
Interpretationreasoning
Cardiac work was preserved following nitrate and citrulline supplementation.
“suggesting that cardiac work was preserved”
Quote in the paperSubstantial claim
Premisecitation
Citrulline use in humans decreased both systolic and diastolic blood pressure following 14-days supplementation.
“citrulline use in humans decreased both SP and DP blood pressure following 14-days supplementation (Sanchez-Gonzalez et al. 2012; Figueroa et al. 2010).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Sanchez-Gonzalez et al. 2012
  Not checked in the free run.
- cites Figueroa et al. 2010 source
  Not checked in the free run.
Premisecitation
Infusion of GTN increased arterial compliance.
“infusion of GTN increased arterial compliance (McVeigh et al. 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites McVeigh et al. 2001 source
  Not checked in the free run.
Interpretationreasoning
The dichotomy between nitrate and citrulline may be a consequence of differences in the mechanism of action for both.
“This dichotomy may be a consequence of differences in the mechanism of action for both nitrate and citrulline.”
Quote in the paperNot a substantial claim
Premisecitation
Previous experiments demonstrate that the effect of nitrate on arterial elasticity is dependent upon nitric oxide or potential metabolites, as NOS inhibitors blunted arterial elasticity that was restored by arginine infusion.
“Previous experiments demonstrate that this effect is dependent upon nitric oxide or potential metabolites as arterial infusion of nitric oxide synthase inhibitors blunted arterial elasticity that was restored by arginine infusion (McVeigh et al. 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites McVeigh et al. 2001 source
  Not checked in the free run.
Premisecitation
The position of the dicrotic notch in the peripheral blood flow signal, estimated as PAR, reflected the general vascular tone in young adults.
“The position of the dicrotic notch in the peripheral blood flow signal, estimated as PAR, reflected the general vascular tone in young adults (Klemsdal et al. 1996).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Klemsdal et al. 1996 source
  Not checked in the free run.
Premisecitation
Similar observations following arginine supplementation in heart failure patients implicate the production of exogenous NO in the reduction of systemic vascular resistance.
“Similar observations have been made following arginine supplementation in HF patients implicating the production of exogenous NO in the reduction of systemic vascular resistance (Bocchi et al. 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Bocchi et al. 2000 source
  Not checked in the free run.
Premisecitation
Previous experiments indicate that citrulline supplementation at similar doses to those used in our experiment decreased arterial stiffness in middle-age men.
“Previous experiments indicate that citrulline supplementation at similar doses to those used for our experiment decreased arterial stiffness in middle-age men (Ochiai et al. 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Ochiai et al. 2012 source
  Not checked in the free run.
Premisecitation
Impaired arginine transport has been noted in heart failure.
“impaired arginine transport has also been noted in HF (Kaye et al. 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kaye et al. 2000 source
  Not checked in the free run.
Interpretationcitation
The decrease in PAR at rest suggests that a decrease in peripheral vascular tone was caused by nitrate or subsequent metabolites.
“suggesting that a decrease in peripheral vascular tone (Bahra et al. 2012) was caused by nitrate or subsequent metabolites (Lund 1986).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Bahra et al. 2012 source
  Not checked in the free run.
- cites Lund 1986 source
  Not checked in the free run.
Interpretationreasoning
The failure of PAR to return to pre-exercise levels suggests that generation of nitric oxide from nitrate was not restored to pre-test levels.
“suggesting that generation of nitric oxide from nitrate was not restored to pre-test levels.”
Quote in the paperNot a substantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
Interpretationreasoning
The reduction in resistance with preserved cardiac performance, estimated as RPP, implies that flow and hence conductance have increased.
“The reduction in resistance with preserved cardiac performance, estimated as RPP, implies that flow and hence conductance have increased.”
Quote in the paperSubstantial claim
Premisecitation
Citrulline has the potential to cause vasodilatation, secondary to an increase in plasma arginine, the substrate for nitric oxide synthase (NOS).
“Given that citrulline also has the potential to cause vasodilatation, secondary to an increase in plasma arginine (Moinard et al. 2008)—the substrate for nitric oxide synthase (NOS)”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Moinard et al. 2008
  Not checked in the free run.
Interpretationreasoning
Nitrate and citrulline may be safe adjuvants to cardiac therapies for patients with heart failure.
“suggesting that they may be safe adjuvants to cardiac therapies for patients with heart failure.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
Interpretationreasoning
Such changes may be responsible for the modest tachycardia noted for subjects consuming citrulline.
“Such changes may be responsible for the modest tachycardia we noted for subjects consuming citrulline.”
Quote in the paperNot a substantial claim
Interpretationreasoning
The mechanism of citrulline may be less sensitive to prevailing effects of oxygen tension, superoxide production and pH than non-enzymic reduction of nitrate.
“This may be less sensitive to prevailing effects of oxygen tension, superoxide production and pH than non-enzymic reduction of nitrate.”
Quote in the paperNot a substantial claim
Interpretationcitation
The changes we note are not likely to reflect difference in oestrogen status for female subjects.
“Together these imply that the changes we note are not likely to reflect difference in oestrogen status for female subjects.”
Quote in the paperNot a substantial claim
Premisecitation
Citrulline supplementation does not increase the plasma concentration of nitrate/nitrite.
“without increasing the plasma concentration of nitrate/nitrite (Hickner et al. 2006: Bailey et al. 2015).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Hickner et al. 2006 source
  Not checked in the free run.
- cites Bailey et al. 2015 source
  Not checked in the free run.

Classified as probably not a substantial claim. 44
May combine two claims. 34
The quote only partly states this claim. 1

Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
In young adults, citrulline supplementation had no significant effect on haemoglobin oxygen saturation.
“Haemoglobin % oxygen saturation, measured by pulse oximetry, was unaffected by citrulline but was decreased 2 % by nitrate supplementation (p < 0.001; Table 2).”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
In young adults, pulse interval measured at the hallux was significantly greater than pulse interval measured at the thumb (p < 0.001).
“Pulse interval measured at the hallux was significantly greater than pulse interval measured at the thumb (p < 0.001; Fig. 3a, b).”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
In young adults, nitrate supplementation decreased pulse interval measured at the thumb by 15 % at rest, but this was not statistically significant.
“both nitrate and citrulline decreased pulse interval measured at the thumb 15 %, for nitrate treatment this did not reach statistical significance (NS; Fig. 3a), whereas for citrulline this was significantly different from untreated subjects (p < 0.05; Fig. 3a).”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data
In young adults, nitrate supplementation led to an 11 % decrease in heart rate during breath-hold, which was not statistically significant.
“Nitrate supplementation led to an 11 % decrease in HR during breath-hold (NS; Fig. 2a) accompanied by a corresponding increase in R–R interval (NS; Fig. 2b).”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
In young adults, nitrate supplementation had no significant effect on pulse amplitude ratio during isometric grip exercise.
“However, during ISGE this trend was lost (NS; Fig. 4a) and at completion of the exercise PAR showed a modest decrease to pre-exercise levels (NS; Fig. 4a).”
Quote in the paperNot a substantial claim
The quote only partly states this claim.
Findingown data
In young adults, acute oral nitrate supplementation (8 mg/kg) decreased diastolic blood pressure.
“Diastolic blood pressure (DP) was reduced 6 % (p < 0.05; Table 2) by nitrate”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
In untreated young adults, isometric grip exercise increased heart rate by 11 % (p < 0.05).
“For untreated subjects, breath-hold increased HR 7 % (NS; Fig. 2a) whilst isometric grip exercise increased HR 11 % (p < 0.05; Fig. 2a).”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data
In untreated young adults, breath-hold increased heart rate by 7 %, which was not statistically significant.
“For untreated subjects, breath-hold increased HR 7 % (NS; Fig. 2a) whilst isometric grip exercise increased HR 11 % (p < 0.05; Fig. 2a).”
Quote in the paperNot a substantial claim
May combine two claims.
Findingreasoning
Neither nitrate nor citrulline altered rate-pressure product (RPP).
“neither nitrate nor citrulline altered RPP”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
Citrulline modestly decreased maximum voluntary contraction for isometric handgrip exercise (ISGE).
“Surprisingly, citrulline modestly decreased maximum voluntary contraction for ISGE.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingreasoning
Citrulline supplementation had only modest effects on cardiac electrical activity, including a small decrease in QRS interval duration for subjects at rest.
“Citrulline supplementation had only modest effects on cardiac electrical activity, including a small decrease in QRS interval duration for subjects at rest.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingnone given
Citrulline, whilst decreasing vascular tone before isometric exercise, restored reduced vascular tone directly after exercise.
“By contrast, citrulline, whilst decreasing vascular tone before isometric exercise, went on to restore reduced vascular tone directly after exercise.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingnone given
The effect of nitrate on PAR was lost on the initiation of hand-grip exercise, raising PAR to levels noted for untreated subjects.
“this effect was lost on the initiation of hand-grip exercise raising the PAR to levels noted for untreated subjects.”
Quote in the paperNot a substantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
May combine two claims.
Findingown data
Both nitrate and citrulline increase vascular conductance.
“and increase vascular conductance”
Quote in the paperSubstantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
May combine two claims.
Findingown data
Both nitrate and citrulline decrease systemic blood pressure.
“We demonstrate that both nitrate and citrulline decrease systemic blood pressure”
Quote in the paperSubstantial claim
- The authors state this as an assumption: All subjects maintained an equivalent nitrate intake throughout the experiment.
May combine two claims.
Findingown data
The modest stimulus presented by isometric exercise confirmed the effect of citrulline on sympathetic tone and was corroborated by the lower augmentation in HR noted during exercise for citrulline-treated subjects.
“The modest stimulus presented by isometric exercise confirmed the effect of citrulline on sympathetic tone and was corroborated by the lower augmentation in HR noted during exercise for citrulline-treated subjects.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Dietary nitrate improved endothelial function and decreased vascular stiffness in older adults.
“dietary nitrate improved endothelial function and decreased vascular stiffness in older adults (Rammos et al. 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Rammos et al. 2014 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Previous experiments demonstrated that both nitrate and citrulline supplementation induced acute vasodilatation in rodents.
“Previous experiments demonstrated that both nitrate and citrulline supplementation induced acute vasodilatation in rodents (Chien et al. 2014)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Chien et al. 2014 source
  Not checked in the free run.
May combine two claims.
Premisecitation
Organic nitrates release nitric oxide in the systemic circulation, reducing left ventricular filling pressure and increasing cardiac index through decreasing preload and afterload.
“the organic nitrates (e.g. glycerol trinitrate-GTN) releasing nitric oxide in the systemic circulation, reducing left ventricular filling pressure and increasing cardiac index suggesting improvement in cardiac performance (Franciosa et al. 1978) through decreasing both preload and afterload (Kelly et al. 1990).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Franciosa et al. 1978 source
  Not checked in the free run.
- cites Kelly et al. 1990 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation
The decrease in haemoglobin oxygen saturation following nitrate consumption is a consequence of methaemoglobin formation.
“We note a decrease in haemoglobin oxygen saturation (SaO2) following nitrate consumption which we propose is a consequence of methaemoglobin (mtHb) formation (Pluta et al. 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Pluta et al. 2011 source
  Not checked in the free run.
Classified as probably not a substantial claim.
Interpretationreasoning
Citrulline may potentially increase peripheral oxygen delivery in patients with heart failure.
“assuming duplication of these effects in patients with HF we speculate that citrulline may potentially increase peripheral oxygen delivery.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: The cardiovascular effects of nitrate and citrulline observed in young healthy adults would be duplicated in patients with heart failure.
May combine two claims.
Interpretationown data
Both nitrate and citrulline supplementation decreased vascular tone at rest.
“Both nitrate and citrulline supplementation decreased vascular tone at rest but citrulline also altered sympathovagal balance to increase sympathetic tone.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning
Both oral nitrate and citrulline may be suitable adjuvants for patients with heart failure to improve peripheral tissue oxygenation.
“We suggest that both oral nitrate and citrulline may be suitable adjuvants for patients with heart failure to improve peripheral tissue oxygenation.”
Quote in the paperNot a substantial claim
- The authors state this as an assumption: The cardiovascular effects of nitrate and citrulline observed in young healthy adults would be duplicated in patients with heart failure.
May combine two claims.
Interpretationreasoning
Preservation of pulse pressure despite decreases in diastolic pressure suggests that cardiac contractile performance and stroke volume are maintained and that the decrease in mean arterial pressure is a consequence of decreased peripheral resistance.
“Preservation of the pulse pressure despite decreases in diastolic pressure suggests that cardiac contractile performance, and hence stroke volume, is maintained and the decrease in MAP is a consequence of decreased peripheral resistance.”
Quote in the paperSubstantial claim
May combine two claims.
Premisecitation
Citrulline increases both plasma arginine and cGMP and is free of side effects.
“increases both plasma arginine and cGMP (Schwedhelm et al. 2007) and is free of side effects.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Schwedhelm et al. 2007 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
In healthy normotensive subjects, inorganic nitrate increased vascular compliance without altering flow-mediated dilatation.
“In healthy normotensive subjects, inorganic nitrate increased vascular compliance without altering flow-mediated dilatation (Bahra et al. 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Bahra et al. 2012 source
  Not checked in the free run.
May combine two claims.
Premisecitation
In patients with heart failure and preserved ejection fraction, nitrate supplementation increased exercise duration, total work, peak oxygen extraction and cardiac output.
“for patients with HF and preserved ejection fraction, nitrate supplementation increased exercise duration, total work and increased both peak oxygen extraction and cardiac output (Zamani et al. 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Zamani et al. 2015 source
  Not checked in the free run.
May combine two claims.
Premisecitation
Acute nitrate-releasing agents decrease heart rate, systolic and diastolic blood pressures, and increase left ventricular ejection fraction.
“Acute exploitation of nitrate-releasing agents decreases heart rate, both systolic and diastolic blood pressures and, as a consequence, increases the left ventricular ejection fraction (Battock et al. 1976).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Battock et al. 1976 source
  Not checked in the free run.
May combine two claims.
Interpretationcitation
Apparent blood flow velocity measured at the hand and foot increased despite decreased blood pressure, implying increased peripheral vascular conductance and suggesting improved tissue oxygenation.
“In addition, apparent blood flow velocity, measured at the hand and foot, was also increased. This occurred despite a decrease in blood pressure, implying an increase in peripheral vascular conductance (Levitt et al. 2015) and suggesting improved tissue oxygenation.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Levitt et al. 2015 source
  Not checked in the free run.
- Rests on an assumption: Pulse interval measured by infra-red plethysmography reflects blood flow velocity.
May combine two claims.
Interpretationcitation
Acute nitrate or chronic citrulline supplementation decreased mean arterial pressure and diastolic pressure, implying a decrease in total peripheral resistance.
“we confirm that either acute nitrate supplementation or chronic citrulline supplementation decreased mean arterial pressure and diastolic pressure, implying a decrease in total peripheral resistance (Cowley et al. 1973).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Cowley et al. 1973 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning
The absence of methaemoglobin with beetroot juice may relate to the use of KNO3 salt in cordial removing matrix effects of food products and increasing rates of uptake.
“In contrast, studies exploiting beetroot juice, rich in nitrate, note no metHb (Kapil et al. 2015) and we postulate that this may relate to the use of KNO3 salt in cordial removing any potential matrix effects of food products and increasing rates of uptake.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kapil et al. 2015 source
  Not checked in the free run.
May combine two claims.
Premisecitation
Citrulline reduced both blood pressure and cardiac augmentation index in obese pre- and hypertensive subjects.
“citrulline has shown promise as an intervention for hypertension, reducing both blood pressure and cardiac augmentation index in obese pre- and hypertensive subjects (Figueroa et al. 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Figueroa et al. 2012 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Earlier studies showed a decrease in QTc interval following acute consumption of citrulline.
“earlier studies showing a decrease in QTc interval (Kameda et al. 2011) following acute consumption of citrulline.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kameda et al. 2011 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning
The origins of the increase in flow velocity may be different for nitrate and citrulline.
“The origins of this increase in velocity may be different for both nitrate and citrulline.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given
Subjects were fasted overnight, well rested, had abstained from caffeine for 12 h and had not undertaken vigorous exercise within the previous 24 h.
“all subjects were fasted overnight, well rested, had abstained from caffeine during the previous 12 h and had not undertaken vigorous exercise within the previous 24 h period.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation
The decrease in maximum voluntary contraction for ISGE may result from excess nitric oxide disrupting mitochondrial oxidative capacity.
“may result from the potential for excess nitric oxide to disrupt mitochondrial oxidative capacity (Bolanos et al. 1996; Clementi et al. 1998)”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Bolanos et al. 1996 source
  Not checked in the free run.
- cites Clementi et al. 1998 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning
The decrease in maximum voluntary contraction for ISGE may be a direct consequence of changes to blood pressure.
“but may also be a direct consequence of changes to blood pressure.”
Quote in the paperNot a substantial claim
Classified as probably not a substantial claim.
Study design and conductown data
Statistical analysis used Student's t test and ANOVA with Bonferroni post hoc test to account for multiple comparisons.
“statistical analysis was carried out using students ‘t’ test to examine the effects of nitrate or citrulline; analysis of variance (ANOVA) was used to quantify the effect of treatments with Bonferroni post hoc test to account for multiple comparisons.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim. May combine two claims.
Study design and conductnone given
Young adult subjects were non-smokers and were excluded for existing cardiac and kidney disease, diabetes, hypertension and Raynaud's disease.
“Young adults who were non-smokers were recruited to the experiments; criteria for exclusion included existing cardiac and kidney disease, diabetes, hypertension and Raynaud’s disease.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Oxidative muscle performance is, in part, governed by blood pressure.
“oxidative muscle performance is, in part, governed by blood pressure (Hobbs and McCloskey 1987)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Hobbs and McCloskey 1987 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
All 12 enrolled subjects completed both the nitrate and citrulline arms of the experiments.
“12 subjects (mean age 22.8 ± 2.0 years; Table 1) enrolled for the experiment and all subjects completed both the nitrate and citrulline arms of the experiments.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Peak muscle blood flow is achieved at 30% MVC-ISGE.
“peak muscle blood flow is achieved at 30 % MVC-ISGE (Barnes 1980)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Barnes 1980 source
  Not checked in the free run.
May combine two claims.
Interpretationreasoning
Both nitrate and citrulline have the potential to decrease blood pressure through direct release of NO or the mobilisation of substrate for NOS.
“Together these observations imply that both nitrate and citrulline have the potential to decrease BP through direct release of NO or the mobilisation of substrate for NOS.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given
All experiments were approved by the University of Leeds ethics committee and complied with the Declaration of Helsinki.
“All experiments were approved by the Maths and Physical Sciences and Engineering joint Faculty Research Ethics Committee (MEEC), University of Leeds (Review Number: MEEC 14-028) and all studies complied with the Declaration of Helsinki.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning
The modest tachycardia caused by citrulline may also contribute to increasing flow velocity.
“By contrast, the modest tachycardia caused by consumption of citrulline may also contribute to increasing flow velocity.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning
This supports the observations of potential increases in flow velocity as a consequence of decreased flow resistance.
“This would, in part, support the observations of potential increases in flow velocity as a consequence of decreased flow resistance.”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
Both nitrate and citrulline may improve the efficiency of oxygen consumption during cycling exercise and may increase the time to exhaustion at fixed exercise loads.
“both nitrate (Bailey et al. 2009) and citrulline (Bailey et al. 2015) may improve the efficiency of oxygen consumption during cycling exercise and, in consequence, may increase the time to exhaustion at fixed exercise loads.”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Bailey et al. 2009 source
  Not checked in the free run.
- cites Bailey et al. 2015 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Previous experiments in an elderly male population suggest that citrulline had no effect on blood flow in skeletal muscle.
“Previous experiments in an elderly male population suggest that citrulline had no effect on blood flow in skeletal muscle (Churchward-Venne et al. 2014)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Churchward-Venne et al. 2014
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Superoxide radicals produced as a consequence of intense exercise may directly remove NO.
“superoxide radicals produced as a consequence of intense exercise may directly remove NO (Li and Forstermann 2000; Silvestro et al. 2002).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Li and Forstermann 2000
  Not checked in the free run.
- cites Silvestro et al. 2002 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
The half-time for NO is dependent upon pH, tissue oxygenation and the availability of nitrate.
“the half-time for NO is dependent upon pH, tissue oxygenation and the availability of nitrate (Kelm 1999)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kelm 1999 source
  Not checked in the free run.
May combine two claims.
Interpretationreasoning
Nitrate, converted to nitric oxide, may increase the dilatation of vessels, decreasing peripheral resistance.
“Nitrate, converted to nitric oxide, may increase the dilatation of vessels, decreasing the peripheral resistance.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation
A greater effect may be provided by decreased resistance.
“implying that a greater effect may be provided by decreased resistance (Sanchez-Gonzalez et al. 2012; Figueroa et al. 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Sanchez-Gonzalez et al. 2012
  Not checked in the free run.
- cites Figueroa et al. 2010 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationcitation
The improved efficiency of oxygen consumption may reflect a decrease in fractional oxygen extraction as a consequence of increased conductance, or increases in the efficiency of oxidative phosphorylation.
“may reflect a decrease in fractional oxygen extraction as a consequence of increased conductance, or increases in the efficiency of oxidative phosphorylation (Bailey et al. 2009, 2015).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Bailey et al. 2009 source
  Not checked in the free run.
- cites Bailey et al. 2015 source
  Not checked in the free run.
May combine two claims.
Premisecitation
Citrulline is an allosteric inhibitor of arginase enzyme, preventing the endothelial enzymic breakdown of arginine, the substrate for NOS, and raising the local arginine concentration.
“citrulline is an allosteric inhibitor of arginase enzyme, hence preventing the endothelial enzymic breakdown of arginine, the substrate for NOS, and raising the local arginine concentration (Berkowitz et al. 2006; Bailey et al. 2015)”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Berkowitz et al. 2006 source
  Not checked in the free run.
- cites Bailey et al. 2015 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Previous experiments suggest that different stages of the menstrual cycle had no effect on cardiac QT interval or autonomic tone.
“previous experiments suggest that different stages of the menstrual cycle had no effect on cardiac QT interval or autonomic tone (Burke et al. 1997)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Burke et al. 1997 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
No estimates of dietary nitrate intake were made for the subjects.
“No estimates of dietary nitrate intake were made for the subjects.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Gender differences in cardiac electrical activity are not a consequence of oestrogen.
“indicate that gender differences in cardiac electrical activity are not a consequence of oestrogen (Burke et al. 1997).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Burke et al. 1997 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation
This suggests little effect on plasma arginine levels during our sampling window.
“suggesting little effect on plasma arginine levels during our sampling window.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Previous experiments estimate that the plasma half-life for citrulline may be 0.9 h compared with 5-8 h for dietary nitrate.
“Previous experiments estimate that the pharmacokinetics of citrulline indicate that the plasma half-life for citrulline may be 0.9 h (Moinard et al. 2008) compared with 5–8 h for dietary nitrate (Tannenbaum 1979)”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Moinard et al. 2008
  Not checked in the free run.
- cites Tannenbaum 1979 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Similar observations were noted for previous experiments exploiting the same dose of citrulline measured after only 60 min, but no direct measure of HR was made during these experiments.
“Similar observations were noted for previous experiments exploiting the same dose of citrulline measured after only 60 min, but no direct measure of HR was made during these experiments (Kameda et al. 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Kameda et al. 2011 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Supplementation of older adults with citrulline elevated plasma arginine concentrations for up to 6 h.
“supplementation of older adults with citrulline elevated plasma arginine concentrations for up to 6 h (Moinard et al. 2015; Schwedhelm et al. 2007)”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Moinard et al. 2015
  Not checked in the free run.
- cites Schwedhelm et al. 2007 source
  Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Interpretationreasoning
Both nitrate and citrulline have the potential to increase peripheral tissue oxygenation.
“with the potential to increase peripheral tissue oxygenation.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation
The time delay between citrulline consumption and repeat experimentation may be critical.
“suggesting that the time delay between citrulline consumption and repeat experimentation may be critical.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Minson et al. (2000) noted no effect of menstrual cycle stage on cardiovagal baroreflex sensitivity or vascular resistance.
“Minson et al. (2000) noted no effect of menstrual cycle stage on cardiovagal baroreflex sensitivity or vascular resistance.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Minson et al. 2000 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given
Our experiment takes no account of gender differences or stage of the menstrual cycle for the female subjects.
“Our experiment takes no account of gender differences or stage of the menstrual cycle for the female subjects.”
Quote in the paperNot a substantial claim

65 of 65

The authors state this as an assumption.
The cardiovascular effects of nitrate and citrulline observed in young healthy adults would be duplicated in patients with heart failure.
“assuming duplication of these effects in patients with HF we speculate that citrulline may potentially increase peripheral oxygen delivery.”
The paper relies on this without support.
Pulse interval measured by infra-red plethysmography reflects blood flow velocity.
“In addition, apparent blood flow velocity, measured at the hand and foot, was also increased.”
The authors state this as an assumption.
All subjects maintained an equivalent nitrate intake throughout the experiment.
“We have assumed that all subjects maintained an equivalent nitrate intake throughout the experiment.”

3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Other studies observed positive effects of l-citrulline including reduced blood pressure.
“Other studies have observed positive effects of l-citrulline including reduced blood pressure (20, 285, 286).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [20]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Conclusion denies a reported change in cardiac electrical activity
Major
The conclusion says cardiac electrical activity was not altered, but the results report a statistically significant decrease in QRS interval after citrulline.
Conflicting descriptions of post-exercise PAR after nitrate
Minor
The results say PAR decreased to its pre-exercise level after exercise, while the discussion says it failed to return to that level.

2 of 2

Persistent inhibition of cell respiration by nitric oxide: Crucial role of S -nitrosylation of mitochondrial complex I and protective action of glutathione
Clementi, E., Brown, G. C., Feelisch, M., & Moncada, S. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7631 · Cited by 863 · see citing works
Dietary nitrate supplementation reduces the O 2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans
Bailey, S. J., Winyard, P., Vanhatalo, A., Blackwell, J. R., DiMenna, F. J., Wilkerson, D. P., Tarr, J., Benjamin, N., & Jones, A. M. (2009) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00722.2009 · Cited by 759 · see citing works
Nitric oxide metabolism and breakdown
Kelm, M. (1999) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(99)00020-1 · Cited by 673 · see citing works
Role of the Baroreceptor Reflex in Daily Control of Arterial Blood Pressure and Other Variables in Dogs
COWLEY, A. W., LIARD, J. F., & GUYTON, A. C. (1973) · Circulation Research · doi:10.1161/01.res.32.5.564 · Cited by 593 · see citing works
Effects of Dietary Nitrate on Blood Pressure in Healthy Volunteers
Larsen, F. J., Ekblom, B., Sahlin, K., Lundberg, J. O., & Weitzberg, E. (2006) · New England Journal of Medicine · doi:10.1056/nejmc062800 · Cited by 587 · see citing works
Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise
Vanhatalo, A., Bailey, S. J., Blackwell, J. R., DiMenna, F. J., Pavey, T. G., Wilkerson, D. P., Benjamin, N., Winyard, P. G., & Jones, A. M. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00206.2010 · Cited by 529 · see citing works
Influence of the Menstrual Cycle on Sympathetic Activity, Baroreflex Sensitivity, and Vascular Transduction in Young Women
Minson, C. T., Halliwill, J. R., Young, T. M., & Joyner, M. J. (2000) · Circulation · doi:10.1161/01.cir.101.8.862 · Cited by 515 · cited 1× · see citing works
“More recently, Minson et al. (2000) noted no effect of menstrual cycle stage on cardiovagal baroreflex sensitivity or vascular resistance.”
Background
Dietary Nitrate Provides Sustained Blood Pressure Lowering in Hypertensive Patients: A Randomized, Phase 2, Double-Blind, Placebo-Controlled Study
Kapil, V., Khambata, R. S., Robertson, A., Caulfield, M. J., & Ahluwalia, A. (2015) · Hypertension · doi:10.1161/hypertensionaha.114.04675 · Cited by 500 · see citing works
Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism
Schwedhelm, E., Maas, R., Freese, R., Jung, D., Lukacs, Z., Jambrecina, A., Spickler, W., Schulze, F., & Böger, R. H. (2008) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2007.02990.x · Cited by 494 · see citing works
Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels
Berkowitz, D. E., White, R., Li, D., Minhas, K. M., Cernetich, A., Kim, S., Burke, S., Shoukas, A. A., Nyhan, D., Champion, H. C., et al. (2003) · Circulation · doi:10.1161/01.cir.0000092948.04444.c7 · Cited by 486 · see citing works
Inorganic Nitrate and Beetroot Juice Supplementation Reduces Blood Pressure in Adults: A Systematic Review and Meta-Analysis
Siervo, M., Lara, J., Ogbonmwan, I., & Mathers, J. C. (2013) · The Journal of Nutrition · doi:10.3945/jn.112.170233 · Cited by 375 · see citing works
Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway
Lidder, S., & Webb, A. J. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04420.x · Cited by 360 · see citing works
Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise
Larsen, F. J., Weitzberg, E., Lundberg, J. O., & Ekblom, B. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.11.006 · Cited by 320 · see citing works
Nitroglycerin has more favourable effects on left ventricular afterload than apparent from measurement of pressure in a peripheral artery
KELLY, R. P., GIBS, H. H., O'ROURKE, M. F., DALEY, J. E., MANG, K., MORGEN, J. J., & AVOLID, A. P. (1990) · European Heart Journal · doi:10.1093/oxfordjournals.eurheartj.a059669 · Cited by 312 · see citing works
Effect of Inorganic Nitrate on Exercise Capacity in Heart Failure With Preserved Ejection Fraction
Zamani, P., Rawat, D., Shiva-Kumar, P., Geraci, S., Bhuva, R., Konda, P., Doulias, P.-T., Ischiropoulos, H., Townsend, R. R., Margulies, K. B., et al. (2015) · Circulation · doi:10.1161/circulationaha.114.012957 · Cited by 307 · see citing works
Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure.
Leier, C. V., Huss, P., Magorien, R. D., & Unverferth, D. V. (1983) · Circulation · doi:10.1161/01.cir.67.4.817 · Cited by 289 · see citing works
Arginine Nutrition and Cardiovascular Function
Wu, G., & Meininger, C. J. (2000) · Journal of Nutrition · doi:10.1093/jn/130.11.2626 · Cited by 288 · see citing works
Nitric oxide-mediated mitochondrial damage: A potential neuroprotective role for glutathione
Bolaños, J. P., Heales, S. J. R., Peuchen, S., Barker, J. E., Land, J. M., & Clark, J. B. (1996) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00240-7 · Cited by 263 · see citing works
Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study
Moinard, C., Nicolis, I., Neveux, N., Darquy, S., Bénazeth, S., & Cynober, L. (2007) · British Journal Of Nutrition · doi:10.1017/s0007114507841110 · Cited by 218 · see citing works
The relationship between maximum isometric strength and intramuscular circulatory occlusion
BARNES, W. S. (1980) · Ergonomics · doi:10.1080/00140138008924748 · Cited by 200 · see citing works
Gender-Specific Differences in the QT Interval and the Effect of Autonomic Tone and Menstrual Cycle in Healthy Adults
Burke, J. H., Ehlert, F. A., Kruse, J. T., Parker, M. A., Goldberger, J. J., & Kadish, A. H. (1997) · The American Journal of Cardiology · doi:10.1016/s0002-9149(96)00707-2 · Cited by 189 · see citing works
Age-related changes in peripheral pulse timing characteristics at the ears, fingers and toes
Allen, J., & Murray, A. (2002) · Journal of Human Hypertension · doi:10.1038/sj.jhh.1001478 · Cited by 179 · see citing works
Dietary Nitrate Reverses Vascular Dysfunction in Older Adults With Moderately Increased Cardiovascular Risk
Rammos, C., Hendgen-Cotta, U. B., Sobierajski, J., Bernard, A., Kelm, M., & Rassaf, T. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.08.691 · Cited by 165 · see citing works
Difference in nitroglycerin dose-response in the venous and arterial beds
Imhof, P. R., Ott, B., Frankhauser, P., Chu, L. C., & Hodler, J. (1980) · European Journal of Clinical Pharmacology · doi:10.1007/bf00874655 · Cited by 160 · see citing works
Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication
Silvestro, A., Scopacasa, F., Oliva, G., de Cristofaro, T., Iuliano, L., & Brevetti, G. (2002) · Atherosclerosis · doi:10.1016/s0021-9150(02)00235-6 · Cited by 159 · see citing works
Nitric oxide modulation of blood vessel tone identified by arterial waveform analysis
McVEIGH, G. E., ALLEN, P. B., MORGAN, D. R., HANRATTY, C. G., & SILKE, B. (2001) · Clinical Science · doi:10.1042/cs1000387 · Cited by 144 · see citing works
Oral supplementation with a combination of l-citrulline and l-arginine rapidly increases plasma l-arginine concentration and enhances NO bioavailability
Morita, M., Hayashi, T., Ochiai, M., Maeda, M., Yamaguchi, T., Ina, K., & Kuzuya, M. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.10.029 · Cited by 140 · see citing works
<scp>l</scp>-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans
Bailey, S. J., Blackwell, J. R., Lord, T., Vanhatalo, A., Winyard, P. G., & Jones, A. M. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00192.2014 · Cited by 136 · see citing works
Short-term effects of l-citrulline supplementation on arterial stiffness in middle-aged men
Ochiai, M., Hayashi, T., Morita, M., Ina, K., Maeda, M., Watanabe, F., & Morishita, K. (2012) · International Journal of Cardiology · doi:10.1016/j.ijcard.2010.10.004 · Cited by 127 · see citing works
Inorganic nitrate ingestion improves vascular compliance but does not alter flow-mediated dilatation in healthy volunteers
Bahra, M., Kapil, V., Pearl, V., Ghosh, S., & Ahluwalia, A. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.01.004 · Cited by 116 · see citing works
Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers
Pluta, R. M., Oldfield, E. H., Bakhtian, K. D., Fathi, A. R., Smith, R. K., DeVroom, H. L., Nahavandi, M., Woo, S., Figg, W. D., & Lonser, R. R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0014504 · Cited by 112 · see citing works
Nitrate effects on cardiac output and left ventricular outflow resistance in chronic congestive heart failure
Franciosa, J. A., Blank, R. C., & Cohn, J. N. (1978) · The American Journal of Medicine · doi:10.1016/0002-9343(78)90047-5 · Cited by 104 · see citing works
Parameters describing the pulse wave
Korpas, D., Hálek, J., & Doležal, L. (2009) · Physiological Research · doi:10.33549/physiolres.931468 · Cited by 97 · see citing works
Watermelon extract supplementation reduces ankle blood pressure and carotid augmentation index in obese adults with prehypertension or hypertension
Figueroa, A., Sanchez-Gonzalez, M. A., Wong, A., & Arjmandi, B. H. (2012) · American Journal of Hypertension · doi:10.1038/ajh.2012.20 · Cited by 96 · see citing works
Oral L-Citrulline Supplementation Attenuates Blood Pressure Response to Cold Pressor Test in Young Men
Figueroa, A., Trivino, J. A., Sanchez-Gonzalez, M. A., & Vicil, F. (2010) · American Journal of Hypertension · doi:10.1038/ajh.2009.195 · Cited by 79 · see citing works
L-Citrulline Reduces Time to Exhaustion and Insulin Response to a Graded Exercise Test
HICKNER, R. C., TANNER, C. J., EVANS, C. A., CLARK, P. D., HADDOCK, A., FORTUNE, C., GEDDIS, H., WAUGH, W., & MCCAMMON, M. (2006) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000210197.02576.da · Cited by 77 · see citing works
Measurement of Stiffness Index by Digital Volume Pulse Analysis Technique: Clinical Utility in Cardiovascular Disease Risk Stratification
Gunarathne, A., Patel, J. V., Hughes, E., & Lip, G. Y. H. (2008) · American Journal of Hypertension · doi:10.1038/ajh.2008.207 · Cited by 69 · see citing works
In Vivo and In Vitro Evidence for Impaired Arginine Transport in Human Heart Failure
Kaye, D. M., Ahlers, B. A., Autelitano, D. J., & Chin-Dusting, J. P. F. (2000) · Circulation · doi:10.1161/01.cir.102.22.2707 · Cited by 68 · see citing works
Two different approaches to restore renal nitric oxide and prevent hypertension in young spontaneously hypertensive rats: l-citrulline and nitrate
Chien, S.-J., Lin, K.-M., Kuo, H.-C., Huang, C.-F., Lin, Y.-J., Huang, L.-T., & Tain, Y.-L. (2014) · Translational Research · doi:10.1016/j.trsl.2013.09.008 · Cited by 61 · see citing works
Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise
Churchward-Venne, T. A., Cotie, L. M., MacDonald, M. J., Mitchell, C. J., Prior, T., Baker, S. K., & Phillips, S. M. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00096.2014 · Cited by 58 · see citing works
Arginine behaviour after arginine or citrulline administration in older subjects
Moinard, C., Maccario, J., Walrand, S., Lasserre, V., Marc, J., Boirie‌, Y., & Cynober, L. (2015) · British Journal Of Nutrition · doi:10.1017/s0007114515004638 · Cited by 55 · see citing works
Acute Dietary Nitrate Supplementation and Exercise Performance in COPD: A Double-Blind, Placebo-Controlled, Randomised Controlled Pilot Study
Curtis, K., O’Brien, K. A., Tanner, R., Polkey, J., Minnion, M., Feelisch, M., Polkey, M. I., Edwards, L. M., & Hopkinson, N. S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0144504 · Cited by 55 · see citing works
Effects of blood pressure on force production in cat and human muscle
Hobbs, S. F., & McCloskey, D. I. (1987) · Journal of Applied Physiology · doi:10.1152/jappl.1987.63.2.834 · Cited by 47 · see citing works
L‐Arginine reduces heart rate and improves hemodynamics in severe congestive heart failure
Bocchi, E. A., De Moraes, A. V., Esteves‐Filho, A., Bacal, F., Auler, J. O., Carmona, M. J., Bellotti, G., & Ramires, A. F. (2000) · Clinical Cardiology · doi:10.1002/clc.4960230314 · Cited by 45 · see citing works
The Effects of Short Term L-Citrulline Supplementation on Wave Reflection Responses to Cold Exposure With Concurrent Isometric Exercise
Sanchez‐Gonzalez, M. A., Koutnik, A. P., Ramirez, K., Wong, A., & Figueroa, A. (2012) · American Journal of Hypertension · doi:10.1093/ajh/hps052 · Cited by 36 · see citing works
Digital pulse plethysmography (DPG) in studies of the hemodynamic response to nitrates — A survey of recording methods and principles of analysis
Lund, F. (1986) · Acta Pharmacologica et Toxicologica · doi:10.1111/j.1600-0773.1986.tb02551.x · Cited by 34 · see citing works
Effects of isosorbide dinitrate and nitroglycerin on central circulatory dynamics in coronary artery disease
Battock, D. J., Levitt, P. W., & Steele, P. P. (1976) · American Heart Journal · doi:10.1016/s0002-8703(76)80044-0 · Cited by 33 · see citing works
Augmented reflex cutaneous vasodilatation following short‐term dietary nitrate supplementation in humans
Levitt, E. L., Keen, J. T., & Wong, B. J. (2015) · Experimental Physiology · doi:10.1113/ep085061 · Cited by 27 · see citing works
Changes to both cardiac metabolism and performance accompany acute reductions in functional capillary supply
Hauton, D., Winter, J., Al-Shammari, A. A., Gaffney, E. A., Evans, R. D., & Egginton, S. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.12.014 · Cited by 16 · see citing works
Self-citation
The Effect of L-citrulline Ingestion on ECG QT Interval and Autonomic Nervous System Activity
Kameda, N., Okigawa, T., Kimura, T., Fujibayashi, M., Asada, T., Kinoshita, R., Baba, S., Morita, M., Morishita, K., & Moritani, T. (2011) · Journal of PHYSIOLOGICAL ANTHROPOLOGY · doi:10.2114/jpa2.30.41 · Cited by 14 · see citing works
Effects of carvedilol and atenolol on arterial pulse curves (plethysmography) and finger temperature after hand cooling
Klemsdal, T. O., Mundal, H. H., & Gjesdal, K. (1996) · European Journal of Clinical Pharmacology · doi:10.1007/s002280050145 · Cited by 10 · see citing works
Pathophysiology of ischaemia-reperfusion injury
Carden, D. L., & Granger, D. N. (2000) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(200002)190:3 · Cited by 5 · see citing works

Flagged first, then by citations

Research works printed but not linked: 2

Li H, Főrstermann U (2000) Nitric oxide in the pathogenesis of vascular disease. J Pathol 190:620–650. doi: 10.1002/(SICI)1096-9896(200002)190 · DOI
Tannenbaum SR (1979) Nitrate and nitrite: origin in humans. Science 205:1334–1337 · DOI · Paper page

Sorted by citations

Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Influence of L-citrulline and watermelon supplementation on vascular function and exercise performance
Figueroa, A., Wong, A., Jaime, S. J., & Gonzales, J. U. (2017) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000340 · Cited by 147 · see citing works

Authors: Alsop, P., & Hauton, D.
Affiliations: University of Leeds (GB)
Corresponding author: Hauton, David
ORCID: Alsop, Paige
Hauton, David
Venue: European Journal of Applied Physiology
Publisher: Springer Science and Business Media LLC
Published: 2016-06-22
Volume: 116
Issue: 9
Pages: 1651-1661
ISSN: 0020-9376 (ISSN-L)
1439-6319
1439-6327
DOI: 10.1007/s00421-016-3418-7
PMC: PMC4983290
OpenAlex: W2467530889
Semantic Scholar: 4eaca9988d472c5df21c748e1c146d8513bc8456
Cited by: 37
References: 52
Citations by year: 2026: 2 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 7 · 2016: 2
FWCI: 5.50
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (unspecified)
Locations: European Journal of Applied Physiology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders: University of Leeds
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Keywords: oral nitrates, citrulline, heart failure, blood pressure, vascular compliance, cardiac electrical activity, pulse transit time, sympathovagal balance, nitric oxide bioavailability, isometric exercise, peripheral blood flow, young adults
MeSH terms: Administration, Oral, Blood Flow Velocity, Blood Pressure, Cardiotonic Agents, Citrulline, Dose-Response Relationship, Drug, Feasibility Studies, Female, Heart Failure, Heart Rate, Humans, Male, Nitrates, Vascular Resistance, Vasodilation, Treatment Outcome, Dietary Supplements

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure

Abstract

AI snapshot

TL;DR

Key findings

Methods

Limitations

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Record

About these checks