What the Medical Studies are Saying about Nitric Oxide

The research into Nitric Oxide and its effects on the human body are extensive. Playing a role in so many aspects of human health, here are a few scientific studies on what Nitric Oxide does.

L-Citrulline increases nitric oxide and improves control in obese asthmatics

The airways of obese asthmatics have been shown to be NO deficient, and this contributes to airway dysfunction and reduced response to inhaled corticosteroids. In cultured airway epithelial cells, L-citrulline, has been shown to restoring NO and reducing oxidative stress. Short-term L-citrulline treatment improved asthma control and NO levels in obese asthmatics with low or normal NO.

Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction

 A total of 24 patients, mean age 56.5 ± 9.8 years, were entered and concluded the study without adverse events. The improvement in the erection hardness score from 3 (mild ED) to 4 (normal erectile function) occurred in 2 (8.3%) of the 24 men when taking placebo and 12 (50%) of the 24 men when taking L-citrulline (P < .01). The mean number of intercourses per month increased from 1.37 ± 0.93 at baseline to 1.53 ± 1.00 at the end of the placebo phase (P = .57) and 2.3 ± 1.37 at the end of the treatment phase (P < .01). All patients reporting an erection hardness score improvement from 3 to 4 reported being very satisfied. 

A combination of oral L-citrulline and L-arginine improved 10-min full-power cycling test performance in male collegiate soccer players: a randomized crossover trial

Results: Power output was significantly greater with Cit + Arg than in the placebo group (242 ± 24 vs. 231 ± 21 W; p < 0.05). Plasma concentrations of post-exercise NOx (p < 0.05), Cit (p < 0.01) and Arg (p < 0.01) were significantly higher in the Cit + Arg than in the placebo group, whereas exercise upregulated plasma NOx concentrations in both groups (p < 0.05). Cit + Arg also gave improved post-exercise subjective perception of "leg muscle soreness" and "ease of pedaling" (both p < 0.05).

Conclusion: Seven days of oral Citrulline (1.2 g/d) and Arginine (1.2 g/d) ingestion improved 10-min cycling performance and the perception of physical exertion in male collegiate soccer players. 

l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans

The purpose of this study was to compare the effects of l-citrulline (Cit) and l-arginine (Arg) supplementation on nitric oxide and exercise performance. In a randomized, placebo (Pla)-controlled, crossover study, 10 healthy adult men completed moderate- and severe-intensity cycling exercise on days 6 and 7 of a 7-day supplementation period.

In conclusion, short-term Citsupplementation can improve blood pressure, V̇o2 kinetics, and exercise performance in healthy adults.

The hypotensive effect of L-arginine is associated with increased expired nitric oxide in humans

Endothelial metabolism of L-arginine to L-citrulline and the potent vasodilator, nitric oxide (NO), is important in the regulation of vascular tone and resting BP. In a randomized, placebo-controlled, crossover trial, 10 healthy male subjects received a 30-min infusion of 0.5 g/kg L-arginine hydrochloride. Subjects underwent continuous monitoring of BP and heart rate (HR) as well as intermittent determination of mixed expired NO concentration and plasma L-arginine and L-citrulline levels. Infusion of L-arginine produced a significant fall in mean BP with a peak effect of -9.3 +/- 0.9% (p<0.005). There was a significant correlation between the hypotensive response to L-arginine and the increase in expired NO. 

Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men

In a double-blind, randomized, placebo-controlled parallel-group trial, 15 healthy male subjects (age: 58.3 ± 4.4 years) with brachial-ankle pulse wave velocity (index of arterial stiffness >1400 cm/sec) were given 5.6g/day of L-citrulline (n=8) or placebo (n=7) for 7 days.

Compared with the placebo group, arterial stiffness was significantly reduced in the L-citrulline group (p<0.01). The serum nitrogen oxide and NO metabolic products were significantly increased only in the L-citrulline group (p<0.05). Moreover, there was a correlation between the increase of plasma arginine and the reduction of arterial stiffness. (r=-0.553, p<0.05).

These findings suggest that short-term L-citrulline supplementation may functionally improve arterial stiffness, independent of blood pressure, in humans. 

Inter-Individual Responses to Citrulline Malate Oral Supplementation on Post-Exercise Hypotension in Hypertensives: A 24-Hour Analysis

Forty hypertensives were randomly assigned to one of the four experimental groups (control-placebo, control-citrulline, exercise-placebo, and exercise-citrulline). They ingested placebo or citrulline malate [CM] (6 grams). During the exercise session, individuals performed 40 minutes of walking/running on a treadmill at 60-70% of HR reserve. For the control session, the individuals remained seated at rest for 40 minutes. Office blood pressure (BP) was taken every 10 minutes until completing 60 minutes after the experimental session. The ambulatory BP device was programmed to take the readings every 20 minutes (awake time) and every 30 minutes (sleep time) over the course of 24 hours of monitoring. Statistical significance was defined as p < 0.05.

Conclusion: CM supplementation can increase the post-exercise hypotensive effects in hypertensives. In addition, the prevalence of non-responders is lower when associated with aerobic exercise and CM supplementation. 

Branched-chain amino acids, arginine, citrulline alleviate central fatigue after 3 simulated matches in taekwondo athletes: a randomized controlled trial

Methods: In a double-blind randomized cross-over design, 12 male taekwondo athletes performed two trials containing three simulated matches each. Each match contained three 2-min rounds of high-intensity intermittent exercise. At the end of the second match, two different supplementations were consumed.

Conclusions: This study suggested that the combined supplementation could alleviate the exercise-induced central fatigue in elite athletes. 

Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline

Oral citrulline supplementation safely increased plasma citrulline and arginine concentrations compared with placebo after cardiopulmonary bypass. Postoperative pulmonary hypertension did not occur in children with naturally elevated citrulline levels or elevations through supplementation. Oral citrulline supplementation may be effective in reducing postoperative pulmonary hypertension.

Oral arginine reduces systemic blood pressure in type 2 diabetes: its potential role in nitric oxide generation

Results: Oral arginine increased plasma citrulline which may reflect an increased conversion of arginine into NO and citrulline. Arginine reduced systolic blood pressure from 135 +/- 7 to 123 +/- 8 mmHg; p < 0.05. Diastolic BP fell from 86.9 +/- 1.7 to 80.7 +/- 2.4 mmHg; p < 0.05). The reduction in BP was noted to occur two hours after starting oral arginine, and BP returned to normal within one hour of stopping the arginine.

These data suggest that oral arginine may increase endothelial nitric oxide synthase (NOS) to increase vascular NO and temporally reduce blood pressure in mildly hypertensive type 2 diabetic patients.

Development and therapeutic applications of nitric oxide releasing materials to treat erectile dysfunction

The role of nitric oxide (NO) in erectile physiology is well documented. NO activates relaxation of corporal cavernosal smooth muscle tissue resulting in increased blood flow into the penis resulting in an erection. At present, pharmacologic treatments for erectile dysfunction, such as the phosphodiesterase-5 inhibitors, potentiate the erectile response generated by NO. However, a new class of treatments at a preclinical stage may allow localized delivery of NO to the penis via cutaneous application. These treatments may be of particular value to patients with a neurogenic component to their erectile dysfunction, and may act synergistically with phosphodiesterase-5 inhibitors to increase their efficacy.

Acute effects of an oral nitric oxide supplement on blood pressure, endothelial function, and vascular compliance in hypertensive patients

Thirty patients with clinical hypertension were recruited and enrolled in a blinded placebo-controlled clinical trial in an outpatient setting. NO supplementation resulted in a significant decrease of 4 mm Hg in resting systolic BP (P<.003) and a significant decrease of 5 mm Hg in diastolic BP (P<.002) from baseline and placebo after 20 minutes. In addition, there was a further statistically significant reduction by 6 mm Hg in both systolic and diastolic pressure after 60 minutes (P<.0001 vs baseline). A single administration of an oral active NO supplement appears to acutely lower BP, improve vascular compliance, and restore endothelial function in patients with hypertension.

Therapeutic Use of Citrulline in Cardiovascular Disease

Supplemental administration of L-citrulline, which is converted to L-arginine in the kidney, vascular endothelium and other cells, is an effective means of elevating plasma and tissue levels of L-arginine. When given orally, supplemental L-citrulline is more effective than L-arginine in raising circulating L-arginine levels because it bypasses metabolism in the gastrointestinal tract and liver. Also, it is not a substrate for arginase and does not induce arginase expression or activity. Therefore, use of L-citrulline supplements is a promising treatment of cardiovascular disease involving L-arginine deficiencies, reduced NO availability and vascular dysfunction. L-citrulline is a natural and apparently safe means of providing L-arginine for constitutive NOS production of NO.