Bigger Muscles With Improved Blood Flow

By Steve Myers – Natural Products Insider

Blood Flow is one important component for building bigger muscles and healing the body, this article explores the various supplements that have been used for building bigger muscles with improved blood flow with references at the end.

Active muscles have higher energy needs, which are sustained by increased blood delivery of nutrients and oxygen. During exercise, circulating blood also helps remove metabolites and byproducts that can contribute to muscle fatigue. To meet changing demands, the body naturally adjusts breathing, heart rate, blood flow and blood pressure during exercise. However, many athletes and active consumers are looking for supplemental ways to enhance blood flow for greater benefits, including muscle performance and development.

Blood flow to match metabolic demands

The muscles need oxygen and glucose to fuel energy production, via cellular respiration, for sustained exercise. Oxygen is delivered via hemoglobin in red blood cells, and unused oxygen can be stored as myoglobin. Glucose is also transported in the blood and can be stored in the muscles, as glycogen.

Due to sharply increased metabolic demands, exercise triggers the body to deliver more oxygen, glucose and other nutrients via the bloodstream “Compared to resting conditions, blood flow during maximal exercise can increase up to twentyfold on average,” explained researchers Ingrid Sarelius, Ph.D., University of Rochester, and Ulrich Pohl, Ph.D., Walter Brendel Centre of Experimental Medicine, Munich.1 “

This enormous increase in blood flow during maximal exercise is necessary to meet the twenty- to fiftyfold enhanced oxygen demands of the muscle tissue. Though these extreme demands may be rarely reached in daily life, it remains essential for physical performance that any increase in muscle work is rapidly and reliably matched by adequate increases in muscle blood flow.”
They noted in resting muscle, oxygen extraction from blood ranges from about 20 to 40 percent, while such extraction during exercise can range from 70 to 80 percent.

However, improved extraction only has a limited ability to meet muscle demands as exercise load increases. “Thus, the far more important way to meet the increased demands is an appropriate increase in muscle blood flow, which also has the effect of increasing the microvascular hematocrit, and hence oxygen flux into the tissue from capillaries,” they stated.

The muscles also need amino acids to start protein synthesis, the process of repairing and building new muscle tissue (hypertrophy). Exercise increases both muscle protein breakdown and muscle protein synthesis (MPS); a perfect balance of the two means muscle mass is maintained, while a greater MPS means muscle tissue is getting bigger. In essence, the muscles adapt to damage and stress from exercise (such as in resistance training) by repairing and building new muscle tissue.

MPS requires increased energy, so improved blood flow provides more energy not only for exercise, but also for recovery or muscle adaptations. Muscle contractions, especially in resistance training, can cause a “pump” resulting from more blood in the muscle tissue. When the muscles engorge with blood, the tissue and skin stretch.

Nitric oxide and Vasorelaxation

Nitric oxide (NO) made in the body from the amino acid L-arginine, oxygen and cofactors such as NO synthase (NOS) enzymes cause vasorelaxation of smooth muscle. This can increase blood flow under the right conditions.
“It is known that very high concentrations of nitric oxide favor cell cycle arrest and programmed cell death,”explained Richard Bloomer, Ph.D., dean and professor in the School of Health Studies at University of Memphis, in a 2010 publication.2 “On the contrary, brief production of nitric oxide at low (nanomolar) concentrations favors beneficial physiological functions including decreased platelet and leukocyte adhesion, decreased smooth muscle cell proliferation, regulation of neurotransmission and muscle atrophy/hypertrophy, the stimulation of satellite cells, and enhanced blood flow and immune defense.”

In this publication, Bloomer cautioned while the theory NO-boosting supplements will improve blood flow that improves performance and muscle development makes some sense given NO’s mechanisms of action, “there exist far too many assumptions with this line of thought that one cannot possibly make these statements with confidence.” He explained that even if a supplement raised NO levels, there is no guarantee blood flow will be enhanced and improve performance and recovery.Since 2010, researchers have tried to demonstrate various ingredients and even multi- ingredient preworkout supplements (MIPS) raise NO and result in performance and muscle enhancement.

Blood flow booster research

The nutritional quest for improved blood flow starts with arginine, as it plays a key role in NO production. However, oral arginine supplementation is challenged by bioavailability issues, including potential elimination by enzymes in the intestines and liver.3 Research on arginine supplements in exercise have produced mixed results on blood flow and muscle strength/performance.
Sports nutrition companies have tried to improve arginine ingredients for better absorption and bioavailability and more consistent study results.

Some combined arginine with alpha-ketoglutarate, which is a key compound in energy production via cellular respiration.
However, the results have not been positive. In 2012, kinesiology researchers from Mississippi State University concluded, “Acute ingestion of 3,000 mg of arginine-alpha- ketoglutarate (AAKG) had no effect on upper or lower body 1RM (one rep max) or TLV (total load volume) in either resistance-trained or untrained men.”4

Likewise, a Baylor University research team found physically active males taking an AAKG supplement (as NO2 Platinum, from MRI) before and after resistance exercise had elevated arginine, NO and blood flow, but comparisons with the placebo group showed no significant differences.5 “The effects observed in brachial artery blood flow and serum nitric oxide and endothelial NOS (eNOS) were attributed to resistance exercise rather than NO2 Platinum,” they concluded.

As with AAKG, a novel inositol-stabilized arginine silicon complex (as Nitrosigine®, from Nutrition 21) was designed to address absorption and bioavailability challenges. In addition to enhancing arginine, silicon may protect vascular integrity.6

Another 2015 study looked at the impact of Nitrosigine supplementation on energy and muscles during workouts, and muscle recovery post-workout in healthy men.8 Results showed daily supplementation with 1,500 mg/d Nitrosigine significantly increased pre- workout energy levels (perceived energy/fatigue), increased muscle pump (leg circumference) immediately following a workout, and decreased biomarkers of muscle damage (creatine kinase [CK]) immediately after a workout and during recovery.

Another approach to improved arginine supplementation is to bond arginine to a peptide. Glanbia Nutritionals discovered a whey peptide (NOP-47) that increased NO synthesis. Researchers from University of Connecticut demonstrated this peptide significantly increased brachial artery flow mediated dilation (FMD) at 30, 60 and 90 minutes post ingestion and increased reactive hyperemia forearm blood flow 120 minutes post ingestion, compared to placebo, in healthy men and women.9

In 2015, a MusclePharm Corp.-led research team compared raw L-arginine, arginine nitrate, arginine peptide and placebo on vasodilation and blood flow following exercise in healthy men. 10 They found raw arginine increased vessel diameter 30 minutes post- exercise, but arginine peptide significantly raised blood flow more than the other treatments and placebo.

Citrulline, like arginine, is a nonessential amino acid that is a precursor to arginine. However, unlike arginine, oral citrulline bypasses the liver and goes straight to the kidneys for conversion into arginine.11 Oral citrulline may be more effective than oral arginine at increasing plasma arginine and NO levels and activity.12

Another 2015 MusclePharm study compared raw and peptide forms of both citrulline and arginine following resistance exercise in healthy men.13 For both raw and peptide comparisons, the citrulline ingredients more effectively increased vasodilation and blood flow, and the researchers concluded, “The whey peptide-bound state may positively influence the effects of supplementation.”

Citrulline can be made synthetically or sourced from watermelon (Rind). Acute ingestion of synthetic or natural citrulline seems to inconsistently improve NO production and subsequent vasodilation, according to a 2017 publication.14 However, the researchers noted chronic citrulline supplementation in either form increases NO synthesis, decreases blood pressure and may increase peripheral blood flow. “These changes are paralleled by improvements in skeletal muscle oxygenation and performance during endurance exercise,” they noted.

A study in healthy recreationally active adult males demonstrated watermelon juice supplementation significantly increased plasma arginine, nitrite and NO levels, as well as muscle oxygenation, compared to placebo, but there were no significant improvements to endurance exercise performance.

As the antioxidant glutathione may protect NO from oxidative reduction, researchers compared citrulline-glutathione (as Setria , from Kyowa Hakko Co. Ltd.) and citrulline alone on NO synthesis in vitro (human umbilical vein endothelial cells) and in vivo (humans and rats).16 In vitro, Setria increased nitrite levels greater than controls. In rats, plasma NOx (nitrite+nitrate) was significantly greater with Setria supplementation than citrulline alone and controls. In humans, plasma NOx and nitrites were significantly higher 30 minutes post-exercise for Setria compared to placebo.

Agmatine, which results from arginine decarboxylation in the body, impacts NO synthase enzymes and the amount of NO released in the blood. Agmatine sulfate is popular in sports pre-workout supplements with claims of increasing blood flow and pump, but there is no evidence to support such claims, according to the 2018 International Society for Sports Nutrition (ISSN) exercise and sports nutrition review update.

“Currently, nearly all research involving agmatine is commonly from animal research models and no human studies have been conducted to examine its impact on blood flow or impacting resistance training adaptations such as strength and body composition,” ISSN concluded. “There does not appear to be any scientific evidence that agmatine supports increases in lean body mass or muscular performance.”

In addition to arginine-related production, NO can be synthesized in the body from nitrites. Soil is rich in nitrates (NO3-), which end up in plant foods, namely root vegetables and leafy greens. When digested, these dietary nitrates are converted by saliva into nitrites (NO2-) that can be used to make NO.

Beetroots are rich in nitrates and have been popular in sports nutrition for improved blood flow and performance. Increased NO production and blood flow from beetroot juice supplementation has been shown to improve mitochondrial respiration from improved oxygen delivery and to strengthen muscle contractions.18

A study of young adults (ages 23 to 27) found beetroot juice supplementation increased forearm vasodilation and blood flow during handgrip exercises, in addition to lowering VO2max, the maximum rate of oxygen consumption.19

A 2018 review of the many studies on beetroot and exercise performance confirmed the supplement’s ability to increase blood flow and oxidative energy production, resulting in improved performance in both endurance and resistance exercise.20

“Numerous investigations have noted that beetroot juice supplementation boosts performance in exercise modalities involving intensive endurance efforts in which the dominant type of energy metabolism is oxidative,” the review explained.

Spinach is another rich source of nitrates. A pharmacokinetic study confirmed a proprietary extract of amaranth (Amaranthus dubius), also known as red spinach, (as OXYSTORM®, from DolCas Biotech LLC via PLT Health Solutions Inc.) increased saliva and plasma nitrate and nitrite levels in healthy adults, compared to placebo, for up to eight hours post ingestion.21

Auburn University researchers studying OXYSTORM supplementation in healthy adults reported increased plasma nitrites 30 minutes post ingestion of red spinach extract, compared to placebo; however, there was no difference between the groups on brachial artery blood flow.22

A subsequent study by a version of this research team showed OXYSTORM supplementation in recreationally active adults increased plasma nitrite levels both before and after graded exercise testing, compared to the placebo group.23 Further, VO2 at the ventilatory threshold was significantly higher in the OXYSTORM group than the placebo group.For other plants, including fruits and herbs, it is not the nitrite content but various phytochemicals that boost NO and/or blood flow for potential muscle-building benefits.

A popular anti-inflammatory botanical, curcumin and its curcuminoids, also may boost NO levels and improve endothelial function and blood flow. In one study, healthy middle-aged and older adults who took 2000 mg/d of curcumin (as Longvida®, from OmniActive) had greater NO-dependent vasodilation and increased brachial artery flow-mediated dilation than the placebo group.24 A Japanese study found combining curcumin ingestion and aerobic exercise training increased flow-mediated dilation in postmenopausal women.25
Other plant-based ingredients with promise to improve blood flow include a range of fruits, but the focus is not nitrate content, but polyphenols such as flavonoids.

Polyphenols

Red wine, in moderation, has long been credited with improved cardiovascular health. As long as intake isn’t absurdly high, even intoxicating levels of alcohol can cause vasodilation. However, Swedish researchers reported both alcoholic and nonalcoholic red wine caused brachial artery dilation and increased blood flow in healthy adult subjects (under age 40), suggesting antioxidants, not just the ethanol, were to credit.26

Grapes contain many polyphenols with health benefits, including proanthocyanidins. These tannin flavonoids, specifically cyanidin and delphinidin, may improve blood flow by influencing eNOS and protecting blood vessel walls against oxidative damage.27

Grapeseed extract contains a wealth of polyphenols shown to relax blood vessels in animal research.28 A human clinical trial found grapeseed extract increased oxygen delivery in conjunction with exercise in prehypertensive adult men.29 The researchers concluded vasodilation was at least partially to credit.

In addition to flavonoids, grapes also contain stilbenoids such as resveratrol. “Resveratrol stimulates NO production from eNOS by a number of mechanisms, including upregulation of eNOS expression, stimulation of eNOS enzymatic activity and reversal of eNOS uncoupling,” German researchers reported.30 “In addition, by reducing oxidative stress, resveratrol prevents oxidative NO inactivation by superoxide, thereby enhancing NO bioavailability.”

Some of the same polyphenols in grapes are in other plants and fruits. Blueberries contain pterostilbene, an analogue of resveratrol shown to increase eNOS phosphorylation, the trigger for NO production.31

Other polyphenol-rich fruits have demonstrated similar effects on the eNOS pathway of NO synthesis, including strawberries,32 apples,33 blackcurrants and pomegranates.

First, in vitro research on human cells showed blackcurrant juice concentrates increased eNOS phosphorylation.34 The researchers noted the the eNOS actions were not impacted by removal of vitamin C from the juice—vitamin C can also stimulate eNOS activity.35
Based on the blood flow benefits of blackcurrant, University of Chichester, England, researchers looked at the impact of black currant supplementation (as CurraNZ, from Health Currancy) on resting cardiovascular function in healthy male triathletes and reported lower total peripheral resistance in the supplement group, compared to placebo.36

They conducted another trial of CurraNZ on oxygen delivery, power output and metabolite (lactate) removal from muscle in male endurance athletes (club level cyclists and triathletes with more than three years of experience).37 They found the black currant supplement group had significantly decreased post-exercise muscle lactate compared to the placebo group. Cycling time trial performance was also improved in the supplement group vs. placebo.

Pomegranates also activate eNOS in addition to attenuating arterial inflammation, which some researchers have suggested is due to egallitannin polyphenols.38
Based on the nitrate and polyphenolic content of pomegranate, a research team from University of North Carolina investigated pomegranate extract (NITRO2GRANIT™, from Dymatize) on blood flow, vessel diameter and exercise performance in active men and women.39

Compared to placebo, ingestion of the extract 30 minutes before exercise significantly increased brachial artery blood flow, increased blood vessel diameter and improved exercise tolerance.

Cocoa is also rich in polyphenols including flavanols. A group of U.S.- and German-based nutrition researchers reported ingestion of flavanol-rich cocoa (Cocoapro powder, from Mars Inc.) was associated with increased circulating NO and improved blood flow.40 They singled out the flavanol (-)-epicatechin as the primary responsible flavanol, as ingesting pure (-)-epicatechin also produced similar vascular effects.

As part of the European Union’s Flaviola Health Study, this team’s subsequent study of both young and elderly men showed consumption of cocoa flavanol-rich drink (containing Cocoapro) for two weeks increased blood flow in both groups, compared to placebo, in addition to lowering total peripheral resistance and increasing arteriolar and microvascular vasodilator capacity.41

Other Flaviola research from this team included a trial on cocoa flavanol consumption in healthy, middle-aged individuals who took 450 mg Cocoapro twice daily for a month.42 Blood flow in the supplement group increased significantly compared to controls.

In 2017, this research group reported while cocoa flavanol intake in healthy volunteers increased vasodilation and blood flow, the effect was enhanced when the flavanols were taken in conjunction with methylxanthines—cocoa contains methylxanthines such as theobromine and caffeine.43 However, methylxanthines alone did not statistically increase dilation and blood flow.

Belgian researchers investigated acute cocoa flavanol supplementation in athletes, finding flavanol intake by well-trained male cyclists one and a half hours and three hours before time trials increased epicatechin levels but did not impact NO production.44
Oat leaves (Avena sativa L.) contain another group of polyphenols called avenanthramides that may interest athletes looking for improved blood flow. Australian researchers reported wild green oat extract (as Neuravena®, from Frutarom) improved vasodilator function in cerebral and systemic arteries in healthy older subjects (over 60).45

A multi-plant-active approach also may be promising. In one study, supplementing with a plant-based botanical complex standardized to 60 percent polyphenols, 30 percent catechins and 3 percent curcumin (as S7™, from Futureceuticals) resulted in a 1.7- to 2.3-times increase in NO bioavailability in healthy subjects.46

Beyond botanicals, several ingredients known primarily for boosting cellular energy production have shown promise on blood flow during exercise.
Adenosine triphosphate (ATP) is the cellular energy molecule—breaking its bonds provides energy for use by the muscles and other parts of the body. The body makes ATP from glucose and fats—proteins can be used to make glucose in fasting states—but ATP is also available as a supplement ingredient.
“Extracellular adenosine triphosphate (ATP) is hypothesized to stimulate vasodilation by binding to endothelial ATP/UTP-selective P2Y2 receptors, a phenomenon which is posited to be accelerated during exercise,” explained researchers in a 2013 publication.47
“Nonetheless, no studies to our knowledge have delineated if supplemental ATP enhances the blood flow response to exercise.”
They studied crystallized oral ATP disodium salt (as Peak ATP®, from TSI) in both animals (Wistar rats) and humans (college-aged, resistance-trained individuals), finding significantly increased blood flow in rats, including during recovery, as well as in humans during recovery from resistance exercise, compared to controls.

L-carnitine is a shuttle for fatty acids in the cellular respiration process of energy/ATP production. Animal and human trials demonstrated L-carnitine can improve endothelial function and blood flow.48

Adding the amino acid glycine appears to enhance the blood flow effect of carnitine— glycine plays a role in NO management.49 Sports science researchers from University of Memphis reported short-term supplementation with glycine propionyl-L-carnitine (GPLC, as GlycoCarn™, from Sigma-tau HealthScience S.p.A) can increase NOx in resistance-trained men.50 “However, as with many dietary supplements, there exist both ‘responders’ and ‘non-responders’ to treatment,” they cautioned.

Researchers from Florida Atlantic University demonstrated short-term GPLC supplementation (from Jarrow Formulas) enhanced peak power production in resistance- trained males and resulted in less lactate accumulation.51 However, their subsequent study of long-term GPLC supplementation in resistance-trained males suggested the benefits to anaerobic work capacity may be dose-dependent and require doses tailored specifically to exercise intensity.52

Many dietary supplement ingredients have exhibited promising impacts on vasodilation, blood flow and the many pathways and biomarkers involved with such vascular functions. Some of these ingredients rely on small trials, often in test tubes or animals, showing actions on NO- and dilation-related compounds and biomarkers, but there is not a lot of human clinical evidence on either increased blood flow surrounding exercise or resulting benefits to muscle development and performance.

For now, most sports supplements containing these and other ingredients use NO or muscle pump claims, relying on the end user to connect the dots between NO, blood flow and muscle benefits.

Despite the publication of more human studies on blood flow boosters and exercise, Bloomer’s advisory on NO-boosting supplements from 2010 still applies today: “Many research questions remain to be answered…whether such products can reliably (a) stimulate an increase in nitric oxide production, (b) stimulate an increase in blood flow, (c) stimulate an increase in nutrient and oxygen transport to exercising muscle, (d) improve exercise performance and recovery, and (e) increase muscle mass,” he cautioned. “Without well-designed research studies focused on the actual product of sale, answers to such questions will remain unknown and this field will remain much more hype than effect.”

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