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L-arginine, L-citrulline and cardiovascular health through the nitric oxide system.    . Kyrié Baca 601 Seminar March 2, 2012. Cardiovascular Disease . Number 1 cause of morbidity and mortality among adults in the United States.

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l arginine l citrulline and cardiovascular health through the nitric oxide system

L-arginine, L-citrulline and cardiovascular health through the nitric oxide system.   

Kyrié Baca

601 Seminar

March 2, 2012

cardiovascular disease
Cardiovascular Disease
  • Number 1 cause of morbidity and mortality among adults in the United States.
  • Atherosclerosis: inflammatory disease characterized by vascular endothelial dysfunction and diminished production of NO.

Gornik, H.L, and M.A Creager. "Arginine and Endothelial and Vascular Health." Journal of Nutrition, 134.10S (2004): 2880S.

l arginine and l citrulline
L-arginine and L-citrulline

L-CITRULLINE

L-ARGININE

  • From Citrullusvulgaris – watermelon*
  • Non-essential Amino Acid
  • Precursor of arginine- Nitric Oxide System
  • Conditionally-essential amino acid: infants, ill, or injured.
  • Nitric Oxide Pathway
  • Vasodilation
  • Overall Cardiovascular health

Moinard, C, I Nicolis, N Neveux, S Darquy, S Benazeth, and L Cynober. "Dose-ranging Effects of Citrulline Administration on Plasma Amino Acids and Hormonal Patterns in Healthy Subjects: The Citrudose Pharmacokinetic Study." The British Journal of Nutrition, 99.4 (2008): 855-862.

Moinard, C, I Nicolis, N Neveux, S Darquy, S Benazeth, and L Cynober. "Dose-ranging Effects of Citrulline Administration on Plasma Amino Acids and Hormonal Patterns in Healthy Subjects: The Citrudose Pharmacokinetic Study." The British Journal of Nutrition, 99.4 (2008): 855-862.

nitric oxide system 4
Nitric Oxide System4

Pizzorno, Lara. “Longevity Medicine Strategies for Cardiovascular Disease: Closing the Statin Gap in Endothelial Dysfunction and Insulin Resistance Naturally, with L-Arginine and Citrulline: Part I” Longevity Medicine Review.

l arginine restores endothelium dependent vasodilation in hypercholesterolemic rats
L-arginine restores endothelium dependent vasodilation in hypercholesterolemic rats

Girerd, X J, A T Hirsch, J P Cooke, V J Dzau, and M A Creager. "L-arginine Augments Endothelium-dependent Vasodilation in Cholesterol-fed Rabbits." Circ Res, 67.6 (1990): 1301-1308.

how citrulline may be the key 2
Cit increases Arg pools and restores N balance

After Cit administration, plasma CIT concentration increases to a maximum then decreases to baseline in 3-5 hours.

After the same Cit administration, plasma ARG increases to reach a maximum and then decreases gradually – NOT TO BASELINE – within 8 hours.

Cit = well tolerated (no side effects)

Did not induce GI issues

Whereas, a bolus of the same dose of Arg Diarrhea

How Citrulline may be the KEY2

Moinard, C, I Nicolis, N Neveux, S Darquy, S Benazeth, and L Cynober. "Dose-ranging Effects of Citrulline Administration on Plasma Amino Acids and Hormonal Patterns in Healthy Subjects: The Citrudose Pharmacokinetic Study." The British Journal of Nutrition, 99.4 (2008): 855-862.

l citrulline and l arginine prevent atherosclerosis animal study
L-citrulline and L-arginine prevent atherosclerosis – Animal Study
  • Objective: evaluate the influence of L-citrulline, L-arginine, and antioxidants on the progression of atherosclerosis in rabbits fed a high-cholesterol diet.
  • 12 weeks
  • L-arginine, L-citrulline, and/or antioxidants = Tx
  • 49 New Zealand White male rabbits: 3-4 mos.
  • 7 groups depending on diet:
    • Gp1-HCD : High Cholesterol Diet
    • Gp2-Arg : HCD + 2.5% L-arginine in water
    • Gp3-Cit: HCD + 2.0% L-citrulline in water
    • Gp4-Arg+Cit : HCD + L-arginine + L-citrulline
    • Gp5-Vit : HCD + Vitamin C (antioxidant) 0.25% in water + Vitamin E (150 mg/kg/day oral gavage)
    • Gp6- Arg + Vit: HCD + L-arginine + Vitamin C + Vitamin E
    • Gp7-Mix : All
    • Gp8-C- Control- Standard Diet

Hayashi, T, PA Juliet, H Matsui-Hirai, A Miyazaki, A Fukatsu, J Funami, A Iguchi, and LJ Ignarro. "L-Citrulline and L-arginine Supplementation Retards the Progression of High-cholesterol-diet-induced Atherosclerosis in Rabbits." Proceedings of the National Academy of Sciences of the United States of America, 102.38 (2005): 13681-13686.

l citrulline and l arginine prevent atherosclerosis animal study1
L-citrulline and L-arginine prevent atherosclerosis – Animal Study

Hayashi, T, PA Juliet, H Matsui-Hirai, A Miyazaki, A Fukatsu, J Funami, A Iguchi, and LJ Ignarro. "L-Citrulline and L-arginine Supplementation Retards the Progression of High-cholesterol-diet-induced Atherosclerosis in Rabbits." Proceedings of the National Academy of Sciences of the United States of America, 102.38 (2005): 13681-13686.

l citrulline and l arginine prevent atherosclerosis animal study2
L-citrulline and L-arginine prevent atherosclerosis – Animal Study

Hayashi, T, PA Juliet, H Matsui-Hirai, A Miyazaki, A Fukatsu, J Funami, A Iguchi, and LJ Ignarro. "L-Citrulline and L-arginine Supplementation Retards the Progression of High-cholesterol-diet-induced Atherosclerosis in Rabbits." Proceedings of the National Academy of Sciences of the United States of America, 102.38 (2005): 13681-13686.

short term effects of l citrulline supplementation on arterial stiffness in middle aged men
Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men
  • 15 healthy male subjects
  • 58.3 + 4.4 years
  • Brachial-ankle pulse wave velocity
  • 5.6 g/day of L-citrulline (N=8) or placebo (N=7)
  • 7 days (short term)
  • baPWV and clinical parameters measured at baseline and after oral supplementation

Ochiai, M, T Hayashi, M Morita, K Ina, M Maeda, F Watanabe, and K Morishita. "Short-term Effects of L-citrulline Supplementation on Arterial Stiffness in Middle-aged Men." International Journal of Cardiology, 155.2 (2012): 257-261.

short term effects of l citrulline supplementation on arterial stiffness in middle aged men1
Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men

Baseline

60 Min.

Day 7

Ochiai, M, T Hayashi, M Morita, K Ina, M Maeda, F Watanabe, and K Morishita. "Short-term Effects of L-citrulline Supplementation on Arterial Stiffness in Middle-aged Men." International Journal of Cardiology, 155.2 (2012): 257-261.

short term effects of l citrulline supplementation on arterial stiffness in middle aged men2
Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men

Ochiai, M, T Hayashi, M Morita, K Ina, M Maeda, F Watanabe, and K Morishita. "Short-term Effects of L-citrulline Supplementation on Arterial Stiffness in Middle-aged Men." International Journal of Cardiology, 155.2 (2012): 257-261.

watermelon
Watermelon
  • Components:
    • Unique source of both citrulline and arginine
    • Watermelon is the richest known source of citrulline.
  • Health Benefits:
    • CVD
    • Cancer (prostate) - rich in lycopene (more than tomatoes!)
  • Watermelon Consumption:
    • Most sold in the US as fresh
    • 50-80% seedless
    • Small percentage is minimally processed (cut or cubed)

Perkins-Veazie, P, J.K Collins, G Wu, and B Clevidence. "Watermelons and Health." ActaHorticulturae, 731 (2007): 121-127.

dietary supplementation with watermelon pomace juice animal study
Dietary Supplementation with Watermelon Pomace Juice - Animal Study
  • 9 week old Zucker Diabetic Fatty Rats
    • (animal model of NIDDM)
  • Groups:
    • Control = 0% arginine
    • 2% L-arginine
    • 63% watermelon pomace juice
    • 0.01% lycopene
    • 0.05% citrus pectin
    • N = 6 per Tx
  • 4 week supplementation period- in drinking water
  • Measures:
    • Blood samples
    • Aortic rings
    • Hearts

Wu, G, JK Collins, P Perkins-Veazie, M Siddiq, KD Dolan, KA Kelly, CL Heaps, and CJ Meininger. "Dietary Supplementation with Watermelon Pomace Juice Enhances Arginine Availability and Ameliorates the Metabolic Syndrome in Zucker Diabetic Fatty Rats." The Journal of Nutrition, 137.12 (2007): 2680-2685.

dietary supplementation with watermelon pomace juice animal study1
Dietary Supplementation with Watermelon Pomace Juice - Animal Study

Wu, G, JK Collins, P Perkins-Veazie, M Siddiq, KD Dolan, KA Kelly, CL Heaps, and CJ Meininger. "Dietary Supplementation with Watermelon Pomace Juice Enhances Arginine Availability and Ameliorates the Metabolic Syndrome in Zucker Diabetic Fatty Rats." The Journal of Nutrition, 137.12 (2007): 2680-2685.

dietary supplementation with watermelon pomace juice animal study2
Dietary Supplementation with Watermelon Pomace Juice - Animal Study

Wu, G, JK Collins, P Perkins-Veazie, M Siddiq, KD Dolan, KA Kelly, CL Heaps, and CJ Meininger. "Dietary Supplementation with Watermelon Pomace Juice Enhances Arginine Availability and Ameliorates the Metabolic Syndrome in Zucker Diabetic Fatty Rats." The Journal of Nutrition, 137.12 (2007): 2680-2685.

dietary supplementation with watermelon pomace juice animal study3
Dietary Supplementation with Watermelon Pomace Juice - Animal Study

Wu, G, JK Collins, P Perkins-Veazie, M Siddiq, KD Dolan, KA Kelly, CL Heaps, and CJ Meininger. "Dietary Supplementation with Watermelon Pomace Juice Enhances Arginine Availability and Ameliorates the Metabolic Syndrome in Zucker Diabetic Fatty Rats." The Journal of Nutrition, 137.12 (2007): 2680-2685.

watermelon consumption increases plasma arginine concentration in adults
Watermelon consumption increases plasma arginine concentration in adults
  • 23 subjects- 12 male, 11 female
  • All consumed control diet
  • 3 Groups: 0, 780, or 1560 g of watermelon juice per day
  • 3 weeks
  • Cross-over design
  • Watermelon Container = 0.26 kg juice

Collins JK, Wu G, Perkins-Veazie P, Spears K, Claypool PL, Baker RA, et al. Watermelon consumption increases plasma arginine concentrations in adults. Nutrition 2007;23:261– 6.

watermelon consumption increases plasma arginine concentration in adults1
Watermelon consumption increases plasma arginine concentration in adults

Collins JK, Wu G, Perkins-Veazie P, Spears K, Claypool PL, Baker RA, et al. Watermelon consumption increases plasma arginine concentrations in adults. Nutrition 2007;23:261– 6.

summary
Summary
  • L-arginine has been proven to promote cardiovascular health
  • CIT is very efficiently absorbed and metabolised to ARG
  • Both amino acids (especially together) are critical in maintaining optimum levels of NO- without which endothelial dysnfunction may present.
  • Watermelon is a good source of both aa but is a unique source of large amounts of dietary CIT!
  • Watermelon supplementation is very tolerated = high compliance
  • Promising Tx for CVD- the #1 cause of death in US
limitations and future studies
Limitations and Future Studies
  • CIT administration in the long term
  • In high doses, does the effect of large amounts of CHO intake negate the cardiovascular benefits of watermelon supplementation?
  • Gene expression in carriers of CIT absorption
  • NO in its cytoxic role in tumor cells + lycopene – Cancer
  • Weight loss
sources
Sources
  • 1. Gornik, H.L, and M.A Creager. "Arginine and Endothelial and Vascular Health." Journal of Nutrition, 134.10S (2004): 2880S.
  • 2. Moinard, C, I Nicolis, N Neveux, S Darquy, S Benazeth, and L Cynober. "Dose-ranging Effects of Citrulline Administration on Plasma Amino Acids and Hormonal Patterns in Healthy Subjects: The Citrudose Pharmacokinetic Study." The British Journal of Nutrition, 99.4 (2008): 855-862.
  • 3. Girerd, X J, A T Hirsch, J P Cooke, V J Dzau, and M A Creager. "L-arginine Augments Endothelium-dependent Vasodilation in Cholesterol-fed Rabbits." Circ Res, 67.6 (1990): 1301-1308.
  • 4. Pizzorno, Lara. “Longevity Medicine Strategies for Cardiovascular Disease: Closing the Statin Gap in Endothelial Dysfunction and Insulin Resistance Naturally, with L-Arginine and Citrulline: Part I” Longevity Medicine Review.
  • 5. Hayashi, T, PA Juliet, H Matsui-Hirai, A Miyazaki, A Fukatsu, J Funami, A Iguchi, and LJ Ignarro. "L-Citrulline and L-arginine Supplementation Retards the Progression of High-cholesterol-diet-induced Atherosclerosis in Rabbits." Proceedings of the National Academy of Sciences of the United States of America, 102.38 (2005): 13681-13686.
  • 6. Ochiai, M, T Hayashi, M Morita, K Ina, M Maeda, F Watanabe, and K Morishita. "Short-term Effects of L-citrulline Supplementation on Arterial Stiffness in Middle-aged Men." International Journal of Cardiology, 155.2 (2012): 257-261.
  • 7. Perkins-Veazie, P, J.K Collins, G Wu, and B Clevidence. "Watermelons and Health." ActaHorticulturae, 731 (2007): 121-127.
  • 8. Wu, G, JK Collins, P Perkins-Veazie, M Siddiq, KD Dolan, KA Kelly, CL Heaps, and CJ Meininger. "Dietary Supplementation with Watermelon Pomace Juice Enhances Arginine Availability and Ameliorates the Metabolic Syndrome in Zucker Diabetic Fatty Rats." The Journal of Nutrition, 137.12 (2007): 2680-2685.
  • 9. Collins JK, Wu G, Perkins-Veazie P, Spears K, Claypool PL, Baker RA, et al. Watermelon consumption increases plasma arginine concentrations in adults. Nutrition 2007;23:261– 6.
sources cont d
Sources- Cont’d
  • 10. Figueroa, A, MA Sanchez-Gonzalez, PM Perkins-Veazie, and BH Arjmandi. "Effects of Watermelon Supplementation on Aortic Blood Pressure and Wave Reflection in Individuals with Prehypertension: A Pilot Study." American Journal of Hypertension, 24.1 (2011): 40-44.
  • 11. Kohli, Ripla, Cynthia J. Meininger, et al. "Dietary L-Arginine Supplementation Enhances Endothelial Nitric Oxide Synthesis in Streptozotocin-Induced Diabetic Rats." Journal of Nutrition. 134. (2004): 600-608. Web. 23 Apr. 2012. <jn.nutrition.org>.
  • 12. McKnight, Jason R., M. Carey Satterfield, et al. "Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health." Amino Acids. 39. (2010): 349-357. Web. 23 Apr. 2012. <http://www.springerlink.com/content/f5371224753j8763/>.
  • 13. Koeners MP, van Faassen EE, et. al. Maternal supplementation with citrulline increases renal nitric oxide in young spontaneously hypertensive rats and has long term antihypertensive effects. Hypertension. 50. (2007): 1077-1084.
  • 14. Moinard, C, I Nicolis, N Neveux, S Darquy, S Benazeth, and L Cynober. "Dose-ranging Effects of Citrulline Administration on Plasma Amino Acids and Hormonal Patterns in Healthy Subjects: The Citrudose Pharmacokinetic Study." The British Journal of Nutrition, 99.4 (2008): 855-862.
  • 15. Schwedhelm, Edzard, Rinke Mass, et al. "Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism." British Journal of Clinical Pharmacology. 65.1 (2007): 51-59. Web. 23 Apr. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291275/>.
  • 16. Romero, Maritza J., and Daniel H. Platt. "Diabetes-induced coronary vascular dysfunction involves increased arginase activity." Journal of the American Heart Association. 102. (2008): 95-102. Web. 23 Apr. 2012. <http://circres.ahajournals.org/content/102/1/95>.
  • 17. Evoy, Denis, Michael D. Lieberman, et al, et al. "Immunotrition: the role of arginine." Nutrition. 14. (1998): 611-617. Print.
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