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 Baca601 SeminarMarch 2, 2012

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

From Citrullus vulgaris – 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

L-CITRULLINEL-ARGININE

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 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

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.

HO

W CITRU

LLINE M

AY BE THE KEY

2

Cit increases Arg pools and restores N

balanceAfter 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

issuesWhereas, a bolus of

the same dose of Arg DiarrheaMoinard, 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 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 DietHayashi, 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 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 STUDY Hayashi, T, PA Juliet, H M

atsui-Hirai, A Miyazaki, A Fukatsu, J Funam

i, A Iguchi, and LJ Ignarro. "L-Citrulline and L-arginine Supplem

entation Retards the Progression of High-cholesterol-diet-induced Atherosclerosis in Rabbits." Proceedings of the N

ational Academy of Sciences of the U

nited States of America, 102.38 (2005):

13681-13686.

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 MEN

Baseline 60 Min. Day 7


SHORT-TERM EFFECTS OF L-CITRULLINE SUPPLEMENTATION ON ARTERIAL STIFFNESS IN MIDDLE-AGED MEN


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." Acta Horticulturae, 731 (2007): 121-127.

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 HeartsWu, 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 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 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 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 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 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

QUESTIONS?

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