L-arginine, L-citrulline and cardiovascular health through - PowerPoint Presentation

Slide1

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

Kyrié Baca

601 Seminar

March 2, 2012Slide2

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.Slide3

L-arginine and L-citrulline

From

Citrullus

vulgaris – watermelon*Non-essential Amino AcidPrecursor of arginine- Nitric Oxide System

Conditionally-essential amino acid: infants, ill, or injured.

Nitric Oxide Pathway

Vasodilation

Overall Cardiovascular health

L-CITRULLINE

L-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.Slide4

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.Slide5

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.Slide6

How

Citrulline

may be the KEY

2Cit 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 issues

Whereas, a bolus of the same dose of

Arg

 Diarrhea

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.Slide7

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 weeksL-arginine, L-citrulline, and/or antioxidants =

Tx49 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 waterGp4-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 EGp7-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.Slide8

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.Slide9

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.Slide10

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

15 healthy male subjects

58.3

+ 4.4 yearsBrachial-ankle pulse wave velocity5.6 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.Slide11

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.Slide12

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.Slide13

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.Slide14

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-arginine63% watermelon pomace juice

0.01%

lycopene

0.05% citrus pectin

N = 6 per Tx

4 week supplementation period- in drinking waterMeasures:Blood samplesAortic 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.Slide15

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.Slide16

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.Slide17

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.Slide18

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 day3 weeksCross-over designWatermelon 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.Slide19

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.Slide20

Summary

L-arginine has been proven to promote cardiovascular health

CIT is very efficiently absorbed and

metabolised to ARGBoth 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 USSlide21

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 absorptionNO in its cytoxic

role in tumor cells + lycopene – CancerWeight lossSlide22

Questions?Slide23

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. Slide24

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.