US006117872A
United States Patent
Maxwell et al.
(11)Patent Number: 6,117,872
(45)Date of Patent: Sep. 12, 2000
(54)ENHANCEMENT OF EXERCISE PERFORMANCE BY AUGMENTING ENDOGENOUS NITRIC OXIDE PRODUCTION OR ACTIVITY
(75) Inventors: Andrew J. Maxwell, Fremont; John P. Cooke, Palo Alto, both of Calif.
(73)Assignee: The Board of Trustees of the Leland Stanford Junior University, Stanford, Calif.
(21) Appl. No.: 09/103,340
(22)Filed: Jun. 23, 1998
(51)Int. Cl.7 ………A61K 31/205; A61K 31/195; A61K 31/16; A61K 31/13; A61K 31/015’ A61K 33/04; A61K 31/495; A61K 31/50; A61K 31/55; A61K 31/34
(52)U.S. Cl. ……………514/249; 424/702; 514/458; 514/474; 514/556; 514/564; 514/565; 514/625; 514/665; 514/763
(58)Field of Search ……………514/249, 458, 514/474, 556, 564, 565, 665, 625, 763; 424/702
(56)References Cited
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US006117872A
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Maxwell, et al., “Limb blood flow during exercise is dependent upon nitric oxide” (Circulation 1998, Accepted for publication).
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Primary Examiner – Kimberly Jordan
Attorney, Agent, or Firm – Bertram I. Rowland; Rae-Venter Law Group P.C.
(57) ABSTRACT
NO precursors are administered at elevated levels in addition to the diet of the individual to enhance exercise performance. Particularly, L-arginine and L-lysine by enhancing endothelial NO production can provide for greater aerobic capacity and improved exercise performance.
14 Claims, 7 Drawing Sheets
Figure 1. Effect of inhibition of ENDO on aerobic capacity.
Figure 2. Systemic Production of Nitric Oxide Before and After Inhibition of ENDO.
Figure 3. Blood Flow to the Hind limbs of Mice Before and After Inhibition of ENDO.
Figure 4. Effect of Cholesterol on Aerobic Capacity.
Figure 5. Vascular Function in Normal and Hypercholesterolemic Mice.
Figure 6. Systemic Nitric Oxide Production Following Exercise after L-arginine.
Figure 7. Aerobic Capacity of Mice on L-arginine.
1
ENHANCEMENT OF EXERCISE PERFORMANCE BY AUGMENTING ENDOGENOUS NITRIC OXIDE PRODUCTION OR ACTIVITY
This invention was made with Government support under contracts HL58638 and HL02660 awarded by the National Institutes of Health. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
Aerobic exercise capacity is partly limited by vascular transport of oxygen and nutrients to end organs such as the heart and skeletal muscles. Vascular transport is, in turn, partly regulated by the elaboration of endothelial-derived nitric oxide (EDNO). Administration of physiologically acceptable compounds which enhance the elaboration of endogenous nitric oxide by the host allow for greater vascular transport and enhanced aerobic performance. Alternatively, compounds or combinations of compounds may be administered to enhance nitric oxide production particularly in conjunction with the administration of a nitric oxide precursor to enhance aerobic performance.
Exercise capacity is limited by the rate by which oxygen can be taken up by a host (Schaible T F, Scheuer J: Cardiac adaptations to chronic exercise. Progress in Cardiovascular Disease 1985; 27:297-324; Wasserman K: Coupling of external to cellular respiration during exercise: the wisdom of the body revisited. American Journal of Physiology 1994; 266:E519-E539). In a generally healthy host, the rate of oxygen uptake, termed maximal velocity of oxygen uptake (VO2max), is mostly limited by the oxygen transport capacity which is determined by the vascular conduction and distribution of blood flow (Barclay J K, Stainsby W N: The role of blood flow in limiting maximal metabolic rate in muscle. Medicine and Science in Sports and Exercise 1975; 7:116-119; di Prampero P E: An analysis of the factors limiting maximal oxygen consumption in healthy subjects. Chest 1992; 101:188S-191S). Therefore, the normal mechanisms which regulate blood flow during exercise can be limiting to aerobic exercise capacity. Furthermore, when these mechanisms are deranged, aerobic capacity may be further limited.
The production of nitric oxide by the endothelium (EDNO) contributes significantly to blood flow regulation and aerobic capacity during exercise (Maxwell A J, Schauble E, Bernstein D, Cooke J P: Limb blood flow during exercise is dependent upon nitric oxide. Circulation 1998;, Accepted for publication). This has been shown by the following series of experiments in the animal model. Administration of an inhibitor of the synthesis of EDNO acutely reduces aerobic capacity as measured by the VO2max, the anaerobic threshold, running distance before exhaustion and aerobic work, as shown herein.
There are a significant number of cardiovascular disorders, where the individuals’ ambulatory abilities are extensively impaired. These include individuals who suffere severe fatigue with exercise, which condition frequently is associated with heart failure. These disorders also include atherosclerosis affecting the coronary or limb arteries which can be manifested by angina (chest pain) or intermittent claudication (leg pain) with walking. Enhancing aerobic capacity to enhance performance would be of great advantage to these patients.
The use of L-arginine for prophylaxis and therapy in the case of atherosclerosis is taught in U.S. Pat. No. 5,5,428,070.
2
SUMMARY OF THE INVENTION
Physical capacity of individuals involved in muscular exertion is improved by administration of high levels of basic amino acids in addition to the diet normal for the individual. The basic amino acids are administered prior to the anticipated muscular exertion, particularly in association with substances which are antioxidants or other substances which enhance vascular nitric oxide synthesis or activity to cause vasodilation of vessels supplying exercising skeletal muscles and thereby enhance aerobic capacity.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 has a series of graphs of various aspects of aerobic capacity showing the effect of inhibition of endothelial-derived nitric oxide (EDNO) on aerobic capacity;
FIG. 2 is a bar graph comparing NO/creatinine production with different mice under different conditions after exercise;
FIG. 3 is a bar graph showing the changes in blood flow to the hind limbs of different mice before and after inhibition of EDNO;
FIG. 4 is a series of bar graphs showing the effect of cholesterol levels in animal models on aerobic capacity.
FIG. 5 is a graph of the change in vascular function in normal and hypercholesterolemic mice;
FIG. 6 is a bar graph showing systemic nitric oxide production following exercise after L-arginine administration; and
FIG. 7 has two bar graphs comparing aerobic capacity of mice on L-arginine.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
In accordance with the subject invention, exercise and athletic performance, aerobic capacity and muscular output are improved by administering high levels of the basic amino acids, L-arginine and L-lysine, individually or combined, to individuals, including humans and race animals, prior to physical exertion. The individuals may be hypercholesterolemic, normocholesterolemic or hypercholesterolemic, where normocholesterolemic falls for total plasma cholesterol level approximately between about 120-240 mg/dL cholesterol.
The physical exertion will usually involve the expenditure rate of at least about 100 Watts, usually at least about 200 Watts, during the course of the activity, which may be as short as a few seconds, as in a 100 meter race, or as long as a few hours, as in a marathon. Thus, the subject invention when involving performance in athletic prowess or physical effort, will require a minimum expenditure of energy in order to warrant the intake of the NO precursor amino acid.
The normal individual in the normal diet ingests about 1-6 grams of arginine per day and about 1.5-7 grams of lysine per day. For the purpose of this invention, within 48 hours prior to the physical exertion, and more preferably within about 6 hours of the physical exertion, at least about a total of 2 g, more usually at least about 3 g, preferably at least about 4 g, more preferably about a total of 4-9 g of basic amino acid, usually not more than about 12 g, will be administered orally as a bolus or in multiple doses, usually not more than about 6 doses, preferably not more than about 4 doses. By comparison, for race animals, the basic amino acids will be administered at at least about 60 mg/kg/day. The ratio of arginine to lysine would generally be in the range of about 0-1:1-0, more usually in the range of about 0.2-1:0.8-0. While there is no maximum amount of the basic amino acids which may be employed, normally the total dosage per day will be under about 16 g, more usually under about 12 g, with individual dosages usually being in the range of 2-6 g.
While for the most part, the amino acids will be administered as oligomers, generally having fewer than 10 units, more usually fewer than 8 units, and preferably having from about 2-6 units.
The administration of the basic amino acids may be a single administration, a few administrations, generally not more than about 8 over a period of 1-2 days, or may be administered on a daily basis. The particular regimen will depend upon the individual, the purpose for taking the basic amino acids for exercise performance enhancement, and whatever other aspects are involved. Since the basic amino acid will be taken to improve aerobic performance, it will generally be taken within one day of the activity and may be taken within 6 h of the activity, particularly within 3 h of the activity.
Desirably, the formulation which is employed for the basic amino acids will include other additives, particularly antioxidants, which prolong the half-life of EDNO, such as vitamins A, C and E; cysteine, glutathione or plant-based antioxidants; or other factors which may enhance EDNO synthesis or activity, including folic acid; biopterins, such as tetrahydrobiopterin, methyltetrahydrobiopterin, sepiapterin; B complex vitamins, specifically, B6 and B12, flavonoids, e.g. resveratrol, and carotenoids, e.g. lycopene, phytoestrogens, where these agents may be used individually or in combination, generally not more than about 5 of the members being used in combination, more usually not more than about 3. In addition, agents which may improve skeletal muscle metabolism may be employed, including L-camitine (0-500 mg), L-creatine (0-20 g) and L-taurine (0-8 g).