Interactions between Homocyst(e)ine and Nitric Oxide During Acute Submaximal Exercise in Adult Males[1]

Experimental studies investigating the effects of exercise on plasma total homocyst(e)ine (H[e]) levels in humans are almost non-existent. H(e) has been demonstrated to represent an independent risk factor for cardiovascular disease. The exact mechanism through which H(e) exerts its effects on the arteries is unknown but it is thought to involve nitric oxide (NO). The present study was designed to assess the effects of acute submaximal exercise on H(e) while levels of NO inhalation were manipulated using an air-filter mask. The study was completed by seven male volunteers, aged 21.6 ± 1.3 yr (X¯ ± SD), V˙O₂max: 48.6 ± 7.6 mL × kg⁻¹ × min⁻¹. During two separate occasions the subjects performed a 1-hour bout of submaximal exercise on a stationary cycle ergometer at 60 % of their V˙O₂max. The two trials were completed in random order (with and without mask). Data were collected before (PRE) and after (POST) the acute exercise bouts. Plasma H(e) was directly measured by HPLC and NO by quantifying the enzymatic oxidation to nitrite (NO₂ ⁻) & nitrate (NO₃ ⁻). Mean H(e) concentrations were 10.89 ± 2.05 nmol/mL (PRE) & 11.21 ± 1.81 nmol/mL (POST) and were not significantly altered by submaximal exercise. When wearing a mask, the correlation of the PRE/POST H(e) differences with the PRE/POST differences in NO₃ ⁻ were 0.77 (P = 0.07). No correlation was found between either H(e) and NO₂ ⁻ or between NO₂ ⁻ and NO₃ ⁻. However, a significant correlation (r = − 0.86, P = 0.03) was also observed between H(e) and NO₂ ⁻ but only for the post-exercise values when wearing a mask. The results suggest that: (1) plasma H(e) levels are not affected by acute submaximal exercise; (2) there is insufficient evidence to support the view that plasma H(e) levels are being mediated by NO during either rest or exercise.

Key words:

Amino acids - cardiovascular disease - homocysteine - nitric oxide

01 Presented in part at the 46th Annual Meeting of the American College of Sports Medicine, Seattle, WA, June 2 to 5, 1999 (Session C-32).

References

• 01 Altman J D, Kinn J, Duncker D J. Effect of inhibition of nitric oxide formation on coronary blood flow during exercise in the dog.  Cardiovasc Res. 1994;  28 119-124
• 02 Blundell G, Jones B G, Rose F A. Homocysteine mediated endothelial cell toxicity and its amelioration.  Atherosclerosis. 1996;  122 163-172
• 03 Brattström L, Lindgren A, Israelsson B. Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke factors.  Eur J Clin Invest. 1992;  22 214-221
• 04 Celermajer D S, Sorensen K, Ryalls M. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents.  J Am Coll Cardiol. 1993;  22 854-858
• 05 De Crée C, Malinow M R, Van Kranenburg G, Geurten P, Longford N T, Keizer H A. Influence of exercise and menstrual cycle phase on plasma homocyst(e)ine levels in premenopausal women. - A prospective study.  Scand J Med Sci Sport. 1999;  9 272-278
• 06 de Groot P G, Willems C, Boers G H. Endothelial dysfunction in homocystinuria.  Eur J Clin Invest. 1983;  13 405-410
• 07 Delp M D, Laughlin M H. Regulation of skeletal muscle perfusion during exercise.  Acta Physiol Scand. 1998;  162 411-419
• 08 Dill D B, Costill D L. Calculation of percentage changes in volumes of blood, plasma, and red cells in dehydration.  J Appl Physiol. 1974;  37 247-248
• 09 Franks B D, Huck S W. Why does everyone use the .05 significance level?.  Res Q Exerc Sport. 1986;  57 245-249
• 10 Gallagher P M, Meleady R, Shields D C. Homocysteine and risk of premature coronary disease: evidence for a common gene mutation.  Circulation. 1996;  94 2154-2158
• 11 Harker L A, Slichter S J, Scott C R. Homocystine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis.  J Clin Invest. 1976;  58 731-741
• 12 Honig C R. Contributions of nerves and metabolites to exercise vasodilation: a unifying hypothesis.  Am J Physiol. 1979;  236 719
• 13 Ignarro L, Murad F. Nitric oxide. Biochemistry molecular biology, and therapeutic implications. In: Ignarro, L, Murad, F (eds) Advances in pharmacology series. San Diego, CA; Academic Press, Inc. 1995: 1-516
• 14 Kang S-S, Wong P W, Malinow M R. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease.  Annu Rev Nutr. 1992;  12 279-298
• 15 Koller-Strametz J, Mattulla B, Wolzt M. Role of nitric oxide in exercise-induced vasodilatation in man.  Life Sci. 1998;  62 1035-1042
• 16 Kraus R M. Exercise, lipoproteins, and coronary artery disease.  Circulation. 1989;  79 1143-1145
• 17 Kuo L, Davis M J, Chilian W M. Endothelium-dependent, flow-induced dilation of isolated coronary arterioles.  Am J Physiol. 1988;  259 1324
• 18 Lane N P, Whiting P H, Cole H, De Crée C. The effects of a sports anti-pollution mask on pulmonary function and free radical formation during sub-maximal exercise (Abstract).  Br J Sports Med. 1999;  33 59
• 19 Laughlin M H. Skeletal muscle blood flow capacity: role of muscle pump in exercise hyperemia.  Am J Physiol. 1987;  253 1004
• 20 Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia.  J Clin Invest. 1996;  98 5-7
• 21 Malinow M R. Homocysteine and arterial occlusive diseases.  J Int Med. 1994;  236 603-617
• 22 Malinow M R, Duell P B, Hess D L. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease.  N Engl J Med. 1998;  338 1009-1015
• 23 Malinow M R, Kang S S, Taylor L M. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease.  Circulation. 1989;  79 1180-1188
• 24 Maxwell A J, Schauble E, Bernstein D. Limb blood flow during exercise is dependent on nitric oxide.  Circulation. 1988;  98 369-374
• 25 McAllister R M, Hirai T, Musch T L. Contribution of endothelium-derived nitric oxide (EDNO) to the skeletal muscle blood flow response to exercise.  Med Sci Sport Exerc. 1995;  27 1145-1151
• 26 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56 111-128
• 27 Nygård O, Vollset S E, Refsum H. Total plasma homocysteine and cardiovascular risk profile. The Hordaland homocysteine study.  JAMA. 1995;  274 1526-1533
• 28 Ray J G. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease.  Arch Intern Med. 1998;  158 2101-2106
• 29 Ross R. The pathogenesis of atherosclerosis - An update.  N Engl J Med. 1986;  314 488-500
• 30 Scheuer J, Tipton C M. Cardiovascular adaptations to physical training.  Ann Rev Physiol. 1977;  39 221-251
• 31 Stamler J S, Osborne J A, Jaraki O. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen.  J Clin Invest. 1993;  91 308-318
• 32 Starkebaum G, Harlan J M. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine.  J Clin Invest. 1986;  77 1370-1376
• 33 Stein J H, McBride P E. Hyperhomocysteinemia and atherosclerotic vascular disease.  Arch Intern Med. 1998;  158 1301-1306
• 34 Stefanick M L, Mackey S, Sheehan M. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol.  N Engl J Med. 1998;  339 12-20
• 35 Thune I, Njølstad I, Løchen M-J. Physical activity improves the metabolic risk profiles in men and women.  Arch Intern Med. 1998;  158 1633-1640
• 36 Ueland P M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease, and drug therapy.  J Lab Clin Med. 1989;  114 473-501
• 37 Upchurch G R Jr, Welch G N, Fabian A J. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase.  J Biol Chem. 1997;  272 17012-17017
• 38 Weiss M, Schmid A, Baum M. Influence of extensive exercise on plasma amino acids and plasma homocysteine (Abstract).  Int J Sports Med. 1998;  19 52
• 39 Wild R A. Obesity, lipids, cardiovascular risk, and androgen excess.  Am J Med. 1995;  98 27
• 40 Wilson J R, Kapoor S. Contribution of endothelium-derived relaxing factor to exercise-induced vasodilation in humans.  J Appl Physiol. 1993;  75 2740-2744
• 41 Wright M, Francis K, Cornwell Ph. Effect of acute exercise on plasma homocysteine.  J Sports Med Phys Fitness. 1998;  38 262-265

01 Presented in part at the 46th Annual Meeting of the American College of Sports Medicine, Seattle, WA, June 2 to 5, 1999 (Session C-32).