Hostname: page-component-cd9895bd7-gbm5v Total loading time: 0 Render date: 2024-12-24T00:48:41.609Z Has data issue: false hasContentIssue false

Phenylbutazone blocks the cytokine response following a high-intensity incremental exercise challenge in horses

Published online by Cambridge University Press:  07 January 2011

Robert A. Lehnhard
Affiliation:
Department of Kinesiology, University of Maine, Orono, ME, USA
Amanda A. Adams
Affiliation:
Department of Veterinary Sciences, University of Kentucky, Maxwell H. Gluck Equine Research Center, Lexington, KY, USA
Alejandra Betancourt
Affiliation:
Department of Veterinary Sciences, University of Kentucky, Maxwell H. Gluck Equine Research Center, Lexington, KY, USA
David W. Horohov
Affiliation:
Department of Veterinary Sciences, University of Kentucky, Maxwell H. Gluck Equine Research Center, Lexington, KY, USA
Nettie R. Liburt
Affiliation:
Equine Science Center, Department of Animal Sciences, Rutgers – the State University of New Jersey, New Brunswick, NJ, USA
Jennifer M. Streltsova
Affiliation:
Equine Science Center, Department of Animal Sciences, Rutgers – the State University of New Jersey, New Brunswick, NJ, USA
William C. Franke
Affiliation:
Center for Advanced Food Technology, Rutgers – the State University of New Jersey, New Brunswick, NJ, USA
Kenneth H. McKeever*
Affiliation:
Equine Science Center, Department of Animal Sciences, Rutgers – the State University of New Jersey, New Brunswick, NJ, USA
*
*Corresponding author: [email protected]
Get access

Abstract

This study tested the hypothesis that phenylbutazone would block the exercise-induced increase in cytokine markers of inflammation in blood. Blood samples were obtained from unfit Standardbred mares (age 10 ± 4 years, ~500 kg) before and after three different trials (standing control (CON), n = 9; exercise with phenylbutazone (EX-bute), n = 9; and exercise with water, n = 9). Comparisons were made for data collected in three trials, one where each horse underwent an incremental exercise test (graded exercise test (GXT)) where they were administered water as a placebo, a GXT following phenylbutazone administration (2 g given orally 2 h before the GXT) or standing parallel control where they stood quietly in stalls. During the GXT, horses ran on a treadmill (1 m s− 1 increases each min until fatigue, 6% grade). Blood samples were obtained 30 min before exercise, immediately after exercise and at 0.5, 1, 2, 4 and 24 h post-GXT or at matched time points during the parallel control trials. Samples were analysed using real-time PCR for measurement of mRNA expression of interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 in samples collected during all three trials, and for IL-1 and IL-10 in samples collected for the CON and EX-bute trials. Data were analysed using ANOVA for repeated measures, and where appropriate, post hoc separation of means utilized the Student–Newman–Keuls test. The null hypothesis was rejected when P < 0.05. There were no changes (P>0.05) in IL-1, IL-6, IFN-γ or TNF-α during CON or following phenylbutazone administration. During the water trial, exercise resulted in significant increases in IFN-γ, IL-1 and TNF-α. It was concluded that high-intensity exercise results in a transient increase in the expression of inflammatory cytokines in blood that is blocked when phenylbutazone is administered to horses.

Type
Research Paper
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Moldoveanu, AI, Shephard, RJ and Shek, PN (2001). The cytokine response to physical activity and training. Sports Medicine 31: 115144.CrossRefGoogle ScholarPubMed
2Pedersen, BK and Hoffman-Goetz, L (2000). Exercise and the immune system: regulation, integration, and adaptation. Physiological Reviews 80: 10551081.CrossRefGoogle ScholarPubMed
3Kimura, H, Suzui, M, Nagao, F and Matsumoto, K (2001). Highly sensitive determination of plasma cytokines by time-resolved fluoroimmunoassay; effect of bicycle exercise on plasma level of interleukin-1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma). Analytical Science 17: 593597.CrossRefGoogle ScholarPubMed
4Ostrowski, K, Rhode, T, Asp, S, Schjerling, P and Pedersen, BK (1999). Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. Journal of Physiology 515: 287291.CrossRefGoogle ScholarPubMed
5Suzuki, K, Nakaju, S, Yamada, M, Totsuka, M, Sato, K and Sugawara, K (2002). Systemic inflammatory response to exhaustive exercise. Cytokine kinetics. Exercise Immunology Reviews 8: 648.Google ScholarPubMed
6Weinstock, C, Konig, D, Harnischmacher, R, Keul, J, Berg, A and Northoff, H (1997). Effect of exhaustive exercise stress on the cytokine response. Medicine and Science in Sport and Exercise 29: 345354.CrossRefGoogle ScholarPubMed
7Adams, AA, Katepalli, MP, Kohler, K, Reedy, SE, Stilz, JP, Vick, MM, et al. (2009). Effect of body condition, body weight and adiposity on inflammatory cytokine responses in old horses. Veterinary Immunology and Immunopathology 127: 286294.CrossRefGoogle ScholarPubMed
8Ainsworth, DM, Appleton, JA, Eicker, SW, Luce, R, Flaminio, MJ and Antczak, DF (2003). The effect of strenuous exercise on mRNA concentrations of interleukin-12, interferon-gamma and interleukin-4 in equine pulmonary and peripheral blood mononuclear cells. Veterinary Immunology and Immunopathology 91: 6171.CrossRefGoogle ScholarPubMed
9Barton, MH, Williamson, L, Jacks, S and Norton, N (2003). Effects on plasma endotoxin and eicosanoid concentrations and serum cytokine activities in horses competing in a 48-, 83-, or 159-km endurance ride under similar terrain and weather conditions. American Journal of Veterinary Research 64: 754761.CrossRefGoogle ScholarPubMed
10Colahan, PT, Kollias-Baker, C, Leutenegger, CM and Jones, JH (2002). Does training affect mRNA transcription for cytokine production in circulating leucocytes? Equine Veterinary Journal Supplement 34: 154158.CrossRefGoogle Scholar
11Donovan, D, Jackson, C, Colahan, P, Norton, N and Hurley, D (2007). Exercise-induced alterations in pro-inflammatory cytokines and prostaglandin F2α in horses. Veterinary Immunology and Immunopathology 118: 263269.CrossRefGoogle ScholarPubMed
12Streltsova, JM, McKeever, KH, Liburt, NR, Manso, HC, Gordon, ME, Horohov, DW, et al. (2006). Effect of orange peel and black tea extracts on markers of performance and cytokine markers of inflammation in horses. Equine and Comparative Exercise Physiology 3: 121130.CrossRefGoogle Scholar
13Liburt, NR, McKeever, KH, Streltsova, JM, Manso, HC, Gordon, ME, Horohov, DW, et al. (2009). Effects of cranberry and ginger on markers of inflammation following acute exercise in horses. Comparative Exercise Physiology 6: 157169.CrossRefGoogle Scholar
14Malm, C (2002). Exercise immunology: a skeletal muscle perspective. Exercise Immunolology Reviews 8: 116167.Google ScholarPubMed
15Elenkov, IJ (2004). Glucocorticoids and the Th1/Th2 balance. Annals of the New York Academy of Science 1024: 138146.CrossRefGoogle ScholarPubMed
16Ijzermans, JNM and Marquet, RL (1989). Interferon-gamma: a review. Immunobiology 179: 456473.CrossRefGoogle ScholarPubMed
17Moyna, NM, Acker, GR, Fulton, JR, Weber, K, Goss, FL, Robertson, RJ, et al. (1996). Lymphocyte function and cytokine production during incremental exercise in active and sedentary males and females. International Journal of Sports Medicine 17: 585591.CrossRefGoogle ScholarPubMed
18Nieman, D, Nehlsen-Cannarella, S, Fagoaga, O, Henson, D, Utter, A, Davis, J, et al. (1998). Influence of mode and carbohydrate on the cytokine response to heavy exertion. Medicine and Science in Sport and Exercise 30: 671678.CrossRefGoogle ScholarPubMed
19Ostrowski, K, Schjerling, P and Pedersen, BK (2000). Physical activity and plasma interleukin-6 in humans-effect of intensity of exercise. European Journal of Applied Physiology 83: 512515.CrossRefGoogle ScholarPubMed
20Pedersen, BK, Steensberg, A and Schjerling, P (2001). Muscle-derived interleukin-6: possible biological effects. Journal of Physiology 536: 329337.CrossRefGoogle ScholarPubMed
21Steensberg, A, Keller, C, Starkie, RL, Osada, T, Febbraio, MA and Pedersen, BK (2002). IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. American Journal of Physiolology 283: E1272E1278.Google ScholarPubMed
22Tobin, T, Chay, S, Kamerling, S, Woods, WE, Weckman, TJ, Blake, JW, et al. (1986). Phenylbutazone in the horse: a review. Journal of Veterinary Pharmacology and Therapeutics 9: 125.CrossRefGoogle ScholarPubMed
23Cho, JY (2007). Immunomodulatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) at the clinically available doses. Archives of Pharmacology Research 30: 6474.CrossRefGoogle ScholarPubMed
24Manohar, M, Goetz, TE, Sullivan, E and Griffin, R (1998). Pulmonary vascular pressures of strenuously exercising Thoroughbred horses after administration of phenylbutazone and frusemide. Equine Veterinary Journal 30: 158162.CrossRefGoogle ScholarPubMed
25Mitten, LA, Hinchcliff, KW and Pate, JL (1996). Phenylbutazone increases right atrial pressure and heart rate of running horses. Journal of Applied Physiology 81: 312317.CrossRefGoogle ScholarPubMed
26Hinchcliff, KW, McKeever, KH and Muir, WW 3rd. (1994). Effect of phenylbutazone on the haemodynamic, acid–base and eicosanoid responses of horses to sustained submaximal exertion. Research in Veterinary Science 56: 352362.CrossRefGoogle ScholarPubMed
27Mills, PC, Ng, JC, Thornton, J, Seawright, AA and Auer, DE (1994). Exercise-induced connective tissue turnover and lipid peroxidation in horses. British Veterinary Journal 150: 5363.CrossRefGoogle ScholarPubMed
28Purohit, RC, Nachreiner, RF, Humburg, JM, Norwood, GL and Beckett, SD (1979). Effect of exercise, phenylbutazone, and furosemide on the plasma renin activity and angiotensin I in horses. American Journal of Veterinary Research 40: 986990.Google ScholarPubMed
29Sullivan, KA, Hill, AE and Haussler, KK (2008). The effects of chiropractic, massage and phenylbutazone on spinal mechanical nociceptive thresholds in horses without clinical signs. Equine Veterinary Journal 40: 420.CrossRefGoogle ScholarPubMed
30Rohde, C, Anderson, DE, Bertone, AL and Weisbrode, SE (2000). Effects of phenylbutazone on bone activity and formation in horses. American Journal of Veterinary Research 61: 537543.CrossRefGoogle Scholar
31Colahan, PT, Bailey, JE, Chou, CC, Johnson, M, Rice, BL, Jones, GL, et al. (2002). Effect of flunixin meglumine on selected physiologic and performance parameters of athletically conditioned Thoroughbred horses subjected to an incremental exercise stress test. Veterinary Therapeutics 3: 3748.Google Scholar
32Keegan, KG, Messer, NT, Reed, SK, Wilson, DA and Kramer, J (2008). Effectiveness of administration of phenylbutazone alone or concurrent administration of phenylbutazone and flunixin meglumine to alleviate lameness in horses. American Journal of Veterinary Research 69: 167173.CrossRefGoogle ScholarPubMed
33Lees, P and Higgins, AJ (1986). Effects of a phenylbutazone paste in ponies: model of acute nonimmune inflammation. American Journal of Veterinary Research 47: 23592363.Google ScholarPubMed
34Beluche, LA, Bertone, AL, Anderson, DE and Rohde, C (2001). Effects of oral administration of phenylbutazone to horses on in vitro articular cartilage metabolism. American Journal of Veterinary Research 62: 19161921.CrossRefGoogle ScholarPubMed
35Breathnach, CC, Sturgill-Wright, T, Stiltner, JL, Adams, AA, Lunn, DP and Horohov, DW (2006). Foals are interferon gamma-deficient at birth. Veterinary Immunology and Immunopathology 112: 199209.CrossRefGoogle ScholarPubMed
36Livak, KJ and Schmittgen, TD (2001). Analysis of relative gene expression data using real-time PCR and the 2(-ΔΔC(T)) method. Methods 25: 402408.CrossRefGoogle Scholar
37Helge, JW, Stallknecht, B, Pedersen, BK, Galbo, H, Kiens, B and Richter, EA (2003). The effect of graded exercise on Il-6 release and glucose uptake in human skeletal muscle. Journal of Physiology 546.1: 299305.CrossRefGoogle Scholar
38Baum, M, Muller-Steinhardt, M, Liesen, H and Kirchner, H (1997). Moderate and exhaustive endurance exercise influences the interferon-gamma levels in whole-blood culture supernatants. European Journal of Applied Physiology and Occupational Physiology 76: 165169.CrossRefGoogle ScholarPubMed
39Haahr, PM, Pedersen, BK, Fomsgaard, A, Tvede, N, Diamant, M, Klarlund, K, et al. (1991). Effect of physical exercise on in vitro production of interleukin-1, interleukin-6, tumor necrosis factor-alpha, interleukin 2 and interferon-gamma. International Journal of Sports Medicine 12: 223227.CrossRefGoogle ScholarPubMed
40Horohov, DW, Keadle, TL, Pourciau, SS, Littlefield-Chabaud, MA, Kamerling, SG, Keowen, ML, et al. (1996). Mechanism of exercise-induced augmentation of lymphokine activated killer (LAK) cell activity in the horse. Veterinary Immunology and Immunopathology 53: 221233.CrossRefGoogle ScholarPubMed
41Horohov, DW, Dimock, A, Guirnalda, P, Folsom, RW, McKeever, KH and Malinowski, K (1999). Effect of exercise on the immune response of young and old horses. American Journal of Veterinary Research 60: 643647.CrossRefGoogle Scholar
42Liao, P, Zhou, J, Ji, LL and Zhang, Y (2010). Eccentric contraction induces inflammatory responses in rat skeletal muscle: role of tumor necrosis factor-alpha. American Journal of Physiolology 298: R599R607.Google ScholarPubMed
43Kasapis, C and Thompson, PD (2005). The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. Journal of the American College of Cardiology 45: 15631569.CrossRefGoogle ScholarPubMed
44Simon, HB (1984). The immunology of exercise. A brief review. Journal of the American Medical Association 252: 27352738.CrossRefGoogle ScholarPubMed
45Meksawan, K, Venkatraman, JT, Awad, AB and Pendergast, DR (2004). Effect of dietary fat intake and exercise on inflammatory mediators of the immune system in sedentary men and women. Journal of the American College of Nutrition 23: 331340.CrossRefGoogle ScholarPubMed
46Peake, J, Nosaka, K and Suzuki, K (2005). Characterization of inflammatory responses to eccentric exercise in humans. Exercise Immunology Reviews 11: 6485.Google ScholarPubMed
47Peterson, JM, Trappe, TA, Mylona, E, White, F, Lambert, CP, Evans, WJ, et al. (2003). Ibuprofen and acetaminophen: effect on muscle inflammation after eccentric exercise. Medicine and Science in Sport and Exercise 35: 892896.CrossRefGoogle ScholarPubMed
48Rhind, SG, Gannon, GA, Shephard, RJ and Shek, PN (2002). Indomethacin modulates circulating cytokine responses to strenuous exercise in humans. Cytokine 19: 153158.CrossRefGoogle ScholarPubMed
49Nieman, DC, Henson, DA, Dumke, CL, Oley, K, McAnulty, SR, Davis, JM, et al. (2006). Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition. Brain Behavior and Immunology 20: 578584.CrossRefGoogle ScholarPubMed
50Dirikolu, L, Woods, WE, Boyles, J, Lehner, AF, Harkins, JD, Fisher, M, et al. (2009). Nonsteroidal anti-inflammatory agents and musculoskeletal injuries in Thoroughbred racehorses in Kentucky. Journal of Veterinary Pharmacology and Therapeutics 32: 271–269.CrossRefGoogle ScholarPubMed
51Dodman, N, Blondeau, N and Marini, AM (2010). Association of phenylbutazone usage with horses bought for slaughter: a public health risk. Food Chemistry and Toxicology 48: 12701274.CrossRefGoogle Scholar
52Barker, SA (2008). Drug contamination of the equine racetrack environment: a preliminary examination. Journal of Veterinary Pharmacology and Therapeutics 31: 466471.CrossRefGoogle ScholarPubMed
53Authie, EC, Garcia, P, Popot, MA, Toutain, PL and Doucet, M (2010). Effect of an endurance-like exercise on the disposition and detection time of phenylbutazone and dexamethasone in the horse: application to medication control. Equine Veterinary Journal 42: 240247.CrossRefGoogle ScholarPubMed
54Beretta, C, Garavaglia, G and Cavalli, M (2005). COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis. Pharmacology Research 52: 302306.CrossRefGoogle ScholarPubMed
55Takada, Y, Bhardwaj, A, Potdar, P and Aggarwal, BB (2004). Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 23: 92479258.CrossRefGoogle ScholarPubMed
56Komatsu, H, Yaju, H, Chiba, K and Okumoto, T (1991). Inhibition by cyclo-oxygenase inhibitors of interleukin-6 production by human peripheral blood mononuclear cells. International Journal of Immunopharmacology 13: 11371146.CrossRefGoogle ScholarPubMed