Abstract
Phosphodiesterases (PDEs) are enzymes responsible for degradation of cAMP and cGMP in cells. Thus, PDE inhibitors may have significant clinical benefit in respiratory diseases associated with inflammation. The aim of the present study was to evaluate the effects of selective PDE4 (rolipram, ROL) and PDE7 inhibitors (BRL50481, BRL) on citric acid-induced cough, in vivo and in vitro airway smooth muscle reactivity in both healthy and ovalbumin sensitized guinea pigs. The drugs tested were administered intraperitoneally to male guinea pigs once daily for 7 days – ROL 1 mg/kg, BRL 1 mg/kg, and ROL+BRL 0.5 mg/kg. Double chamber whole body plethysmography was used for the evaluation of citric acid (0.6 M)-induced cough and specific airway resistance. An organ bath method was used for the measurement of tracheal and lung tissue strip contractions evoked by cumulative doses (10−8–10−3 mol/L) of acetylcholine (ACH) and histamine (HIS). In healthy guinea pigs, the only significant relaxation was observed after ROL in ACH-induced contractions in vitro and the effect on cough was negligible. In ovalbumin-sensitized animals, more pronounced in vitro relaxing effects of BRL in HIS-induced contractions and of combination (ROL+BRL) in ACH-induced contractions were observed, with similar results in vivo, and no significant change in the number of cough efforts was observed in any of the groups tested. The results suggest that PDE4 and PDE7 inhibitors have stronger anti-inflammatory effects compared with direct effects on smooth muscle and cough, with a potential benefit of their concomitant administration.
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References
Antoniu, S. A. (2006). Roflumilast for the treatment of chronic obstructive pulmonary disease. Current Opinion in Investigational Drugs, 7, 412–417.
Beeh, K. M., Beier, J., Lerch, C., Schulz, A. K., & Buhl, R. (2004). Effects of piclamilast, a selective phosphodiesterase-4 inhibitor, on oxidative burst of sputum cells from mild asthmatics and stable COPD patients. Lung, 182, 369–377.
Bender, A. T., & Beavo, J. A. (2006). Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacological Reviews, 58, 488–520.
Chung, K. F. (2006). Phosphodiesterase inhibitors in airways disease. European Journal of Pharmacology, 533, 110–117.
Fabbri, L. M., Beghe, B., Yasothan, U., & Kirkpatrick, P. (2010). Roflumilast. Nature Reviews. Drug Discovery, 9, 761–762.
Franova, S., Nosalova, G., Pechanova, O., & Sutovska, M. (2007). Red wine polyphenolic compounds inhibit tracheal smooth muscle contraction during allergen-induced hyperreactivity of the airways. Journal of Pharmacy and Pharmacology, 59, 727–732.
Giembycz, M. A. (2005a). Life after PDE4: Overcoming adverse events with dual-specificity phosphodiesterase inhibitors. Current Opinion in Pharmacology, 5, 238–244.
Giembycz, M. A. (2005b). Phosphodiesterase-4: Selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society, 2, 326–333.
Giembycz, M. A., & Field, S. K. (2010). Roflumilast: First phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Design, Development and Therapy, 4, 147–158.
Karish, S. B., & Gagnon, J. M. (2006). The potential role of roflumilast: The new phosphodiesterase-4 inhibitor. The Annals of Pharmacotherapy, 40, 1096–1104.
Lipworth, B. J. (2005). Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet, 365, 167–175.
Mokra, D., & Mokry, J. (2010). Meconium aspiration syndrome. From pathomechanisms to treatment (1st ed., p. 130). New York: Nova Science Publishers.
Mokry, J., & Nosalova, G. (2007). Evaluation of the cough reflex and airway reactivity in toluene- and ovalbumin-induced airway hyperresponsiveness. Journal of Physiology and Pharmacology, 58(Suppl 5), 419–426.
Mokry, J., Mokra, D., Nosalova, G., Beharkova, M., & Feherova, Z. (2008). Influence of selective inhibitors of phosphodiesterase 3 and 4 on cough and airway reactivity. Journal of Physiology and Pharmacology, 59(Suppl. 6), 473–482.
Mokry, J., Nosalova, G., & Mokra, D. (2009). Influence of xanthine derivatives on cough and airway reactivity in guinea pigs. Journal of Physiology and Pharmacology, 60(Suppl 5), 87–91.
Nosalova, G., & Mokry, J. (2001). The mechanism of action of xanthine derivatives and suppression of cough. Acta Medica Martiniana, 1, 14–18.
Rabe, K. F., Bateman, E. D., O’Donnel, D., Witte, S., Bredenbroker, D., & Bethke, T. D. (2005). Roflumilast: An oral anti-inflammatory treatment for chronic obstructive pulmonary disease: A randomised controlled trial. Lancet, 366, 563–571.
Smith, S. J., Cieslinski, L. B., Newton, R., Donnelly, L. E., Fenwick, P. S., Nicholson, A. G., Barnes, P. J., Barnette, M. S., & Giembycz, M. A. (2004). Discovery of BRL 50481 [3-(N, N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: In vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Molecular Pharmacology, 66, 1679–1689.
Spina, D., Landells, L. J., & Page, C. P. (1998). The role of theophylline and phosphodiesterase4 isoenzyme inhibitors as antiinflammatory drugs. Clinical and Experimental Allergy, 28(Suppl 3), 24–34.
Strapkova, A., Nosalova, G., Banovcin, P., & Giacova, D. (1995). Changes in airway smooth muscle reactivity after exposure to toluene. Studia Pneumologica et Phthiseologica, 55, 263–271.
Sutovska, M., Franova, S., & Sutovsky, J. (2009). The influence of animal species on the relationship between ATP-sensitive potassium ion channels and defense reflexes of the airways. Bratislava Medical Journal, 110(5), 269–275.
Usmani, O. S., Belvisi, M. G., Patel, H. J., Crispino, N., Birrell, M. A., Korbonits, M., Korbonits, D., & Barnes, P. J. (2005). Theobromine inhibits sensory nerve activation and cough. The FASEB Journal, 19, 231–233.
Acknowledgments
Authors thank to M. Duchonova, M. Kocmalova, and M. Repcakova for technical assistance. Supported by VEGA grant 1/0030/11 and by the Center of Experimental and Clinical Respirology II – ‘Project co-financed from EU sources’.
Conflicts of interest: The authors declare no conflicts of interest in relation to this article.
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Mokry, J., Joskova, M., Mokra, D., Christensen, I., Nosalova, G. (2013). Effects of Selective Inhibition of PDE4 and PDE7 on Airway Reactivity and Cough in Healthy and Ovalbumin-Sensitized Guinea Pigs. In: Pokorski, M. (eds) Respiratory Regulation - The Molecular Approach. Advances in Experimental Medicine and Biology, vol 756. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4549-0_8
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