Effects of Selective Inhibition of PDE4 and PDE7 on Airway Reactivity and Cough in Healthy and Ovalbumin-Sensitized Guinea Pigs
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.
KeywordsCough Airway resistance Ovalbumin Inflammation Acetylcholine Histamine Phosphodiesterase inhibitors Rolipram
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.
- Mokra, D., & Mokry, J. (2010). Meconium aspiration syndrome. From pathomechanisms to treatment (1st ed., p. 130). New York: Nova Science Publishers.Google Scholar
- Nosalova, G., & Mokry, J. (2001). The mechanism of action of xanthine derivatives and suppression of cough. Acta Medica Martiniana, 1, 14–18.Google Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.Google Scholar
- 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.Google Scholar