Dose dependent effects of tadalafil and roflumilast on ovalbumin-induced airway hyperresponsiveness in guinea pigs

ABSTRACT

Introduction: Chronic obstructive diseases of airways associated with cough and/or airway smooth muscle hyperresponsiveness are usually treated with bronchodilating and anti-inflammatory drugs. Recently, selective phosphodiesterase (PDE) 4 inhibitors have been introduced into the therapy of chronic obstructive pulmonary disease. Several studies have demonstrated their ability to influence the airway reactivity and eosinophilic inflammation by increasing the intracellular cAMP concentrations also in bronchial asthma. Furthermore, the expression of PDE5 in several immune cells suggests perspectives of PDE5 inhibitors in the therapy of inflammation, as well. Purpose: The aim of this study was to assess the dose-dependent effects of PDE4 and PDE5 inhibitors in allergic inflammation. Therefore, the effects of 7-days administration of PDE4 inhibitor roflumilast and PDE5 inhibitor tadalafil at two different doses in experimentally-induced allergic inflammation were evaluated. Materials and Methods: In the study, male adult guinea pigs were used. Control group was non-sensitized. Other animals were sensitized with ovalbumin over two weeks and thereafter treated intraperitoneally for 7 days with roflumilast or tadalafil (daily dose 0.5 mg/kg or 1.0 mg/kg b.w.), or with vehicle. Results: Both roflumilast and tadalafil reduced specific airway resistance after nebulization of histamine (marker of in vivo airway reactivity) at both doses used. The in vitro airway reactivity to cumulative doses of acetylcholine was significantly reduced for roflumilast at higher dose, predominantly in the lung tissue strips. Histamine-induced contractile responses were significantly influenced in both lung and tracheal tissue strips, predominantly at the higher doses. Tadalafil led to a decrease in contractile responses induced by both acetylcholine and histamine, with more significant effects in the lung tissue strips. These changes were associated with decreased numbers of circulating leukocytes and eosinophils and concentrations of interleukin (IL)-4, IL-5 and TNF-α in the lung homogenate. Conclusions: The selective PDE4 and PDE5 inhibitors alleviated allergic airway inflammation, with more significant effects at the higher doses.

KEYWORDS:

• Phosphodiesterase
• PDE inhibition
• airways
• bronchial asthma
• hyperresponsiveness
• smooth muscle
• inflammation
• roflumilast
• tadalafil

Acknowledgements

Authors thank to K. Jesenská for technical assistance.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding

This study was supported by VEGA grant 1/0260/14, Slovak Research and Development Agency under the contract number APVV-0305-12 and APVV-16-0030, by Grant UK/74/2017, and by the project „Biomedical Center Martin“, ITMS code: 26220220187, the project is co-financed from EU sources.