Selective Inhibition of Phosphodiesterase 7 (PDE7) by BRL50481 in Healthy and Ovalbumin-Sensitized Guinea Pigs

Phosphodiesterase (PDE) inhibitors may have significant clinical benefit in respiratory diseases associated with inflammation. The aim was to evaluate effects of selective PDE7 inhibitor (BRL50481) on citric acid induced cough, in vivo and in vitro airway smooth muscle reactivity in both healthy and ovalbumin sensitized guinea pigs, as well as its effectiveness in changes of blood cells count.

Tested drugs were administered intraperitoneally to male guinea pigs once daily for 7 days either vehicle 10% DMSO (dimethyl sulfoxide) 3 ml/kg (as control) or BRL50481 1 mg/kg. Double chamber whole body plethysmograph was used for evaluation of citric acid (0.6 M) induced cough and specific airway resistance. Organ bath method was used for measurement of tracheal and lung tissue strips contractions evoked by cumulative doses (10^-8 - 10^-3 mol/L) of acetylcholine (ACH) and histamine (HIS).

In healthy guinea pigs we did not observe significant effect of tested drug BRL50481 on in vitro contractions (similarly to in vivo conditions). The effect on cough was in healthy animals negligible. In ovalbumin-sensitized animals, more pronounced in vitro relaxing effect of BRL50481 in HIS induced contractions was observed with similar results in vivo and no significant change in number of cough efforts.

Our results suggest that PDE7 inhibitors have stronger anti-inflammatory effect compared to its direct effect on smooth muscle and cough.