Salbutamol potentiates the relaxant effects of selective phosphodiesterase inhibitors on guinea pig isolated trachea.

Abstract

The ability of low concentrations of salbutamol to potentiate the relaxant effects of the phosphodiesterase (PDE) inhibitors, rolipram, Ro 20-1724 (PDE type IV inhibitor), siguazodan and milrinone (PDE type III inhibitor) was studied on guinea pig isolated trachea. These PDE inhibitors were strong relaxants of guinea pig trachealis under basal tone, but had only a weak activity on tissues precontracted with histamine (10(-5) M). In both cases, PDE type IV inhibitors showed a relaxant effect composed of two phases. The first phase represented 20 and 40% and the second, 90 and 140%, respectively, of relaxation of basal tone and histamine-induced tone. A second characteristic of PDE type IV inhibitors was the very fast and partially reversible relaxation observed at concentrations greater than 3 x 10(-8) M (for histamine-induced tone) at the first addition of inhibitor, followed by a residual relaxant activity. The latter relaxant effect was stable at concentrations of 3 x 10(-8)-10(-5) M and was equivalent to a 20% relaxation (for histamine-induced tone). In the presence of low concentrations (10(-9) and 10(-8) M) of salbutamol, there was a significant concentration-dependent potentiation of the effects of PDE inhibitors on trachea precontracted with histamine. Salbutamol, at a concentration of 10(-9) M, potentiated the effects of PDE inhibitors between 1.4- and 3.6-fold. In the presence of salbutamol 10(-8) M, the potentiation was more marked for siguazodan (37.9-fold), milrinone (11.0-fold) and Ro 20-1724 (14.5-fold) than for rolipram (4.3-fold). These results suggest that low concentrations of salbutamol can potentiate the relaxant effects of both PDE type III and PDE type IV inhibitors. Thus, PDE type IV inhibitors, which have antiinflammatory properties, could also provide adequate bronchodilation when used in combination with lower than usual doses of beta 2-agonists.