Interaction between prostaglandins and selective phosphodiesterase inhibitors in isolated guinea-pig trachea in vitro

The possible interaction between spontaneously synthesized relaxant prostaglandins and the relaxation produced by three different isoenzyme-selective phosphodiesterase inhibitors was investigated in the isolated guinea-pig trachea in vitro. The relaxant action of siguazodan (phosphodiesterase III inhibitor), rolipram (phosphodiesterase TV inhibitor) and zaprinast (phosphodiesterase V inhibitor) was investigated in preparations with either spontaneously tone alone or in preparations with spontaneous tone and additionally stimulated with histamine (1 mu M) In addition, relaxant effects were assessed in preparations without spontaneous tone (inhibited by indomethacin 2 mu M) and precontracted with histamine (1 mu M) or prostaglandin F-2 alpha (10 mu M), either alone or in the presence of a non-relaxant concentration (20 nM) of prostaglandin E-2. All three phosphodiesterase inhibitors preferentially relaxed preparations with spontaneous tone and showed increased relaxant effects in preparations with spontaneous tone and additionally stimulated with histamine compared to preparations contracted by histamine alone. This enhanced relaxing effect observed in the presence of initial spontaneous tone was mimicked by exogenous application of prostaglandin E-2 to indomethacin treated preparations either precontracted by histamine or prostaglandin F-2 alpha Furthermore, the study revealed marked differences in the relaxant profiles of siguazodan, rolipram and zaprinast, differences which most likely are related to the functional importance of the phosphodiesterase isoenzymes inhibited by these drugs. It is concluded that endogenously synthesized relaxant prostaglandins and exogenously applied prostaglandin E-2 are capable of enhancing the relaxant action of the phosphodiesterase inhibitors siguazodan, rolipram and zaprinast and that cyclooxygenase inhibition is an important way to avoid this interaction in experimental studies of airway smooth muscle relaxants in isolated guinea-pig trachea in vitro. (C) 1997 Elsevier Science B.V.