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 IV 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 microM). In addition, relaxant effects were assessed in preparations without spontaneous tone (inhibited by indomethacin 2 microM) and precontracted with histamine (1 microM) or prostaglandin F2 alpha (10 microM), either alone or in the presence of a non-relaxant concentration (20 nM) of prostaglandin E2. 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 E2 to indomethacin treated preparations either precontracted by histamine or prostaglandin F2 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 E2 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.
Thirstrup
S
S
Institute of Pharmacology, University of Aarhus, Denmark. st@farm.aau.dk
Dahl
R
R
Nielsen-Kudsk
F
F
D000818:Animals; D016861:Cyclooxygenase Inhibitors; D015237:Dinoprost; D015232:Dinoprostone; D004347:Drug Interactions; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine; D066298:In Vitro Techniques; D007213:Indomethacin; D008297:Male; D009119:Muscle Contraction; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010120:Oxytocics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D006146:Guanidines; D010120:Oxytocics; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011724:Pyridazines; D011760:Pyrrolidinones; C056215:siguazodan; D006632:Histamine; D015237:Dinoprost; C011145:zaprinast; D020889:Rolipram; D015232:Dinoprostone; D007213:Indomethacin