Comparison of the effects of selective inhibitors of phosphodiesterase types III and IV in airway smooth muscle with differing beta-adrenoceptor subtypes.
1. The relaxant properties of the type IV adenosine 3',5'-cyclic monophosphate phosphodiesterase (cyclic AMP PDE) inhibitor, rolipram and the beta 2-selective and non-selective beta-adrenoceptor agonists salbutamol and isoprenaline, were compared on the guinea-pig, bovine, and mouse trachea and porcine bronchus all precontracted with methacholine (EC30). 2. Rolipram and both beta-agonists produced concentration-dependent reversal of the methacholine-induced tone in the four airway preparations. 3. Isoprenaline and salbutamol were similar in potency on the guinea-pig (-log10IC50:8.43, 8.06) and bovine (-log10 IC50:8.52, 8.40) airways. In contrast, salbutamol was much less potent than isoprenaline on the mouse trachea (> 1000 fold) and the porcine bronchus (> 100,000 fold). 4. The potency of rolipram approached that of isoprenaline on the guinea-pig and bovine trachea (beta 2-adrenoceptors predominate). However, rolipram was significantly less active than isoprenaline on the porcine bronchus (1000 fold) and mouse trachea (> 2000 fold) where beta 2-adrenoceptors predominate. 5. Siguazodan, the type III cyclic AMP PDE inhibitor, produced concentration-dependent relaxations of the porcine bronchus and guinea-pig trachea contracted with methacholine. Siguazodan was 100 fold more active than rolipram in pig tissues indicating the type III isoenzyme may be of greater functional significance in this tissue. In contrast, siguazodan was 15 times less potent that rolipram in guinea-pig airways suggesting a greater role for the type IV PDE. 6. These findings may reflect a possible relationship between the beta 2-adrenoceptor subtype and the functional importance of the type IV PDE isoenzyme. A similar relationship may exist between beta 1-adrenoceptors and the PDE type III isoenzyme.
Tomkinson
A
A
Rhône-Poulenc Rorer Ltd., Dagenham Research Centre, Essex.
Karlsson
J A
JA
Raeburn
D
D
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D006146:Guanidines; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; D016210:Methacholine Chloride; C056215:siguazodan; D020889:Rolipram; D007545:Isoproterenol; D000420:Albuterol