Prevention by phosphodiesterase inhibitors of antigen-induced contraction of guinea-pig colonic smooth muscle.
1. The ability of various phosphodiesterase (PDE) inhibitors to reduce the initial and/or late response to ovalbumin (OVA) in isolated strips of guinea-pig colonic smooth muscle from sensitized animals was examined. 2. Both the initial and late responses to OVA (0.05 mg ml-1) were inhibited by the non-selective PDE inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX, EC50 = 26.0 and 6.1 microM, respectively), and the selective inhibitors of low Km cyclic AMP specific PDE (PDE IV), (R)- and (S)-rolipram. The (S)-isomer (EC50 = approximately 1.0 microM for both responses) was about 10 fold less potent than the (R)-isomer (EC50 = approximately 0.1 microM for both responses). 3. Zaprinast, a selective inhibitor of the cyclic GMP-specific PDE (PDE V) inhibited only the late response (EC50 = 1.4 microM). 4. SK&F 94120, a selective inhibitor of the cyclic GMP-inhibited low Km cyclic AMP PDE (PDE III), inhibited the initial response (45.9 +/- 11.9%, P < 0.05) at the highest concentration tested (100 microM), and had no effect on the late response. 5. The results suggest that PDE inhibitors, especially PDE IV inhibitors, can attenuate the contractile response of guinea-pig colon to OVA.
Grous
M
M
Department of Inflammation & Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Barnette
M
M
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D000941:Antigens / Q000276:immunology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D007114:Immunization; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010047:Ovalbumin / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram
D000941:Antigens; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011719:Pyrazines; D011760:Pyrrolidinones; C048350:5-(4-acetamidophenyl)pyrazin-2(1H)-one; D010047:Ovalbumin; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine