Regulation by phosphodiesterase isoenzymes of non-adrenergic non-cholinergic contraction in guinea-pig isolated main bronchus.
1. We have investigated the role of phosphodiesterase isoenzymes in modulating electric field stimulation (EFS), substance P and capsaicin-induced contraction of the guinea-pig isolated main bronchus. 2. Non-adrenergic non-cholinergic contractile responses were elicited by EFS (3 Hz, 20 s) in the guinea-pig isolated main bronchus in the presence of the non-selective muscarinic antagonist, atropine (0.1 microM), the non-selective beta-adrenoceptor antagonist, propranolol (1 microM), the neutral endopeptidase inhibitor, thiorphan (10 microM) and the cyclo-oxygenase inhibitor, indomethacin (5 microM). The type III, type III/IV, type IV and type V phosphodiesterase isoenzyme inhibitor, SKF 94836, benzafentrine, Ro-20-1724 and zaprinast respectively, significantly attenuated the contractile response to EFS. The IC50 (95% confidence limits) value for SKF 94836, benzafentrine, Ro-20-1724 and zaprinast was 8.3 microM (0.89-78); 0.7 microM (0.1-4.5); 0.5 microM (0.2-1.2) and 13 microM (2-87) respectively. 3. The phosphodiesterase isoenzyme inhibitors, SKF 94836, Ro-20-1724 and zaprinast, partially attenuated the contractile response to substance P (10 nM). Benzafentrine significantly inhibited the contractile response to substance P, yielding an IC50 value of 1.9 microM (0.9-3.8). 4. The phosphodiesterase isoenzyme inhibitor, Ro-20-1724 (0.1-100 microM) failed to reduce significantly the contractile potency of capsaicin (P > 0.05). In contrast, SKF 94836 (1 microM), benzafentrine (10 microM) and zaprinast (100 microM) significantly reduced the contractile potency of capsaicin (P < 0.05). 5 The selective phosphodiesterase isoenzyme inhibitors, SKF 94836, benzafentrine, Ro-20-1724 andzaprinast (0.01-100 microM) reversed in a concentration-dependent manner the contractile response toexogenously administered capsaicin (EC50) yielding ICm values of 3.91 microM (0.68-22); 3.37 microM (1.86-6.11); 0.366 microM (0.201-0.564) and 50.1 microM (18.6- 135) respectively.6 In conclusion, phosphodiesterase isoenzymes appear to regulate the contractile response to electricalfield stimulation and our results provide circumstantial evidence for a regulatory role ofphosphodiesterase type IV isoenzyme on sensory nerve function in vitro.
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Sackler Institute of Pulmonary Pharmacology, Department of Thoracic Medicine, King's College School of Medicine and Dentistry, London.
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D000818:Animals; D001341:Autonomic Nervous System / Q000201:enzymology / Q000502:physiology*; D001980:Bronchi / Q000201:enzymology / Q000294:innervation / Q000502:physiology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology
D007527:Isoenzymes; D009479:Neuropeptides; D010726:Phosphodiesterase Inhibitors; D013373:Substance P; D010727:Phosphoric Diester Hydrolases