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Regulation by phosphodiesterase isoenzymes of non‐adrenergic non‐cholinergic contraction in guinea‐pig isolated main bronchus

1995; Wiley; Volume: 116; Issue: 4 Linguagem: Inglês

10.1111/j.1476-5381.1995.tb15074.x

1476-5381

Domenico Spina, S. Harrison, Clive P. Page,

Nitric Oxide and Endothelin Effects

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. 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 μ m ), the non‐selective, β‐adrenoceptor antagonist, propranolol (1 μ m ), the neutral endopeptidase inhibitor, thiorphan (10 μ m ) and the cyclooxygenase inhibitor, indomethacin (5 PM). 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 IC 50 (95% confidence limits) value for SKF 94836, benzafentrine, Ro‐20–1724 and zaprinast was 8.3 μ m (0.89‐78); 0.7, μ m (0.1–4.5); 0.5 μ m (0.2‐1.2) and 13 μ m (2–87) respectively. 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 IC 50 value of 1.9 μ m (0.9‐3.8). The phosphodiesterase isoenzyme inhibitor, Ro‐20–1724 (0.1–100 μ m ) failed to reduce significantly the contractile potency of capsaicin (P>0.05). In contrast, SKF 94836 (1 μ m ), benzafentrine (10 μ m ) and zaprinast (100 μ m ) significantly reduced the contractile potency of capsaicin (P<0.05). The selective phosphodiesterase isoenzyme inhibitors, SKF 94836, benzafentrine, Ro‐20–1724 and zaprinast (0.01–100 μ m ) reversed in a concentration‐dependent manner the contractile response to exogenously administered capsaicin (EC 50 ) yielding IC 50 values of 3.91 μ m (0.68‐22); 3.37 μ m (1.86‐6.11); 0.366 μ m (0.201‐0.564) and 50.1, μ m (18.6–135) respectively. In conclusion, phosphodiesterase isoenzymes appear to regulate the contractile response to electrical field stimulation and our results provide circumstantial evidence for a regulatory role of phosphodiesterase type IV isoenzyme on sensory nerve function in vitro .