Abstract
Theophylline has been reported to inhibit excitatory noncholinergic but not cholinergic-neurotransmission in guinea-pig bronchi. As theophylline might exert this effect through an inhibition of phosphodiesterases (PDE), and since many types of PDE have now been described, the aim of this study was to investigate the effects of three specific inhibitors of PDE on the electrical field stimulation (EFS) of the guinea-pig isolated main bronchus in vitro. The drugs used were siguazodan, rolipram and zaprinast, which specifically inhibit PDE types, III, IV and V, respectively. Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 ms, 320 mA for 10 s) in the presence of indomethacin 10(-6) M and propranolol 10(-6) M. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. Rolipram (10(-9) to 10(-6) M) but not siguazodan or zaprinast, inhibited the peptidergic contraction in a concentration-dependent manner. Conversely, the cholinergic response was unaffected. Contractile responses induced by exogenous acetylcholine (10(-8) to 10(-3) M) or [Nle10]NKA(4-10) (10(-10) to 10(-6) M) were also unaffected by rolipram, siguazodan and zaprinast (10(-7) M). These results demonstrate that concentrations of rolipram, similar to those which inhibit PDE, reduce the release of sensory neuropeptides from C-fibre endings, and suggest that the cyclic adenosine monophosphate (AMP) PDE type IV is specifically involved in this effect, as in other anti-inflammatory effects.
Highlights
Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 ms, 320 mA for 10 s) in the presence of indomethacin 10-6 M and propranolol 10-6 M
These results demonstrate that concentrations of rolipram, similar to those which inhibit PDE, reduce the release of sensory neuropeptides from C-fibre endings, and suggest that the cyclic adenosine monophosphate (AMP) PDE type IV is involved in this effect, as in other anti-inflammatory effects
At least five distinct phosphodiesterase isoenzymes are present in mammalian airway smooth muscle cells, each having different selectivities and Km values of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate
Summary
Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 ms, 320 mA for 10 s) in the presence of indomethacin 10-6 M and propranolol 10-6 M. Contractile responses induced by exogenous acetylcholine (10-8 to 10-3 M) or [Nle10]NKA(4-10) (10-10 to 10-6 M) were unaffected by rolipram, siguazodan and zaprinast (10-7 M) These results demonstrate that concentrations of rolipram, similar to those which inhibit PDE, reduce the release of sensory neuropeptides from C-fibre endings, and suggest that the cyclic adenosine monophosphate (AMP) PDE type IV is involved in this effect, as in other anti-inflammatory effects. Stimulation of bronchial C-fibres induces bronchoconstriction and inflammation, by means of central reflex pathways and local release of the sensory neuropeptides, substance P, neurokinin A and calcitonin gene-related peptide [1] These peptides cause multiple effects, including contraction of airway smooth muscle, mucus hypersecretion, increase in microvascular permeability, release of inflammatory mediators, and inflammatory cell chemotaxis [2,3,4]. One experimental approach to C-fibre stimulation and control is the study of guinea-pig bronchial reactivity to electrical field stimulation (EFS) in vitro, since EFS causes both a rapid cholinergic and a long-lasting noncholinergic contraction of bronchial smooth muscle, due to release of sensory neuropeptides from C-fibre endings [1, 5,6,7,8]
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