Influence of (±)-CP-96,345 and SR 48968 on electrical field stimulation of the isolated guinea-pig main bronchus

Abstract

The aim of this study was to investigate the effects of (±)-CP-96,345 and SR 48968, two new nonpeptide antagonists of neurokinin NK 1 and NK 2 receptors, respectively, on the response of isolated guinea pig main bronchi to electrical field stimulation (EFS). 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. Both responses were abolished by tetrodotoxin (10 −6 M) whereas only the first rapid phase was abolished by atropine (10 −6 M). The late and prolonged second phase was strongly reduced by the ncurokinin A (NK 2) receptor antagonist SR 48968 (10 −11 to 10 −8 M) with an EC 50 of 0.056 nM and a maximal inhibition of 83.3 ± 10.8% (10 −8 M, n = 4). This second response was partially inhibited by the substance P (NK 1) receptors antagonist (±)-CP-96,345 (10 −8 to 10 −6 M). An incubation of 2 h was necessary for SR 48968 to inhibit the EFS-evoked noncholinergic contraction. These results confirm that EFS of guinea-pig bronchi involves stimulation of cholinergic and noncholinergic excitatory nerves and demonstrate that the new developed tachykinin receptors nonpeptide antagonists (±)-CP-96,345 and especially SR 48968 are potent inhibitors of the noncholinergic contraction induced by EFS of the isolated guinea-pig main bronchus.