INFLUENCE OF (+/-)-CP-96,345 AND SR-48968 ON ELECTRICAL-FIELD STIMULATION OF THE ISOLATED GUINEA-PIG MAIN BRONCHUS

The aim of this study was to investigate the effects of (+/-)-CP-96,345 and SR 48968, two new nonpeptide antagonists of neurokinin NK1 and NK2 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 neurokinin A (NK2) receptor antagonist SR 48968 (10(-11) to 10(-8) M) with an EC50 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 (NK1) 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.