Description:
Sensory mechanisms play an important role in the vagal regulation of tracheobronchial smooth muscle tone. We examined the effect of KW‐4679, an anti‐allergic drug, on guinea‐pig tachykinin‐mediated contractile responses induced by electrical field stimulation (EFS) in guinea‐pig bronchial muscles.EFS (8 Hz, 0.5 ms, 15 V, for 15 s) evoked biphasic contractile responses in the guinea‐pig isolated main bronchus in the presence of 5 μm indomethacin. The contractions consisted of a fast phase of an atropine‐sensitive transient contraction and a slow phase of a sustained contraction which was inhibited by a combination of the tachykinin NK1 receptor antagonist, (±)‐CP‐96,345 (1 μm) and the NK2 receptor antagonist, SR 48968 (0.1 μm).KW‐4679 preferentially inhibited the slow phase in a concentration‐dependent manner by 43.2 ± 7.7% at 10 μm, whereas the drug had no effect on the fast phase at concentrations up to 10 μm. KW‐4679, at a concentration of 100 μm, inhibited not only the slow phase by 49.2 ± 11.4%, but also the fast phase by 36.8 ± 9.3%.KW‐4679 (10 μm and 100 μm) did not affect the substance P‐induced or neurokinin A‐induced contraction. Against the acetylcholine‐induced contractile responses, 100 μm KW‐4679 had a marked effect producing a 10.2 fold shift to the right in the curve.The inhibitory effect of KW‐4679 (10 μm) on the slow phase contraction was not influenced by treatment with naloxone (100 nM), propranolol (1 μm), thioperamide (1 μm), saclofen (50 μm), yohimbine (1 μm), methiothepin (1 μm) or methysergide (1 μm).The inhibitory effect of KW‐4679 (10 μm) on the slow phase contraction was not influenced by treatment with intermediate or large conductance Ca2+‐activated K+ channel blockers (charybdotoxin (10 nM) or iberiotoxin (10 nM)), but suppressed by treatment with small conductance Ca2+‐activated K+ channel blockers, apamin (500 nM) or scyllatoxin (300 nM). Apamin or scyllatoxin per se did not influence the slow phase contractions.The results suggest that KW‐4679 preferentially inhibits the release of tachykinins from the bronchial sensory nerves through activation of small conductance Ca2+‐activated K+ channels.