KW-4679-INDUCED INHIBITION OF TACHYKININERGIC CONTRACTION IN THE GUINEA-PIG BRONCHI BY PREJUNCTIONAL INHIBITION OF PERIPHERAL SENSORY NERVES

1 Sensory mechanisms play an important role in the vagal regulation of tracheobronchial smooth muscle tone. We examined the effect of KW-467 9, an anti-allergic drug, on guinea-pig tachykinin-mediated contractil e responses induced by electrical field stimulation (EFS) in guinea-pi g bronchial muscles. 2 EFS (8 Hz, 0.5 ms, 15 V, for 15 s) evoked bipha sic contractile responses in the guinea-pig isolated main bronchus in the presence of 5 mu M indomethacin. The contractions consisted of a f ast phase of an atropine-sensitive transient contraction and a slow ph ase of a sustained contraction which was inhibited by a combination of the tachykinin NK1 receptor antagonist, (+/-)-CP-96,345 (1 mu M) and the NK2 receptor antagonist, SR 48969 (0.1 mu M). 3 KW-4679 preferenti ally inhibited the slow phase in a concentration-dependent manner by 4 3.2+/-7.7% at 10 mu M whereas the drug had no effect on the fast phase at concentrations up to 10 mu M. KW-4679, at a concentration of 100 m u M, inhibited not only the slow phase by 49.2+/-11.4%, but also the f ast phase by 36.8+/-8.4%. 4 KW-4679 (10 mu M and 100 mu M) did not aff ect the substance P-induced or neurokinin A-induced contraction. Again st the acetylcholine-induced contractile responses, 100 mu M KW-4679 h ad a marked effect producing a 10.2 fold shift to the right in the cur ve. 5 The inhibitory effect of KW-4679 (10 mu M) on the slow phase con traction was not influenced by treatment with naloxone (100 nM), propr anolol (1 mu M), thioperamide (1 mu M), saclofen (50 mu M), yohimbine (1 mu M), methiothepin (1 mu M) or methysergide (1 mu M). 6 The inhibi tory effect of KW-4679 (10 mu M) on the slow phase contraction was not influenced by treatment with intermediate or large conductance Ca2+-a ctivated K+ channel blockers (charybdotoxin (10 nM) or iberiotoxin (10 nM)), but suppressed by treatment with small conductance Ca2+-activat ed K+ channel blockers, apamin (500 nM) or scyllatoxin (300 nM). Apami n or scyllatoxin per se did not influence the slow phase contractions. 7 The results suggest that KW-4679 preferentially inhibits the releas e of tachykinins from the bronchial sensory nerves through activation of small conductance Ca2+-activated K+ channels.