KW‐4679‐induced inhibition of tachykininergic contraction in the guinea‐pig bronchi by prejunctional inhibition of peripheral sensory nerves

Abstract

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 48969 (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±8.4%. 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.

Inhibitory Effect of Olopatadine Hydrochloride on the Sneezing Response Induced by Intranasal Capsaicin Challenge in Guinea Pigs

“…The antihistaminic action of olopatadine is unlikely to be involved in the inhibition by this drug of the sneeze response, as the conventional antihistamines did not affect the response (Table 1). It is reported that the inhibition by olopatadine of the tachykininergic contraction of isolated guinea pig bronchi was diminished by the SKCa channel inhibitors and not by naloxone (2). These results suggest that olopatadine inhibits the sneezing response by suppressing the tachykinin release presynaptically through the activation of the SKCa channels and not the opioid receptors.…”

“…The previous in vitro study (2) demonstrated that olopatadine, which did not affect the contraction induced by exogenous substance P (SP) or neurokinin A, inhibited the tachykininergic contraction induced by electrical field stimulation (EFS) in guinea pig bronchial muscles without affecting the cholinergic contraction. Moreover, the inhibitory effect of olopatadine on the tachykininergic contraction was suppressed by the small conductance Ca 2+ -activated K + (SKCa) channel blocker, apamin or scyllatoxin.…”

Pharmacological, Pharmacokinetic and Clinical Properties of Olopatadine Hydrochloride, a New Antiallergic Drug

“…Apamin or scyllatoxin per se did not influence the slow phase contraction. These results suggest that olopatadine preferentially inhibits the release of tachykinins from the bronchial sensory nerves through activation of small conductance Ca 2+ -activated K + channel (41). Electrical stimulation of the vagus nerve in atropine-treated and propranolol-treated guinea pigs under anesthetization caused a 38.1% decrease in Cdyn, which was suppressed by the combination of (±)-CP-96,345 and SR 48968.…”

“…The fast phase and slow phase of contraction are mediated by acetylcholine released from parasympathetic nerves and tachykinins released from unmyelinated sensory nerves, respectively (40). Ikemura et al examined the effect of olopatadine on contractile responses induced by EFS in guinea pig bronchial muscles (41). EFS (8 Hz, 0.5 ms, 15 V, for 15 s) evoked biphasic contractile responses in the guinea pig main bronchus in the presence of indomethacin to prevent the formation of contractile prostaglandins.…”

Effect of KW-4679, an Orally Active Anti-allergic Drug, on Antigen-Induced Airway Hyperresponsiveness in Actively Sensitized Guinea Pigs

“…KW-4679 also inhibits the production and/or release of PAF and leukotriene B4 (LTB4) in human neutrophils (8). KW-4679 reduces the electrical field stimulation induced tachykininergic contraction through reduction in the release of transmitters from sensory nerve endings in the isolated guinea pig main bronchus (9). Receptor binding studies have shown this compound to be a hista mine H1-receptor antagonist with a K; value of 16 nM (10).…”