neurokinin-a and fenspiride

Neural mechanisms contribute to control of mucus secretion in the airways. Fenspiride is a non-steroidal antiinflammatory agent which has a variety of actions, including inhibition of neurogenic bronchoconstriction. The effect of fenspiride on neurally-mediated mucus secretion was investigated in vitro in electrically-stimulated ferret trachea, using(35)SO(4)as a mucus marker. Cholinergic secretory responses were isolated using adrenoceptor and tachykinin receptor antagonists. Tachykinin responses were isolated using cholinoceptor and adrenoceptor antagonists. Electrical stimulation increased cholinergic secretion by;90% and tachykininergic secretion by;40%. Fenspiride (1 microM-1 mM) tended to inhibit cholinergic secretion in a concentration-dependent manner, although only at 1 mM was inhibition (by 87%) significant. Inhibition by fenspiride of tachykininergic secretion was not concentration-dependent, and again significant inhibition (by 85%) was only at 1 mM. Inhibition was not due to loss of tissue viability, as assessed by restitution of secretory response after washout. Fenspiride also inhibited secretion induced by acetylcholine, but did not inhibit substance P-induced secretion. Histamine receptor antagonists increased basal secretion by 164%, whereas fenspiride did not affect basal secretion. We conclude that, in ferret trachea in vitro, fenspiride inhibits neurally-mediated mucus secretion, with antimuscarinic action the most plausible mechanism of action, but not necessarily the only mechanism.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Electric Stimulation; Ferrets; Histamine Antagonists; Male; Mucus; Neurokinin A; Parasympathetic Nervous System; Receptors, Neurokinin-1; Spiro Compounds; Substance P; Sulfates; Sulfur Radioisotopes; Trachea

Fenspiride is a drug with potential benefits in the treatment of obstructive airways disease. It has antibronchoconstriction and anti-inflammatory properties. The aim of this study was to investigate the effect of this drug on the contractions induced in the guinea-pig isolated main bronchus and perfused lung by electrical field stimulation (EFS) or exogenously added agents. Bronchi were stimulated transmurally in the presence of indomethacin 10(-6) M and propranolol 10(-6) M, and isometric tension was measured. In the perfused lung model calcitonin gene-related peptide (CGRP) release was determined in the perfusate fractions as a measure of neuropeptide production. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to local release of neuropeptides from C-fibre endings. Fenspiride (10(-6) to 10(-4) M) inhibited the nonadrenergic, noncholinergic (NANC) component of the contraction of the guinea-pig isolated main bronchus induced by EFS. Fenspiride significantly affected contractions induced by exogenously added substance P or [Nle10]-NKA(4-10) only at concentrations higher than 10(-3) M. In the guinea-pig perfused lung, fenspiride inhibited low pH- but not capsaicin-evoked release of CGRP. At higher concentrations (10(-4) M to 3x10(-4) M) fenspiride exhibited a significant inhibitory effect both on the cholinergic component of contractile response induced by EFS in the guinea-pig isolated main bronchus and on exogenously added acetylcholine. In conclusion, the result of this study suggests that fenspiride, in moderate concentrations, reduces the release of neuropeptides, including tachykinins, from sensory nerve endings at a prejunctional level. At higher concentrations, postjunctional actions on bronchial smooth muscle are also present.

Topics: Adrenergic beta-Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchi; Bronchodilator Agents; Calcitonin Gene-Related Peptide; Capsaicin; Electric Stimulation; Guinea Pigs; In Vitro Techniques; Indomethacin; Lung; Nerve Fibers; Neurokinin A; Neuropeptides; Peptide Fragments; Propranolol; Spiro Compounds; Substance P

Fenspiride is a nonsteroidal anti-inflammatory agent, which we have previously shown to have an in vivo antibronchoconstrictor action in guinea pigs. We have currently studied this action using the constrictors Substance P, neurokinin A, citric acid and capsaicin in anaesthetized guinea-pigs. Fenspiride has also been reported to produce a subjective improvement in cough in patients. We have used a conscious guinea-pig model of cough as a more definitive method to study the effect of fenspiride on capsaicin- and citric acid-induced cough. Aerosolized fenspiride (1 mg.mL-1) caused a 58% reversal of capsaicin-induced bronchoconstriction; and i.v. fenspiride (1mg.kg-1) a 45% reversal of citric acid induced bronchoconstriction. Substance P- and neurokinin A-induced bronchoconstriction were unaffected by 1 mg.kg-1 i.v. fenspiride. Aerosolized fenspiride (1, 3 and 10 mg.mL-1) administered for 4 min reduced citric acid (300 mM) induced cough, but 0.1 mg.mL-1 was without effect. Pretreatment with aerosolized fenspiride (10 mg.mL-1) caused a shift in the citric acid dose response curve to the right. For citric acid-induced cough, the duration of action of aerosolized fenspiride (10 mg.mL-1) was found to be 5 and 15 min post-treatment. Aerosolized capsaicin (30 microM) induced cough was also reduced by 3 and 10 mg.mL-1 aerosolized fenspiride, but no significant effect was found with 1 mg.mL-1. We conclude that aerosolized fenspiride reduces capsaicin- and citric acid-induced bronchoconstriction as well as induced cough in guinea-pigs in vivo. Whether a pathway common to both cough and bronchoconstriction is the site of action of fenspiride remains to be established. We postulate that fenspiride, acting as an antitussive and antibronchoconstrictor agent, would be beneficial in the clinical situation for those patients with hyperresponsive airways.

Topics: Acetates; Acetic Acid; Aerosols; Airway Resistance; Animals; Antitussive Agents; Bronchoconstriction; Bronchodilator Agents; Capsaicin; Cough; Dose-Response Relationship, Drug; Guinea Pigs; Male; Neurokinin A; Spiro Compounds; Substance P