Pre- and postjunctional inhibitory effects of fenspiride on guinea-pig bronchi.
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.
Girard
V
V
Faculté de Médecine Paris-Ouest, Université Paris V, France.
Naline
E
E
Crambes
O
O
Malbezin
M
M
Malmström
R E
RE
Lundberg
J M
JM
Advenier
C
C
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D002211:Capsaicin / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D009412:Nerve Fibers / Q000378:metabolism; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D009479:Neuropeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*; D013373:Substance P / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; D009479:Neuropeptides; D010446:Peptide Fragments; D013141:Spiro Compounds; C061060:neurokinin A (4-10), Nle(10)-; D013373:Substance P; D015288:Neurokinin A; D011433:Propranolol; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; C084775:fenspiride; D007213:Indomethacin