title: Endothelin-1 increases cholinergic nerve-mediated contraction of human bronchi via tachykinin synthesis induction.
abstract: 1. In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse trachea and in human isolated airway preparations. 2. We investigated the role of secondary mediators in ET-1 induced potentiation of cholinergic nerve-mediated contraction in human bronchi, in particular the possible role of neuropeptides in this phenomenon. 3. Bronchial tissues after endothelin treatment were exposed to a standard electrical field stimulation (EFS) (30% of EFS 30 Hz)-induced contraction. In addition, in some experiments, preparations were treated with a tachykinin NK(2) receptor antagonist and subsequently exposed to the same protocol. HPLC and RIA were performed on organ bath fluid samples. Moreover, the human bronchi were used for the beta-PPT (preprotachykinin) mRNA extraction and semiquantitative reverse transcription polymerase chain reaction (RT - PCR), prior to and 30-40 min following ET-1 challenge. 4. The selective tachykinin NK(2) receptor antagonist, SR48968, was effective to reduce ET-1 potentiation of EFS mediated contraction. HPLC or RIA showed significant increased quantities of NKA in organ bath effluents after EFS stimulation in bronchi pretreated with ET-1. Finally, beta-PPT mRNA level after stimulation of bronchi with ET-1 was increased about 2 fold respect to control untreated bronchi. 5. In conclusion, this study demonstrated that, at least in part, the ET-1 potentiation of cholinergic nerve-mediated contraction is mediated by tachykinin release, suggesting that in addition to nerves, several type of cells, such as airway smooth muscle cell, may participate to neuropeptide production.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology 'Leonardo Donatelli' Faculty of Medicine and Surgery, 2nd University of Naples, Italy. bruno.dagostino@unina2.it
authors.forename: B
authors.initials: B
authors.lastname: D'Agostino
authors.forename: C
authors.initials: C
authors.lastname: Advenier
authors.forename: M
authors.initials: M
authors.lastname: Falciani
authors.forename: L
authors.initials: L
authors.lastname: Gallelli
authors.forename: G
authors.initials: G
authors.lastname: Marrocco
authors.forename: E
authors.initials: E
authors.lastname: Piegari
authors.forename: A
authors.initials: A
authors.lastname: Filippelli
authors.forename: F
authors.initials: F
authors.lastname: Rossi
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002799:Cholinergic Fibers / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D015288:Neurokinin A / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000378:metabolism; D015320:Tachykinins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001549:Benzamides; D019332:Endothelin-1; D010880:Piperidines; D011498:Protein Precursors; D012333:RNA, Messenger; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; D014665:Vasodilator Agents; C044206:preprotachykinin; D013373:Substance P; C073839:SR 48968; D015288:Neurokinin A; D000109:Acetylcholine