PMID- 37907918 OWN - NLM STAT- MEDLINE DCOM- 20231102 LR - 20231103 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 24 IP - 1 DP - 2023 Oct 31 TI - Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways. PG - 262 LID - 10.1186/s12931-023-02580-6 [doi] LID - 262 AB - INTRODUCTION: The standard therapy for bronchial asthma consists of combinations of acute (short-acting ss(2)-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ss(2)-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T(H)2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease. METHODS: After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ss(2)-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function. RESULTS: Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1(-/-)) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol. CONCLUSION: Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T(H)2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled. CI - (c) 2023. The Author(s). FAU - Hempel, Paulina AU - Hempel P AD - Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Klein, Virag AU - Klein V AD - Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Michely, Anna AU - Michely A AD - Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Boll, Svenja AU - Boll S AD - Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Rieg, Annette D AU - Rieg AD AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. AD - Department of Anaesthesiology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Spillner, Jan AU - Spillner J AD - Department of Thoracic and Cardiovascular Surgery, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Braunschweig, Till AU - Braunschweig T AD - Institute of Pathology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - von Stillfried, Saskia AU - von Stillfried S AD - Institute of Pathology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Wagner, Norbert AU - Wagner N AD - Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. FAU - Martin, Christian AU - Martin C AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. FAU - Tenbrock, Klaus AU - Tenbrock K AD - Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. FAU - Verjans, Eva AU - Verjans E AD - Department of Pediatrics, Medical Faculty, RWTH Aachen, University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. everjans@ukaachen.de. AD - Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen, University Hospital Aachen, Aachen, Germany. everjans@ukaachen.de. LA - eng PT - Journal Article DEP - 20231031 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0W5ETF9M2K (Methacholine Chloride) RN - 1806D8D52K (Amitriptyline) RN - 820484N8I3 (Histamine) RN - 0 (Bronchodilator Agents) RN - 333DO1RDJY (Serotonin) RN - N9YNS0M02X (Acetylcholine) RN - 0 (Sympathomimetics) RN - TBT296U68M (1-Methyl-3-isobutylxanthine) RN - QF8SVZ843E (Albuterol) RN - 0 (Endothelins) RN - 0 (Thromboxanes) SB - IM MH - Mice MH - Rats MH - Humans MH - Animals MH - Guinea Pigs MH - *Bronchoconstriction MH - Methacholine Chloride/pharmacology MH - Amitriptyline/pharmacology/therapeutic use MH - Histamine/pharmacology MH - Bronchodilator Agents/pharmacology/therapeutic use MH - Serotonin/pharmacology/therapeutic use MH - Acetylcholine/pharmacology MH - Sympathomimetics/pharmacology/therapeutic use MH - 1-Methyl-3-isobutylxanthine/pharmacology/therapeutic use MH - Dilatation MH - Lung MH - *Asthma/drug therapy MH - Albuterol MH - Endothelins/pharmacology/therapeutic use MH - Thromboxanes/pharmacology/therapeutic use PMC - PMC10617234 OTO - NOTNLM OT - Amitriptyline OT - Bronchoconstriction OT - Bronchodilation OT - EFS OT - IPL OT - Inhibition OT - Muscarine receptor OT - PCLS OT - flexiVent COIS- The authors declare that they have no competing interests. EDAT- 2023/11/01 06:43 MHDA- 2023/11/02 12:42 PMCR- 2023/10/31 CRDT- 2023/11/01 01:03 PHST- 2023/08/12 00:00 [received] PHST- 2023/10/25 00:00 [accepted] PHST- 2023/11/02 12:42 [medline] PHST- 2023/11/01 06:43 [pubmed] PHST- 2023/11/01 01:03 [entrez] PHST- 2023/10/31 00:00 [pmc-release] AID - 10.1186/s12931-023-02580-6 [pii] AID - 2580 [pii] AID - 10.1186/s12931-023-02580-6 [doi] PST - epublish SO - Respir Res. 2023 Oct 31;24(1):262. doi: 10.1186/s12931-023-02580-6.