title: Mast cell degranulation mediates bronchoconstriction via serotonin and not via renin release.
abstract: To verify the recently proposed concept that mast cell-derived renin facilitates angiotensin II-induced bronchoconstriction bronchial rings from male Sprague-Dawley rats were mounted in Mulvany myographs, and exposed to the mast cell degranulator compound 48/80 (300 microg/ml), angiotensin I, angiotensin II, bradykinin or serotonin (5-hydroxytryptamine, 5-HT), in the absence or presence of the renin inhibitor aliskiren (10 micromol/l), the ACE inhibitor captopril (10 micromol/l), the angiotensin II type 1 (AT1) receptor blocker irbesartan (1 micromol/l), the mast cell stabilizer cromolyn (0.3 mmol/l), the 5-HT2A/2C receptor antagonist ketanserin (0.1 micromol/l) or the alpha1-adrenoceptor antagonist phentolamine (1 micromol/l). Bath fluid was collected to verify angiotensin generation. Bronchial tissue was homogenized to determine renin, angiotensinogen and serotonin content. Compound 48/80 contracted bronchi to 24+/-4% of the KCl-induced contraction. Ketanserin fully abolished this effect, while cromolyn reduced the contraction to 16+/-5%. Aliskiren, captopril, irbesartan and phentolamine did not affect this response, and the angiotensin I and II levels in the bath fluid after 48/80 exposure were below the detection limit. Angiotensin I and II equipotently contracted bronchi. Captopril shifted the angiotensin I curve approximately 10-fold to the right, whereas irbesartan fully blocked the effect of angiotensin II. Bradykinin-induced constriction was shifted approximately 100-fold to the left with captopril. Serotonin contracted bronchi, and ketanserin fully blocked this effect. Finally, bronchial tissue contained serotonin at micromolar levels, whereas renin and angiotensinogen were undetectable in this preparation. In conclusion, mast cell degranulation results in serotonin-induced bronchoconstriction, and is unlikely to involve renin-induced angiotensin generation.
authors.affiliation: Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Manne
authors.initials: M
authors.lastname: Krop
authors.forename: Zeynep G
authors.initials: ZG
authors.lastname: Ozünal
authors.forename: Wenxia
authors.initials: W
authors.lastname: Chai
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.forename: Durk
authors.initials: D
authors.lastname: Fekkes
authors.forename: Angelique M
authors.initials: AM
authors.lastname: Bouhuizen
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000577:Amides / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology; D066298:In Vitro Techniques; D000077405:Irbesartan; D008297:Male; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016210:Methacholine Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000808:Angiotensinogen; D001713:Biphenyl Compounds; D002216:Captopril; D005650:Fumarates; D000077405:Irbesartan; D016210:Methacholine Chloride; D012083:Renin; D012701:Serotonin; D013777:Tetrazoles; D003189:p-Methoxy-N-methylphenethylamine; D000092502:Renin Inhibitors; C446481:aliskiren