title: Effects of capsazepine on human small airway responsiveness unravel a novel class of bronchorelaxants.
abstract: Capsazepine is known as a transient receptor potential channel vanilloid subfamily 1 (TRPV(1)) antagonist that inhibits bronchoconstriction evoked in animals by TRPV(1) agonists. In this study, effects of capsazepine and chemically related analogues, so called capsazepinoids, were examined in vitro on contractile effects in human small airway preparations. Repeated cycles with 1h of LTD(4)-free physiological saline solution followed by 30min exposure to LTD(4) (10nM) demonstrated that the contractile responsiveness of the preparations exhibited little change over time despite repeated challenges (>12h). Capsazepine (1-100microM) reversibly and concentration-dependently inhibited the contractile response to LTD(4) with EC(50) approximately 10microM and approximately 90% relaxation at 100microM. Capsazepine (10microM) was approximately equally effective to attenuate the contractions evoked by several different inflammatory contractile agonists (LTD(4), PGD(2), histamine), and it relaxed preparations with established tonic contraction due to LTD(4). Higher concentrations of capsazepine were needed to relax ACh-contractions. The effect of capsazepine on LTD(4)-induced contractions was not significantly reduced by pre-treating the preparations with either of propranolol (10microM)+atropine (1microM), L-NAME (1mM), indomethacin (1microM), iberiotoxin (0.1microM), capsaicin (10microM), and nifedipine (10microM). Although the mechanism of action of the present capsazepine-induced bronchorelaxation remains unknown it emerged here that they represent a generally effective principle exerting a functional antagonism against contractile mediators but distinct from beta receptor agonists and inhibitors of L-type calcium channels. The inhibitory effect of capsazepine is shared by chemical analogues, but not with other TRPV(1) antagonists, suggesting the possibility that capsazepine represents a novel class of bronchorelaxants effective in human small airways. These findings were not predicted by previous observations that have concerned quite limited effects of capsazepine on airway tone in different animal test systems. If potency can be further increased and the results translated to in vivo, compounds representing the capsazepinoid class of bronchorelaxants might become useful in the treatment of patients suffering from asthma and COPD.
authors.affiliation: Respiratorius AB, Magistratsvägen 10, SE-226 43 Lund, Sweden. staffan.skogvall@respiratorius.se
authors.forename: Staffan
authors.initials: S
authors.lastname: Skogvall
authors.forename: Magnus
authors.initials: M
authors.lastname: Berglund
authors.forename: María F
authors.initials: MF
authors.lastname: Dalence-Guzmán
authors.forename: Katrin
authors.initials: K
authors.lastname: Svensson
authors.forename: Per
authors.initials: P
authors.lastname: Jönsson
authors.forename: Carl G A
authors.initials: CG
authors.lastname: Persson
authors.forename: Olov
authors.initials: O
authors.lastname: Sterner
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D001993:Bronchodilator Agents / Q000737:chemistry / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors; D011433:Propranolol / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D001993:Bronchodilator Agents; D018678:Cholinergic Agents; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D050916:TRPV Cation Channels; D014665:Vasodilator Agents; D017998:Leukotriene D4; C064719:iberiotoxin; D001285:Atropine; D006632:Histamine; D011433:Propranolol; D009543:Nifedipine; C071423:capsazepine; D000109:Acetylcholine; D015230:Prostaglandin D2; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin