Involvement of endothelins in immediate and late asthmatic responses of guinea pigs.
To explore the pathophysiological roles of endothelin isopeptides and receptor subtypes in asthmatic responses, a guinea pig model for asthma was used to test the effects of antiendothelin (ET) serum and selective ET receptor antagonists for antigen-induced specific airway conductance changes as measured by whole-body plethysmography. In this model, all of the animals so far tested demonstrated both the immediate and late asthmatic responses. Although preimmune serum had no apparent effects, anti-ET antiserum suppressed the maximal reduction of specific airway conductance in both the immediate and late asthmatic responses, which suggested that ET(s) are involved in the pathophysiology of both the immediate and late asthmatic responses. The ETB selective antagonists, BQ788 and RES701-1, blocked the immediate asthmatic response but not the late asthmatic response, whereas the ETA antagonists, BQ123 and (Shionogi) 97-139, suppressed only the late asthmatic response without influencing the immediate asthmatic response. In vitro constrictive responses of isolated tracheas and bronchi to ET1 were inhibited mainly by BQ123 and BQ788, respectively, which suggested that distribution of ETA and ETB receptors for bronchoconstriction are topographically distinct along airways. Furthermore, thromboxane A2 and platelet activating factor (PAF) antagonists were effective in suppressing the late asthmatic response but not the immediate asthmatic response. Taken together, our present observations suggest that ET(s) influences pulmonary functions by constricting airway smooth muscle via ETB receptors during the immediate asthmatic response and by modulating pulmonary inflammation via ETA receptors during the late asthmatic response, respectively.
Uchida
Y
Y
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA.
Jun
T
T
Ninomiya
H
H
Ohse
H
H
Hasegawa
S
S
Nomura
A
A
Sakamoto
T
T
Sardessai
M S
MS
Hirata
F
F
D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D013997:Time Factors; D014132:Trachea / Q000187:drug effects
D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)