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 asthm a was used to test the effects of antiendothelin (ET) serum and select ive ET receptor antagonists for antigen-induced specific airway conduc tance 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 ef fects, 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 bot h the immediate and late asthmatic responses. The ET(B) selective anta gonists, BQ788 and RES701-1,blocked the immediate asthmatic response b ut not the late asthmatic response, whereas the ET(A) antagonists, BQ1 23 and (Shionogi) 97-139, suppressed only the late asthmatic response without influencing the immediate asthmatic response. In vitro constri ctive responses of isolated tracheas and bronchi to ET1 were inhibited mainly by BQ123 and BQ788, respectively, which suggested that distrib ution of ET(A), and ET(B) receptors for bronchoconstriction are topogr aphically distinct along airways. Furthermore, thromboxane A(2) and pl atelet activating factor (PAF) antagonists were effective in suppressi ng the late asthmatic response but not the immediate asthmatic respons e. Taken together, our present observations suggest that ET(s) influen ces pulmonary functions by constricting airway smooth muscle via ET(B) receptors during the immediate asthmatic response and by modulating p ulmonary inflammation via ET(A) receptors during the late asthmatic re sponse, respectively.