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CK Buckner, JS Fedyna, JL Robertson, JA Will, DM England, RD Krell and R Saban
Department of Pharmacology, ICI Pharmaceuticals Group, ICI Americas Inc., Wilmington, Delaware.
The influence of the epithelium on antagonism by ICI 204,219 of contractile responses to peptide leukotriene (LT) agonists was examined in guinea pig tracheal and human bronchial rings. The -log molar KB values for ICI 204,219 were found to be independent of the epithelium in both tissues. Even though uninfluenced by the epithelium, the -log molar KB values for ICI 204,219 were about 10-fold smaller in human airways than in guinea pig trachea. Removal of the epithelium from guinea pig trachea resulted in small leftward shifts of the concentration-response curves to LTC4 and LTD4 and rightward shifts of the concentration-response curves to LTE4 when examined in the presence of indomethacin. The potentiation of LTC4 and LTD4 by epithelium removal was not seen in the presence of inhibitors of the transformation of LTC4 to LTD4 and LTD4 to LTE4. The influence of the epithelium on responses to LTE4 remained in the presence of these metabolic inhibitors. The lipoxygenase inhibitors nordihydroguaiaretic acid, B755C, Rev 5901 and AA861 antagonized responses to LTE4 in the presence, but not in the absence of epithelium. In human airways, epithelium removal resulted in a small leftward shift of the concentration-response curve to LTD4 whereas responses to LTC4 and LTE4 were unaltered. This effect was not observed in the presence of indomethacin, relating it to reduced release of cyclooxygenase products. These data suggest that contractile responses of guinea pig trachea to LTE4 are modulated by LTE4-induced release of 5-lipoxygenase product(s) only when the epithelium is present.(ABSTRACT TRUNCATED AT 250 WORDS)
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