Endothelin receptors and activity differ in human, dog and rabbit
lung.
McKay, Karen O., Carol L. Armour, and Judith L. Black.
Departments of Pharmacology and Pharmacy, The University of Sydney,
NSW 2006 AUSTRALIA
APStracts 2:0128L, 1995.
In this study, we have examined dog and rabbit airways as potential
models for human airways in regard to the activity of endothelin. The
receptors involved in the response to endothelin-1 in airway tissue
from human, rabbit and dog lung were investigated, as was the
mechanism responsible for the contraction to endothelin-1 in tissue
from the three species. By using specifc endothelin receptor agonists
and antagonists, we have demonstrated that endothelinB receptors
predominate in rabbit and human airways and endothelinA receptors in
dog airways. The contraction to endothelin-1 is not dependent on
cyclooxygenase products of arachidonic acid, as indomethacin had no
effect on the response to endothelin-1. Extracellular calcium influx
via voltage dependent channels is necessary for contraction to
endothelin-1 in rabbit and dog airways. These results are in contrast
to our previously reported results in human airways, in which neither
removal of extracellular calcium nor verapamil affected the
endothelin-1 response. The sustained phase of the contraction to
endothelin-1 in all three species may be mediated in part by
activation of protein kinase C, as the inhibitor staurosporine
significantly altered the time course of the response to endothelin.
We therefore conclude that in rabbit airways, endothelin-1 activates
endothelinB receptors, triggers the influx of extracellular calcium
through voltage-dependent channels, and induces a contractile
response that is, in part, dependent upon stimulation of protein
kinase C. The same mechanism is triggered in dog bronchus, however,
the receptors involved in this species are of the endothelinA type.
Finally in human airways, the contractile response to endothelin-1,
while independent of extracellular calcium influx, is dependent upon
protein kinase C activation after binding of the peptide to
endothelinB receptors.
Received 20 March 1995; accepted in final form 19 July 1995.
APS Manuscript Number L86-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 14 August 1995.