Endothelin receptors and activity differ in human, dog, and rabbit lung.
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 (ET-1) in airway tissue from human, rabbit, and dog lung were investigated, as was the mechanism responsible for the contraction to ET-1 in tissue from the three species. By using specific endothelin receptor agonists and antagonists, we have demonstrated that ETB receptors predominate in rabbit and human airways and ETA receptors in dog airways. The contraction to ET-1 is not dependent on cyclooxygenase products of arachidonic acid, as indomethacin had no effect on the response to ET-1. Extracellular calcium influx via voltage-dependent channels is necessary for contraction to ET-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 ET-1 response. The sustained phase of the contraction to ET-1 in all three species may be mediated in part by activation of protein kinase C (PKC), as the inhibitor staurosporine significantly altered the time course of the response to endothelin. We therefore conclude that in rabbit airways ET-1 activates ETB receptors, triggers the influx of extracellular calcium through voltage-dependent channels, and induces a contractile response that is, in part, dependent upon stimulation of PKC. The same mechanism is triggered in dog bronchus; however, the receptors involved in this species are of the ETA type. Finally, in human airways, the contractile response to ET-1, while independent of extracellular calcium influx, is dependent upon PKC activation after binding of the peptide to ETB receptors.
McKay
K O
KO
Department of Pharmacology, University of Sydney, New South Wales, Australia.
Armour
C L
CL
Black
J L
JL
D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004285:Dogs / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011817:Rabbits / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C075771:BQ 3020; D014700:Verapamil; D019311:Staurosporine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium; D007213:Indomethacin