ENDOTHELIN RECEPTORS AND ACTIVITY DIFFER IN HUMAN, DOG, AND RABBIT LUNG

In this study, we have examined dog and rabbit airways as potential mo dels for human airways in regard to the activity of endothelin. The re ceptors involved in the response to endothelin-1 (ET-1) in airway tiss ue from human, rabbit, and dog lung were investigated, as was the mech anism responsible for the contraction to ET-1 in tissue from the three species. By using specific endothelin receptor agonists and antagonis ts, we have demonstrated that ET(B) receptors predominate in rabbit an d human airways and ET(A) 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 contrac tion 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 respo nse. The sustained phase of the contraction to ET-1 in all three speci es 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 airwa ys ET-1 activates ET(B) receptors, triggers the influx of extracellula r calcium through voltage-dependent channels, and induces a contractil e response that is, in part, dependent upon stimulation of PKC. The sa me mechanism is triggered in dog bronchus; however, the receptors invo lved in this species are of the ET(A) 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 ET(B) receptors.