Actions of endothelins and sarafotoxin 6c in the rat isolated perfused lung.
1. Endothelin (ET) receptors within the vasculature and airways were studied in a rat perfused lung model in which pulmonary perfusion pressure (PPP), pulmonary inflation pressure (PIP) and lung weight were continuously monitored. 2. The vascular potencies of ETs (ET-1 > ET-2 > ET-3) suggest an action via ETA receptors. This was confirmed by use of the antagonist, BQ123 (2 microM). The vasoconstrictor effects of sarafotoxin 6c (SX6C) also indicated the presence of ETB receptors. 3. Lung weight increases induced by ETs appeared to be a consequence of their vasoconstrictor potencies. The mixed ET receptor antagonist, bosentan (5 microM), markedly attenuated the responses of ET-1 and SX6C on PPP and lung weight, further implicating activation of both ETA and ETB receptors in these responses. 4. Endothelin-1 (ET-1) induced an accumulation of albumin-bound Evans blue dye in orthogradely perfused lungs. Retrograde perfusion attenuated the extravasation and increase in lung weight due to ET-1 but significantly augmented those induced by SX6C. 5. The bronchoconstrictor actions of ETs (ET-1 = ET-2 = ET-3) and SX6C suggest this is an ETB-mediated response. However SX6C was more potent than ETs and the dose-response curve was significantly steeper and achieved a higher maximum. 6. Indomethacin did not affect the vascular or bronchial responses to ET-1 or SX6C. 7. These findings indicate that rat pulmonary vasculature contains both ETA and ETB receptors. Retrograde perfusion suggests that ETB receptors are located arterially whereas ETA receptors are predominantly venous in distribution. Differences in the bronchoconstrictor potency of SX6C (compared to ETs) and the antagonism by bosentan may indicate ETB receptor heterogeneity in the airways.
Lal
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Pharmacology group, School of Pharmacy and Pharmacology, University of Bath, Claverton Down.
Woodward
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B
Williams
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D000818:Animals; D000077300:Bosentan; D016084:Bronchoconstriction / Q000187:drug effects; D004396:Coloring Agents / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D005070:Evans Blue / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D010477:Perfusion; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014757:Viper Venoms / Q000494:pharmacology*
D004396:Coloring Agents; D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D005070:Evans Blue; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D007213:Indomethacin