title: Characterisation of the endothelin receptor mediating contraction of human pulmonary artery using BQ123 and Ro 46-2005.
abstract: We have characterised the endothelin receptor mediating contraction of human isolated pulmonary artery. Endothelin-1 induced a concentration-dependent contraction of human endothelium-denuded pulmonary artery (EC50 5.6 nM). In contrast, endothelin-3 produced only a small contraction (approximately 12% of maximum endothelin-1 response) at the highest concentration tested (1 microM). The ETB receptor-selective agonist, sarafotoxin S6c (0.1 nM to 1 microM) did not cause contraction of human pulmonary artery. Pretreatment of human pulmonary artery with BQ123 (1-10 microM), an ETA receptor-selective blocking drug, resulted in a concentration-dependent, surmountable antagonism of endothelin-1-induced contractions (apparent pKB 6.6-7.0). Schild analyses yielded a shallow slope (0.58), which was significantly less than unity and, consequently, the calculated pA2 (8.1) was greater than the individual pKB values. Pretreatment of human pulmonary artery with Ro 46-2005 (30 microM), a non-peptide. non-selective endothelin receptor-blocking drug, resulted in a surmountable antagonism of endothelin-1-induced contractions (apparent pKB 5.5). In conclusion, endothelin-1-induced contraction of human pulmonary artery appears to be mediated predominantly via ETA receptors, although the shallow Schild slope observed with BQ123 indicates possible receptor heterogeneity.
authors.affiliation: Biology Division, Glaxo Research and Development Ltd., Herts, UK.
authors.forename: K W
authors.initials: KW
authors.lastname: Buchan
authors.forename: H
authors.initials: H
authors.lastname: Magnusson
authors.forename: K F
authors.initials: KF
authors.lastname: Rabe
authors.forename: M J
authors.initials: MJ
authors.lastname: Sumner
authors.forename: I S
authors.initials: IS
authors.lastname: Watts
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017466:Receptors, Endothelin / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D011743:Pyrimidines; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C083751:Ro 46-2005; D000096926:Benzenesulfonamides; C072247:cyclo(Trp-Asp-Pro-Val-Leu)