Characterisation of the endothelin receptor mediating contraction of human pulmonary artery using BQ123 and Ro...

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.