Endothelin receptor subtypes in human and guinea‐pig pulmonary tissues

Abstract

In this study the endothelin (ET) receptor subtypes mediating contractions produced by ET‐1 in human and guinea‐pig pulmonary tissues were investigated. In addition the receptor responsible for ET‐1‐induced prostanoid release in human bronchus was determined. In human bronchus and human pulmonary artery ET‐1 (0.1 nm–0.3 μm) was a potent and effective contractile agent (pD2 = 7.58 ± 0.15, n = 6, and 8.48 ±0.11, n = 7, respectively). BQ‐123 (1–10 μm), a potent and selective ETA receptor antagonist, potently antagonized ET‐1‐induced contraction in human pulmonary artery (pKB = 6.8 with 1 μm BQ‐123, n = 7) but had no effect in human bronchus (n = 6). Sarafotoxin S6c (0.1 nm–0.1 μm), the ETB‐selective agonist, did not contract human pulmonary artery (n = 5), but potently and effectively contracted human bronchus: pD2 = 8.41 ± 0.17, maximum response = 74.4 ± 3.1% of 10 μm carbachol; n = 5. BQ‐123 (1–10 μm) did not antagonize sarafotoxin S6c‐induced contraction in human bronchus (n = 5). ET‐1 potently contracted guinea‐pig trachea, bronchus, pulmonary artery and aorta (pD2 = 8.15 ± 0.14, 7.72 ± 0.12, 8.52 ± 0.12, and 8.18 ± 0.12, respectively, n = 6–14). BQ‐123 (0.1–10 μm) antagonized ET‐1‐induced contractions in guinea‐pig pulmonary artery (pKB = 6.7 with 1 μm BQ‐123, n = 6), aorta (pKB = 7.1 with 1 μm BQ‐123, n = 6) and trachea (pKB = 6.2 with 1 μm BQ‐123, n = 6) but was without marked effect in bronchus (n = 4). In contrast, sarafotoxin S6c (0.1 nm–0.1 μm) did not contract guinea‐pig aorta (n = 4) or guinea‐pig pulmonary artery (n = 6) but potently and effectively contracted guinea‐pig bronchus: pD2 = 8.55 ± 0.1; maximum contraction = 63.6 ± 3.1% of 10 μm carbachol, n = 4. Sarafotoxin S6c (0.1 nm–0.1 μm) was a much less effective agonist in guinea‐pig trachea: maximum contraction = 13.9 ± 2.5% of 10 μm carbachol, n = 4; P < 0.0001, compared to bronchus. Contractions produced by sarafotoxin S6c in guinea‐pig bronchus or trachea were unaffected by BQ‐123 (10 μm, n = 4). Significant differences were observed in the efficacy, relative to carbachol, but not the potency of sarafotoxin S6c in guinea‐pig airways, with a much greater maximum contractile response in bronchus (69.6 ± 2.4% of 10 μm carbachol, n = 6) or lower region of the trachea (48.5 ± 5.9% of 10 μm carbachol, n = 6) than in the middle region of the trachea (14.4 ± 4.0% of 10 μm carbachol, n = 6) or the upper region of the trachea (19.3 ± 2.7% of 10 μm carbachol, n = 6). There were minimal regional differences in either ET‐1‐induced contraction or the potency of BQ‐123 (3 μm) for inhibition of responses to ET‐1 in guinea‐pig airways. Release of various prostanoids in human bronchus induced by ET‐1 (0.3 μm) was essentially abolished with 10 μm BQ‐123. These data provide evidence that distinct ET receptors mediate ET‐1‐induced contraction in human pulmonary artery, guinea‐pig pulmonary artery and guinea‐pig aorta (ETA subtype) compared with human bronchus and guinea‐pig bronchus (non‐ETA, perhaps ETB subtype). Contractions to ET‐1 in guinea‐pig trachea appear to involve both ETA and non‐ETA (ETB?) receptor subtypes. Furthermore, regional differences appear to exist in the relative distribution of ET receptor subtypes in guinea‐pig airways. In human bronchus ET‐1‐induced prostanoid release, unlike the contractile response, appears to be mediated via ETA receptor activation. 1993 British Pharmacological Society