ENDOTHELIN RECEPTOR SUBTYPES IN HUMAN AND GUINEA-PIG PULMONARY TISSUES

1 In this study the endothelin (ET) receptor subtypes mediating contra ctions produced by ET-1 in human and guinea-pig pulmonary tissues were investigated. In addition the receptor responsible for ET-1-induced p rostanoid release in human bronchus was determined. 2 In human bronchu s and human pulmonary artery ET-1 (0.1 nM-0.3 muM) was a potent and ef fective contractile agent (pD2 = 7.58 +/- 0.15, n = 6, and 8.48 +/- 0. 11, n = 7, respectively). BQ-123 (1-10 muM), a potent and selective ET A receptor antagonist, potently antagonized ET-1-induced contraction i n human pulmonary artery (pK(B) = 6.8 with 1 muM BQ-123, n = 7) but ha d no effect in human bronchus (n = 6). 3 Sarafotoxin S6c (0.1 nM - 0.1 muM), the ET(B)-selective agonist, did not contract human pulmonary a rtery (n = 5), but potently and effectively contracted human bronchus: pD2 = 8.41 +/- 0.17, maximum response 74.4 +/- 3.1% of 10 muM carbach ol; n = 5. BQ-123 (110 muM) did not antagonize sarafotoxin S6c-induced contraction in human bronchus (n = 5). 4 ET-1 potently contracted gui nea-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 muM) antagonized ET-1-induced contractions in guinea-pig pulmonary artery (pK(B) = 6.7 with 1 muM BQ-123, n = 6), a orta (pK(B) = 7.1 with 1 muM BQ-123, n = 6) and trachea (pK(B) = 6.2 w ith 1 muM BQ-123, n = 6) but was without marked effect in bronchus (n = 4). In contrast, sarafotoxin S6c (0.1 nm-0.1 muM) did not contract g uinea-pig aorta (n = 4) or guinea-pig pulmonary artery (n = 6) but pot ently and effectively contracted guinea-pig bronchus: pD2 = 8.55 +/- 0 .1; maximum contraction = 63.6 +/- 3.1 % of 10 muM carbachol, n = 4. S arafotoxin S6c (0.1 nM-0.1 muM) was a much less effective agonist in g uinea-pig trachea: maximum contraction = 13.9 +/- 2.5% of 10 muM carba chol, n = 4; P < 0.0001, compared to bronchus. Contractions produced b y sarafotoxin S6c in guinea-pig bronchus or trachea were unaffected by BQ-123 (10 muM, n = 4). 5 Significant differences were observed in th e efficacy, relative to carbachol, but not the potency of sarafotoxin S6c in guinea-pig airways, with a much greater maximum contractile res ponse in bronchus (69.6 +/- 2.4% of 10 muM carbachol, n = 6) or lower region of the trachea (48.5 +/- 5.9% of 10 muM carbachol, n = 6) than in the middle region of the trachea (14.4 +/- 4.0% of 10 mum carbachol , n = 6) or the upper region of the trachea (19.3 +/- 2.7% of 10 muM c arbachol, n = 6). There were minimal regional differences in either ET -1-induced contraction or the potency of BQ-123 (3 muM) for inhibition of responses to ET-1 in guinea-pig airways. 6 Release of various pros tanoids in human bronchus induced by ET-1 (0.3 muM) was essentially ab olished with 10 muM BQ-123. 7 These data provide evidence that distinc t ET receptors mediate ET-1-induced contraction in human pulmonary art ery, guinea-pig pulmonary artery and guinea-pig aorta (ET(A) subtype) compared with human bronchus and guinea-pig bronchus (non-ET(A), perha ps ET(B) subtype). Contractions to ET-1 in guinea-pig trachea appear t o involve both ET(A) and non-ET(A) (ET(A) receptor subtypes. Furthermo re, 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 t o be mediated via ET(A) receptor activation.