title: Endothelin receptors and calcium translocation pathways in human airways.
abstract: Tension and phosphatidyl inositol (PI) turnover experiments were conducted to investigate the receptors and signal transduction pathways responsible for contractions elicited by endothelin (ET) ligands in human bronchus. Nicardipine (1 microM), the L-type calcium channel inhibitor, or incubation in Ca2+-free medium, produced marked inhibition of contractions to the ET(B) receptor-selective agonist, sarafotoxin S6c, and especially those induced by KCl. In contrast, Ca2+-free medium was without appreciable effect against contraction produced by endothelin-1 (ET-1), the non-selective ET(A) and ET(B) receptor agonist. In Ca2+-free medium, ryanodine (10 microM), which inhibits intracellular calcium mobilization, reduced sarafotoxin S6c- and ET-1-induced responses, but was without effect on responses to KCl. Similarly, nickel chloride (Ni2+; 1 mM) caused marked inhibition of contractions induced by sarafotoxin S6c or ET-1, but had no significant effect on KCI concentration-response curves. The mixed ET(A)/ET(B) receptor antagonist SB 209670 (3 microM) inhibited responses to sarafotoxin S6c and ET-1 such that concentration-response curves were shifted rightward, at the 30% maximum response level, by 10.0- and 3.8-fold, respectively, whereas BQ-123 (3 microM), the ET(A) receptor antagonist, was without effect on responses induced by either agonist. ET-1 (1 nM-0.3 microM) caused a concentration-dependent stimulation of PI turnover, whereas sarafotoxin S6c (0.3 nM-0.1 microM) induced only small and variable increases, except at the highest concentration. The increase in PI turnover evoked by ET-1 was inhibited by SB 209670 (3 microM), and also by BQ-123 (3 microM). This is consistent with linkage of ET(A) receptors to activation of inositol phosphate generation in human bronchial smooth muscle cells. Collectively, the data suggest that differences exist in the relative contributions of intracellular and extracellular Ca2+ mobilization mechanisms elicited by ET(A) and ET(B) receptor activation. Thus, sarafotoxin S6c-induced, ET(B) receptor-mediated contraction in human bronchial smooth muscle appears to be dependent, in part, upon extracellular Ca2+, although a significant component of the response was also mediated by intracellular Ca2+ release, including from ryanodine-sensitive stores. ET(A) receptor-mediated contraction of human airway smooth muscle was activated largely via the release of intracellular Ca2+.
authors.affiliation: Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. douglas_w_hay@sbphrd.com
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: M A
authors.initials: MA
authors.lastname: Luttmann
authors.forename: R M
authors.initials: RM
authors.lastname: Muccitelli
authors.forename: R G
authors.initials: RG
authors.lastname: Goldie
mesh_terms: D001980:Bronchi / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000819:agonists / Q000187:drug effects*; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; D007295:Inositol Phosphates; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D011189:Potassium Chloride; D009529:Nicardipine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium