Document Detail


Endothelin receptors and calcium translocation pathways in human airways.
MedLine Citation:
PMID:  10498291     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
D W Hay; M A Luttmann; R M Muccitelli; R G Goldie
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  359     ISSN:  0028-1298     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  1999 May 
Date Detail:
Created Date:  1999-09-28     Completed Date:  1999-09-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  404-10     Citation Subset:  IM    
Affiliation:
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. douglas_w_hay@sbphrd.com
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MeSH Terms
Descriptor/Qualifier:
Bronchi / metabolism*
Calcium / metabolism*
Calcium Channel Blockers / pharmacology
Dose-Response Relationship, Drug
Endothelin-1 / pharmacology
Humans
Indans / pharmacology
Inositol Phosphates / metabolism
Muscle Contraction / drug effects
Muscle, Smooth / drug effects
Nicardipine / pharmacology
Peptides, Cyclic / pharmacology
Potassium Chloride / pharmacology
Receptors, Endothelin / agonists,  antagonists & inhibitors,  drug effects*
Viper Venoms / pharmacology
Chemical
Reg. No./Substance:
0/Calcium Channel Blockers; 0/Endothelin-1; 0/Indans; 0/Inositol Phosphates; 0/Peptides, Cyclic; 0/Receptors, Endothelin; 0/Viper Venoms; 0/sarafotoxins s6; 136553-81-6/cyclo(Trp-Asp-Pro-Val-Leu); 157659-79-5/SB 209670; 55985-32-5/Nicardipine; 7440-70-2/Calcium; 7447-40-7/Potassium Chloride

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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