Mechanical and biochemical responses to endothelin-1 and endothelin-3 in human bronchi.
In human bronchi, contractions to endothelin-1 were unaltered by atropine (10(-5) M), indomethacin (10(-6) M), nifedipine (10(-5) M), or phosphoramidon (3.67 x 10(-5) M). Endothelin-3-evoked contractions were markedly enhanced by phosphoramidon (3.67 x 10(-5) M), unaffected by atropine (10(-5) M), and attenuated by indomethacin (10(-6) M) or nifedipine (10(-5) M). Phorbol 12,13-dibutyrate (PDB, 10(-8) M) enhanced both endothelin-1- and endothelin-3 (plus phosphoramidon)-evoked responses, an effect abolished by Ro 31-8220 (3 x 10(-8) M). Contractions to endothelin-1 or endothelin-3 alone were unaltered by staurosporine 10(-8)-3 x 10(-7) M) or Ro 31-8220 (3 x 10(-9)-3 x 10(-8) M). Endothelin-1 (3 x 10(-7) M), but not endothelin-3 (10(-10)-3 x 10(-7) M), evoked a rise in levels of inositol (1,4,5) trisphosphate (Ins(1,4,5)P3). These results suggest that endothelin-1 does not act via cyclo-oxygenase metabolites nor require Ca2+ influx via dihydropyridine-sensitive channels. It evokes Ins(1,4,5)P3 production, but does not rely upon protein kinase C activation for contraction. Endothelin-3-evoked contractions are partly mediated by cyclo-oxygenase metabolites. Endothelin-3 does not stimulate phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, nor utilise protein kinase C to produce contraction, but its actions may rely upon extracellular Ca2+.
Nally
J E
JE
Autonomic Physiology Unit, Glasgow University, UK.
McCall
R
R
Young
L C
LC
Wakelam
M J
MJ
Thomson
N C
NC
McGrath
J C
JC
D001285:Atropine / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors
D016232:Endothelins; D006020:Glycopeptides; D007211:Indoles; D011480:Protease Inhibitors; D015240:Phorbol 12,13-Dibutyrate; D001285:Atropine; D015544:Inositol 1,4,5-Trisphosphate; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D009543:Nifedipine; D002118:Calcium; C008890:phosphoramidon; C064758:Ro 31-8220; D007213:Indomethacin