MECHANICAL AND BIOCHEMICAL RESPONSES TO ENDOTHELIN-1 AND ENDOTHELIN-3IN HUMAN BRONCHI

In human bronchi, contractions to endothelin-l were unaltered by atrop ine (10(-5) M), indomethacin (10(-6) M), nifedipine (10(-5) M), or pho sphoramidon (3.67 X 10(-5) M). Endothelin-3-evoked contractions were m arkedly enhanced by phosphoramidon (3.67 x 10(-5) M), unaffected by at ropine (10(-5) M), and attenuated by indomethacin (10(-6) M) or nifedi pine (10(-5) M). Phorbol 12,13-dibutyrate (PDB, 10(-8) M) enhanced bot h endothelin-1- and endothelin-3 (plus phosphoramidon)-evoked response s, an effect abolished by Ro 31-8220 (3 x 10(-8) M). Contractions to e ndothelin-l 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-l (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)P-3). The se results suggest that endothelin-l does not act via cyclo-oxygenase metabolites nor require Ca2+ influx via dihydropyridine-sensitive chan nels. It evokes Ins(1,4,5)P-3 production, but does not rely upon prote in kinase C activation for contraction. Endothelin-3-evoked contractio ns are partly mediated by cyclo-oxygenase metabolites. Endothelin-3 do es not stimulate phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolys is, nor utilise protein kinase C to produce contraction, but its actio ns may rely upon extracellular Ca2+.