Molecular mechanism of action of the vasoconstrictor peptide endothelin.
Endothelin, one of the most potent vasoconstrictor known, has been suggested to act as an endogenous agonist of L-type Ca2+ channels. In this paper we show that endothelin stimulates the metabolism of inositol phosphates and induces the mobilization of intracellular Ca2+ stores. The transient activation of Ca2+-sensitive K+ channel provokes an hyperpolarization of the membrane. It is followed by a sustained depolarization which is due to the opening of a non-specific cation channel which is permeable to Ca2+ and Mg2+. The depolarization then activates L-type Ca2+ channels. This mechanism of action explains why part of the endothelin-induced vasocontriction is eliminated by L-type Ca2+ channel blockers.
Van Renterghem
C
C
Centre de Biochimie du Centre National de la Recherche Scientifique, Nice, France.
Vigne
P
P
Barhanin
J
J
Schmid-Alliana
A
A
Frelin
C
C
Lazdunski
M
M
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D004594:Electrophysiology; D016232:Endothelins; D004730:Endothelium, Vascular; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D017275:Isradipine; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects*; D014667:Vasopressins / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016232:Endothelins; D007295:Inositol Phosphates; D010069:Oxadiazoles; D010455:Peptides; D010716:Phosphatidylinositols; D014667:Vasopressins; D000804:Angiotensin II; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium; D017275:Isradipine