title: Endothelin-1 potently induces Leão's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura?
abstract: According to the 'neuronal' theory, cortical spreading depression (CSD) is the pathophysiological correlate of migrainous aura. However, the 'vascular' theory has implicated altered vascular function in the induction of aura symptoms. The possibility of a vascular origin of aura symptoms is supported, e.g. by the clinical observation that cerebral angiography frequently provokes migrainous aura. This suggests that endothelial irritation may somehow initiate one of the pathways resulting in migrainous aura. Up to now, an endothelium-derived factor has never been shown to trigger CSD. Here, for the first time, we demonstrate and characterize the ability of the vasoconstrictor and astroglial/neuronal modulator endothelin-1 to trigger Leão's 'spreading depression of activity' in vivo in rats. At a concentration range between 10 nM and 1 microM, endothelin-1 induced changes characteristic of CSD with regard to the rate of propagation, steady (direct current) potential and extracellular K(+)-concentration. A spreading hyperaemia followed by oligaemia was observed similar to those in K(+)-induced CSD. Endothelin-1 did not provoke changes characteristic of a terminal depolarization. The mechanism by which endothelin-1 generated CSD involved the N-methyl-D-asparate receptor. Cerebral blood flow decreased slightly, but significantly, before endothelin-1 generated CSD. A vasodilator (NO*-donor) shifted the threshold for CSD induction to higher concentrations of endothelin-1. Endothelin-1, in contrast to K(+), did not induce CSD in rat brain slices suggesting indirectly that endothelin-1 may require intact perfusion to exert its effects. In conclusion, endothelin-1 was found in the experiment to be the most potent inducer of CSD currently known. We propose endothelin-1 as a possible candidate for the yet enigmatic link between endothelial irritation and migrainous aura.
authors.affiliation: Department of Experimental Neurology, Charité, Humboldt-University, Berlin, Germany. jens.dreier@charite.de
authors.forename: Jens P
authors.initials: JP
authors.lastname: Dreier
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeberg
authors.forename: Gabor
authors.initials: G
authors.lastname: Petzold
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Olaf
authors.initials: O
authors.lastname: Windmüller
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Orzechowski
authors.forename: Ute
authors.initials: U
authors.lastname: Lindauer
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
authors.forename: Karl M
authors.initials: KM
authors.lastname: Einhäupl
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004594:Electrophysiology; D019332:Endothelin-1 / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D017078:Laser-Doppler Flowmetry; D008297:Male; D020325:Migraine with Aura / Q000209:etiology* / Q000503:physiopathology; D008954:Models, Biological; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013096:Spermine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013096:Spermine; D016291:Dizocilpine Maleate; D011188:Potassium