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ET-1 induces cortical spreading depression via activation of the ET_A receptor/phospholipase C pathway in vivo

Departments of Neurology and Experimental Neurology, Humboldt University, 10117 Berlin, Germany

Submitted 13 March 2003 ; accepted in final form 25 November 2003

Recently, it has been shown that brain topical superfusion of endothelin (ET)-1 at concentrations around 100 nM induces repetitive cortical spreading depressions (CSDs) in vivo. It has remained unclear whether this effect of ET-1 is related to a primary neuronal/astroglial effect, such as an increase in neuronal excitability or induction of interastroglial calcium waves, or a penumbra-like condition after vasoconstriction. In vitro, ET-1 regulates interastroglial communication via combined activation of ET_A and ET_B receptors, whereas it induces vasoconstriction via single activation of ET_A receptors. We have determined the ET receptor profile and intracellular signaling pathway of ET-1-induced CSDs in vivo. In contrast to the ET_B receptor antagonist BQ-788 and concentration dependently, the ET_A receptor antagonist BQ-123 completely blocked the occurrence of ET-1-induced CSDs. The ET_B receptor antagonist did not increase the efficacy of the ET_A receptor antagonist. Direct stimulation of ET_B receptors with the selective ET_B agonist BQ-3020 did not trigger CSDs. The phospholipase C (PLC) antagonist U-73122 inhibited CSD occurrence in contrast to the protein kinase C inhibitor Gö-6983. Our findings indicate that ET-1 induces CSDs through ET_A receptor and PLC activation. We conclude that the induction of interastroglial calcium waves is unlikely the primary cause of ET-1-induced CSDs. On the basis of the receptor profile, likely primary targets of ET-1 mediating CSD are either neurons or vascular smooth muscle cells.

endothelin-1; endothelin receptor antagonists; interastroglial calcium waves; gap junction communication; protein kinase C inhibition; arachidonic acid; cortical spreading depression

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