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

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