BACKGROUND: The vasoconstrictor endothelin-1(1-21) (ET-1) seems to induce cerebral vasospasm after aneurismal subarachnoid hemorrhage (aSAH). Moreover, ET-1 causes spreading depolarization (SD) via vasoconstriction/ischemia. ET-1(1-31) is an alternate metabolic intermediate in the generation of ET-1. Our aim was to investigate whether endothelin-1(1-31) causes SD in a similar fashion to ET-1. METHOD: Increasing concentrations of either ET-1, ET-1(1-31) or vehicle were brain topically applied in 29 rats. Each concentration was superfused for one hour while regional cerebral blood flow (rCBF) and direct current electrocorticogram (DC-ECoG) were recorded. FINDINGS: In response to the highest concentration of 10(-6) M, all animals of both ET groups developed typical SD. At concentrations below 10(-6) M only ET-1 induced SD (n=14 of 19 rats). Thus, the efficacy of ET-1(1-31) to induce SD was significantly lower (P<0.001, two-tailed Fisher's Exact Test). CONCLUSIONS: Our findings suggest that ET-1(1-31) less potently induces SD compared to ET-1 which implicates that it is a less potent vasoconstrictor. Speculatively, it could be interesting to shift the metabolic pathway towards the alternate intermediate ET-1(1-31) after aSAH as an alternative strategy to ETA receptor inhibition. This could decrease ET-induced vasoconstriction and SD generation while a potentially beneficial basal ETA receptor activation is maintained.
BACKGROUND: The vasoconstrictor endothelin-1(1-21) (ET-1) seems to induce cerebral vasospasm after aneurismal subarachnoid hemorrhage (aSAH). Moreover, ET-1 causes spreading depolarization (SD) via vasoconstriction/ischemia. ET-1(1-31) is an alternate metabolic intermediate in the generation of ET-1. Our aim was to investigate whether endothelin-1(1-31) causes SD in a similar fashion to ET-1. METHOD: Increasing concentrations of either ET-1, ET-1(1-31) or vehicle were brain topically applied in 29 rats. Each concentration was superfused for one hour while regional cerebral blood flow (rCBF) and direct current electrocorticogram (DC-ECoG) were recorded. FINDINGS: In response to the highest concentration of 10(-6) M, all animals of both ET groups developed typical SD. At concentrations below 10(-6) M only ET-1 induced SD (n=14 of 19 rats). Thus, the efficacy of ET-1(1-31) to induce SD was significantly lower (P<0.001, two-tailed Fisher's Exact Test). CONCLUSIONS: Our findings suggest that ET-1(1-31) less potently induces SD compared to ET-1 which implicates that it is a less potent vasoconstrictor. Speculatively, it could be interesting to shift the metabolic pathway towards the alternate intermediate ET-1(1-31) after aSAH as an alternative strategy to ETA receptor inhibition. This could decrease ET-induced vasoconstriction and SD generation while a potentially beneficial basal ETA receptor activation is maintained.
Authors: Robert F James; Daniel R Kramer; Zaid S Aljuboori; Gunjan Parikh; Shawn W Adams; Jessica C Eaton; Hussam Abou Al-Shaar; Neeraj Badjatia; William J Mack; J Marc Simard Journal: Curr Treat Options Neurol Date: 2016-08 Impact factor: 3.598