Endothelin-1(1-31) induces spreading depolarization in rats.
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.


METHODS
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.


RESULTS
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.
Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany.
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D
Jorks
S
S
Major
A I
AI
Oliveira-Ferreira
J
J
Kleeberg
J P
JP
Dreier
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D019332:Endothelin-1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects
D019332:Endothelin-1; D010446:Peptide Fragments; C114932:endothelin-1 (1-31)