Background: Delayed cerebral vasospasm (dCVS) following aneurysmal subarachnoid
hemorrhage (aSAH) is (next to possible aneurysm rebleeding, cortical spreading depression and
early brain injury) one of the main factors contributing to poor overall patient outcome. Since decades,
intensive research has been ongoing with the goal of improving our understanding of the
pathophysiological principles underlying dCVS. Endothelin-1 (ET-1) and prostaglandin F2 alpha
(PGF2a) seem to play a major role during dCVS. The synthesis of ET-1 is enhanced after subarachnoid
hemorrhage (SAH) to mediate a long-lasting vasoconstriction, and PGF2a contributes to
cerebral inflammation and vasoconstriction. Under physiological conditions, levosimendan (LS)
demonstrates an antagonistic effect on PGF2a-induced cerebral vasoconstriction. Thus, the intention
of the present study was to analyze potentially beneficial interactions in a pathophysiological
Methods: A modified double hemorrhage model was used. Functional interactions between the
calcium-sensitizing action of LS and the vasoconstrictive properties of PGF2a were investigated.
Results: After pre-incubation with LS, followed by application of PGF2a, a significant decrease in
maximum contraction (Emax) for sham-operated animals was found (Emax 28% with LS, Emax 56%
without LS). Using the same setting after SAH, the vessel segments did not reach a statistically
significant contraction (but similar like the sham-operated vessels), neither for Emax nor pD2
(-log10EC50) nor EC50 (i.e., the concentration at which half of the maximal effect occurs).
LS series in sham animals were performed by pre-incubation with PGF2a. The resultant Emax
showed a statistically strong significance concerning a higher vasorelaxation compared with a solvent
control group. Vessel segment relaxation was significantly stronger in the same experimental
setup after SAH.
Conclusion: Under physiological and pathophysiological circumstances, LS reduced and dosedependently
reversed PGF2a-induced vasoconstriction. These results can be applied to further
developing methods to antagonize dCVS after aSAH.