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Levosimendan, a new therapeutic approach to prevent delayed cerebral vasospasm after subarachnoid hemorrhage?

  • Experimental Research - Vascular
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Abstract

Background

Under physiological cerebral conditions, levosimendan, a calcium-channel sensitizer, has a dose-dependent antagonistic effect on prostaglandin F2alpha (PGF)-induced vasoconstriction. This circumstance could be used in antagonizing delayed cerebral vasospasm (dCVS), one of the main complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and ischemic neurological deficits. Data already exist that identified neuroprotective effects of levosimendan in a traumatic brain injury model and additionally, it has been proven that this compound prevents narrowing of the basilar artery (BA) luminal area after SAH in an in vitro rabbit model. Takotsubo cardiomyopathy, a severe ventricular dysfunction, is also a well-known complication after SAH, associated with pulmonary edema and prolonged intubation.

Methods

The polypeptide endothelin-1 (ET-1) plays a key role in the development of dCVS after SAH. Therefore, the aim of the present investigation was to detect functional interactions between the calcium-sensitizing and the ET-1-dependent vasoconstriction after experimental-induced SAH; interactions between levosimendan and a substrate-specific vasorelaxation in the BA were also examined. It was reviewed whether levosimendan has a beneficial influence on endothelin(A) and/or endothelin(B1) receptors (ET-(A) and ET-(B1) receptors) in cerebral vessels after SAH. We also examined whether this drug could have antagonistic effects on a PGF-induced vasoconstriction.

Results

Under treatment with levosimendan after SAH, the endothelin system seems to be affected. The ET-1-induced contraction is decreased, not significantly. In addition, we detected changes in the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway. Preincubation with levosimendan causes a modulatory effect on the ET-(B1) receptor-dependent vasorelaxation. It induces an upregulation of the NO-cGMP pathway with a significantly increased relaxation. Even after PGF-induced precontraction a dose-dependent relaxation was registered, which was significantly higher (Emax) and earlier (pD2) compared to the concentration–effect curve without levosimendan.

Conclusions

After experimental-induced dCVS, levosimendan seems to restore the well-known impaired function of the vasorelaxant ET-(B1) receptor. Levosimendan also reversed the PGF-induced contraction dose-dependently. Both of these mechanisms could be used for antagonizing dCVS in patients suffering SAH. Levosimendan could even be used additionally in treating patients developing takotsubo cardiomyopathy.

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Acknowledgments

We thank Marina Heibel for her excellent technical support. Furthermore, we are grateful for the experimental assistance of Dr. A. Theisen.

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Authors and Affiliations

  1. Department of Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

    Juergen Konczalla, Jan Mrosek, Johannes Platz & Volker Seifert

  2. Department of Neurosurgery, Inselspital University Hospital Bern, Freiburgstrasse 4, 3010, Bern, Switzerland

    Stefan Wanderer

  3. Department of Neurosurgery, Rheinische Friedrich-Wilhelms-University, Bonn, Germany

    Erdem Gueresir, Patrick Schuss & Hartmut Vatter

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  1. Juergen Konczalla
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Correspondence to Stefan Wanderer.

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No funding was received for this research.

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Levosimendan, as already mentioned, was kindly provided by Jouko Levijoki, M. Sc. (Pharm.) from Orion Corporation, Orion Pharma (Espoo, Finland).

Animal experiments

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Juergen Konczalla and Stefan Wanderer shared first authorship.

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Konczalla, J., Wanderer, S., Mrosek, J. et al. Levosimendan, a new therapeutic approach to prevent delayed cerebral vasospasm after subarachnoid hemorrhage?. Acta Neurochir 158, 2075–2083 (2016). https://doi.org/10.1007/s00701-016-2939-5

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  • DOI: https://doi.org/10.1007/s00701-016-2939-5

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