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Vasomodulatory effects of the angiotensin II type 1 receptor antagonist losartan on experimentally induced cerebral vasospasm after subarachnoid haemorrhage

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A Correction to this article was published on 22 December 2017

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Abstract

Background

Cerebral vasospasm following subarachnoid haemorrhage (SAH) remains one of the major factors contributing to poor overall patient outcome. Prostaglandin F2-alpha (PGF2a) induces vasoconstriction. After SAH, PGF2a leads to cerebral inflammation and enhanced vasoconstriction, resulting in cerebral vasospasm. Losartan is already known to have beneficial effects in stroke models and also on several cerebral inflammatory processes. Therefore, the aim of the study was to analyse the effect of losartan on PGF2a-enhanced vasoconstriction after SAH.

Methods

To investigate the effect of losartan on PGF2a-enhanced vasoconstriction after SAH, cerebral vasospasm was induced by a double-haemorrhage model. Rats were killed on day 3 and 5 after SAH followed by measurement of the isometric force of basilar artery ring segments in an organ bath.

Results

PGF2a induced a dose-dependent contraction. After pre-incubation with losartan, the maximum contraction (Emax) for sham-operated animals was significantly lowered [Emax 6% in losartan 3 × 10−4 molar (M) vs. 56% without losartan]. Also, after induced SAH, PGF2a induced no vasoconstriction in pre-incubated vessels with losartan 3 × 10−4 M on day 3 (d3) as well as on day 5 (d5). For the vasorelaxative investigations, vessel segments were pre-incubated with PFG2a. Cumulative application of losartan completely resolved the pre-contraction in sham-operated animals (non SAH: 95% relaxation). After SAH, losartan not only resolved the pre-contraction (d5: 103%), but also exceeded the pre-contraction (d3: 119%). Therefore, a statistically significantly increased and earlier relaxation was calculated for all losartan concentrations [Emax (d3/d5) and pD2 (d3/d5)] compared with the solvent control group.

Conclusion

In a physiological and pathophysiological setup, losartan reduces a PGF2-induced vasoconstriction and reverses a PGF2a-precontraction completely. This fact can be integrated in pushing forward further concepts trying to antagonise/prevent cerebral vasospasm after SAH.

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Change history

  • 22 December 2017

    The original version of this paper unfortunately captured the names of Florian Gessler and Volker Seifert incorrectly and are now corrected in this paper.

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Acknowledgments

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

This study was not funded.

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Authors and Affiliations

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

    Stefan Wanderer, Jan Mrosek, Florian Gessler, Volker Seifert & Juergen Konczalla

  2. Department of Neurosurgery, Kantonsspital Aarau, Tellstrasse 25, 5001, Aarau, Switzerland

    Stefan Wanderer

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  1. Stefan Wanderer
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  2. Jan Mrosek
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  3. Florian Gessler
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Correspondence to Stefan Wanderer.

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The authors confirm that this article content has no conflicts of interest. The authors have no personal, financial or institutional interest in any of the drugs, materials or devices described in this article.

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Comments

This is an experimental study looking at the physiology of PGF2a-dependent vasoconstriction and the potential amelioration of this effect by the blocking agent losartan. This is a bench-type basic investigation. The clinical correlate, of course, would be to show that somehow losartan or a similar compound could ameliorate cerebral vasospasm following SAH. To be clear, however, there are no clinical results or data in this preclinical study presented here.

Considering the method, the study is well designed to evaluate PGF2a physiology in both sham vessels and vessels subjected toe experimental SAH. It is clear that PGF2a induces a vasoconstriction response and equally clear that losartan can either prevent this response or produce vasorelaxation after experimental SAH.

What we take from this elegant series of experiments is that we need to learn more about PGF2a and losartan. Like so many interventions previously tried for post-SAH vasospasm, there is a long and arduous path between preclinical success and clinical relief for patients. This agent is no different. We look forward to further investigations to elucidate the mechanisms of losartan action and perhaps someday a clinical trial.

Christopher Miranda Loftus

PA, USA

The original version of this article was revised: Authornames are corrected in this paper.

A correction to this article is available online at https://doi.org/10.1007/s00701-017-3441-4.

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Wanderer, S., Mrosek, J., Gessler, F. et al. Vasomodulatory effects of the angiotensin II type 1 receptor antagonist losartan on experimentally induced cerebral vasospasm after subarachnoid haemorrhage. Acta Neurochir 160, 277–284 (2018). https://doi.org/10.1007/s00701-017-3419-2

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