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

  • Stefan Wanderer
  • Jan Mrosek
  • Gessler Florian
  • Seifert Volker
  • Juergen Konczalla
Original Article - Vascular
  • 23 Downloads

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.

Keywords

Cerebrovasculature Losartan ET-1 Endothelin-1 SAH Aneurysmal subarachnoid haemorrhage Cerebral vasospasm Prostaglandin F2alpha PGF2a 

Notes

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.

Compliance with ethical standards

Conflict of interest

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.

Ethical approval

All applicable international, national and/or institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2017

Authors and Affiliations

  • Stefan Wanderer
    • 1
    • 2
  • Jan Mrosek
    • 1
  • Gessler Florian
    • 1
  • Seifert Volker
    • 1
  • Juergen Konczalla
    • 1
  1. 1.Department of NeurosurgeryGoethe-University HospitalFrankfurt am MainGermany
  2. 2.Department of NeurosurgeryAarauSwitzerland

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