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Volume 16 Supplement 3

Sepsis 2012

  • Poster presentation
  • Open Access

Manipulation of nitric oxide levels with a modified hydroxyethyl starch molecule

  • 1,
  • 1,
  • 2,
  • 3,
  • 1,
  • 2 and
  • 1
Critical Care201216 (Suppl 3) :P66

https://doi.org/10.1186/cc11753

  • Published:

Keywords

  • Nitric Oxide
  • Phenylephrine
  • Sodium Nitroprusside
  • Thiolated
  • Papaverine

Background

As mortality of patients with severe sepsis and septic shock is still inappropriately high [1], innovative therapeutic approaches are urgently needed. In the presence of hypovolemia, fluid therapy is typically initiated to compensate for intravascular volume deficits [2]. However, administration of fluids may not necessarily correct a disturbed blood flow on the microcirculatory level [3]. Microcirculatory failure during sepsis is, at least in part, caused by pathological nitric oxide (NO) levels [4, 5]. To achieve an optimal NO availability, approaches including NO donors or inhibitors may be useful. The aim of the present study was to assess the ability of our test substance S-nitrosothiol-HES (S-NO-HES) to act as NO donor and exert a pharmacological activity.

Methods

The investigated test substance S-NO-HES is a novel molecule consisting of NO coupled to a thiolated derivative of hydroxyethyl starch (HES). The ability of S-NO-HES to release NO was demonstrated. Furthermore, the effect of S-NO-HES on myocardial function was studied in isolated Langendorff-perfused hearts from guinea pigs and compared with that of the reference substance sodium nitroprusside. The thiolated HES derivative (SH-HES) served as negative control. In addition, isolated aortic rings from rats were pre-contracted by phenylephrine. After defined incubation periods with reference, test, or control items, the NO-induced relaxation was determined. S-nitrosoglutathione served as reference compound, HES and in one experiment also SH-HES as control substances. At the end of the 180-minute experiment, papaverine was applied in order to completely relax the aortic rings and to define the 100% relaxation level.

Results

S-NO-HES significantly increased the heart rate of Langendorff-perfused guinea pig hearts and additionally reduced both the QT interval and QTc-B values. In addition, S-NO-HES exerted a significant vasodilatory effect on phenylephrine pre-contracted rat aortic rings that was dose dependent. The effect was not only observed under light, which is known to trigger NO release from S-nitroso compounds, but also under exclusion of light and therefore more physiological conditions.

Conclusion

We demonstrated for the first time that the S-NO-HES molecule released NO and exhibited corresponding pharmacological properties. In future experiments, the effectiveness of S-NO-HES to substitute NO deficiency under septic conditions has to be studied.

Authors’ Affiliations

(1)
Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany
(2)
Fresenius Kabi Deutschland GmbH, Friedberg, Germany
(3)
Academic Medical Center, Amsterdam, the Netherlands

References

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  4. Davis JS, Darcy CJ, Yeo TW, Jones C, McNeil YR, Stephens DP, Celermajer DS, Anstey NM: Asymmetric dimethylarginine, endothelial nitric oxide bioavailability and mortality in sepsis. PloS One 2011, 6: e17260. 10.1371/journal.pone.0017260PubMed CentralView ArticlePubMedGoogle Scholar
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Copyright

© Lupp et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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