- Poster presentation
- Open Access
Manipulation of nitric oxide levels with a modified hydroxyethyl starch molecule
© Lupp et al.; licensee BioMed Central Ltd. 2012
- Published: 14 November 2012
- Nitric Oxide
- Sodium Nitroprusside
As mortality of patients with severe sepsis and septic shock is still inappropriately high , innovative therapeutic approaches are urgently needed. In the presence of hypovolemia, fluid therapy is typically initiated to compensate for intravascular volume deficits . However, administration of fluids may not necessarily correct a disturbed blood flow on the microcirculatory level . 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.
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.
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.
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.
- Melamed A, Sorvillo FJ: The burden of sepsis-associated mortality in the United States from 1999 to 2005: an analysis of multiple-cause-of-death data. Crit Care 2009, 13: R28. 10.1186/cc7733PubMed CentralView ArticlePubMedGoogle Scholar
- Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36: 296-327. 10.1097/01.CCM.0000298158.12101.41View ArticlePubMedGoogle Scholar
- Ospina-Tascon G, Neves AP, Occhipinti G, Donadello K, Buchele G, Simion D, Chierego ML, Silva TO, Fonseca A, Vincent JL, et al.: Effects of fluids on microvascular perfusion in patients with severe sepsis. Intensive Care Med 2010, 36: 949-955. 10.1007/s00134-010-1843-3View ArticlePubMedGoogle Scholar
- 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
- Engelberger RP, Pittet YK, Henry H, Delodder F, Hayoz D, Chiolero RL, Waeber B, Liaudet L, Berger MM, Feihl F: Acute endotoxemia inhibits microvascular nitric oxide-dependent vasodilation in humans. Shock 2011, 35: 28-34. 10.1097/SHK.0b013e3181ec71abView ArticlePubMedGoogle Scholar
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