Effects of nitric oxide manipulation on microcirculatory blood flow and tissue oxygenation in endotoxemic renal failure in the rat

• Applicant: Dr. Tanja Johannes
• Subject Area: Anaesthesiology
• Term: from 2004 to 2006
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5445867

Sepsis is a disorder of the microcirculation [1]. The release of inflammatory components such es cytokines and nitric oxide results in a loss of microcirculatory autoregulation, which causes a pathologic heterogeneity in microvascular blood flow föllowed by regional dysoxia and organ failure [2]. One of the organs, most sensitive to ischemia, are the kidneys. In order to improve treatment, more knowledge on resuscitation of local renal blood flow and its efficiency in correcting renal tissue oxygenation is needed. A controversially discussed molecule to play a role in the pathogenesis of sepsis is nitric oxide [3]. The septic shock is thought to occur es a result of iNOS (inducible nitric oxide synthase) expression. Therefore, selective inhibitors of nitric oxide have been advocated of being beneficial in the correction of shock [4]. Clinically, the most used compound known to inhibit iNOS is dexamethasone [5]. However, it remains unknown as yet whether tissue oxygenation is negatively affected by its vasoconstrictive effects or whether its inhibitory effect on iNOS reduces pathological heterogeneity of flow and, thus, distributes oxygen transport more evenly by reducing shunting. Such pathological flow distribution is known to occur in the kidney during endotoxemia [6;7]. That is why our ability to measure microvascular pO2 at different depths in the kidney non-invasively by optical spectroscopy allows us to test the hypothesis that nitric oxide disorders in the kidney during sepsis cause pathological flow distribution. Within our experiments in a rat model of endotoxemia we want to measure: a) quantitative microvascular pO2 at two different depths by use of Pd-porphyrin quenching of phosphorescence b) microvascular blood flow by micro laserdoppler measurements at two different depths reflecting cortical and medullar areas. This approach is unique in the opportunity to detect the highly heterogeneous blood flow and microvascular oxygenation within the kidney in a non-invasive way which was not possible in previous investigations due to technical limitation. The purpose of this project is to investigate how renal microcirculatory oxygenation and its intra-renal distribution are affected durinng endotoxemia and during manipulation of nitric oxide levels. With this integrative aproach we hope to gain important insights into the pathogenesis of septic renal failure.

• DFG Programme: Research Fellowships
• International Connection: Netherlands