Sepsis is one of the biggest challenges for modern medicine. The mortality rate is very high, the incidence rate is rising worldwide and the cost for the health sector is enormous. A crucial share in the pathophysiology must be attributed to cardiocirculatory failure triggered by a generalised vasodilatation as well as septic cardiomyopathy. An important mediator for these two phenomena is nitrogen monoxide. It was the object of the present dissertation to examine the nitrogen-oxide-mediated effects on septic haemodynamics in a murine CLP model and to clarify the significance attributable to the respective NO synthases in this connection. To this end, the following experiments were conducted in wild-type and eNOS-/- mice with and without a selective blockade of the inducible and neuronal NO synthase: In order to quantify the formation of nitrogen monoxide, the nitrite and nitrate levels were measured basally and after the induction of sepsis both in the plasma and in the cardiac tissue. The cardiovascular function was examined before and after the application of noradrenaline by means of invasive pressure/volume measurement via a miniature catheter. In order to measure the effect of nitrogen monoxide on the myocardial inflammatory reaction, a histological analysis of the infiltration of leucocytary cells into the cardiac muscle tissue was conducted. Likewise, the sepsis-modulated expression rate of the iNOS was measured by means of quantitative RT-PCR and in a separate population, the mean survival time of the various groups of laboratory animals was determined. Our results show that, in septic animals, there was a severe increase in the plasma NOx level as well as in the inflammatory reaction of the cardiac muscle. The consequence was a pronounced cardiovascular dysfunction associated with catecholamine resistance, which ultimately accounted for a mortality rate of 100% and a mean survival time of only twenty-nine (29) hours. The expression rate of the inducible NO synthase increased on account of the induction of sepsis. The highly selective iNOS blockade caused a reduction of the plasma NOx levels and also of the inflammatory cell infiltration into the cardiac muscle. As a result, the cardiac function was largely maintained and also the mean survival time of the wild types was about doubled. These results show that the iNOS plays a decisive role in the NO production and cardiovascular dysfunction going along with a sepsis. The inhibition of the nNOS actually led to an even higher reduction of the NOx values, surprisingly, however, not to an improved but to a reduced LV function. This manifestation was particularly pronounced in the eNOS-/- mice. Also the mean survival time of the inhibited wild-type animals increased but to a small extent and was clearly lower than that of the iNOS-inhibited animals. This shows that, on the one hand, the nNOS has a hitherto unexpected significance for the NO synthesis in the course of a sepsis and, moreover, has a cardioprotective effect. This is most likely based on the cardiomyocyte localisation of the nNOS in the sarcoplasmic reticulum and may have contributed to the sobering results of the unselective NOS inhibition as a therapeutic approach in septic shock. In all test series, the eNOS-/- animals achieved the best results. In comparison with the drug-blocked animals, these showed the lowest NOx values as well as the lowest inflammatory impairment and were therefore protected against myocardiac depression and catecholamine resistance. This was reflected also by the longest survival period with a mean survival time of 69.5 hours. The lack of increase in the iNOS expression rate in septic eNOS-/- animals conforms in relation to the iNOS with a pro-inflammatory, regulative function of the endothelial NO synthase. In survival tests, the inhibition of both the inducible and the neuronal NO synthase in eNOS-/- mice did not lead to a further increase in the mean survival time. This shows that excessive inhibition of the NO synthases associated with consecutive subphysiological NO values may have a negative effect on the survival time. The background for this may be the lack of the likewise existing positive effects of the nitrogen monoxide on the cardiac function as well as the diminished NO-mediated bactericidal effects. On the whole, the data of the present study show that NOS inhibition as a therapy for septic shock is promising only if it is highly selective, if the positive effects of nitrogen monoxide are not suppressed and if the right time for the initiation of the therapy is chosen. The fact that the central role of the endothelial NO synthase has been shown in our experiments suggests that, at least in the early phases of sepsis, a therapy by means of a selective eNOS inhibition should be attempted. For this purpose, however, further preclinical studies are required
