Experimentelle Untersuchungen zur Mikrozirkulation isoliert perfundierter Rattenherzen unter Einfluß bakterieller Exotoxine

Abstract

Cardiac performance is severely depressed in sepsis and septic shock. The morphological and functional alterations are known as septic cardiomyopathy and consist of reduced left and right ventricular ejection fractions, myocardial hypokinesis and dilatation of both ventricles. The heart is not able to compensate the fall in systemic blood pressure of the septic patient, although heart rate is highly elevated. This contributes to therapy resistant cardiovascular collapse which in 50% of all cases is lethal. In this context bacterial pathogenecity factors obviously play an important part. Since early sepsis research everybody focused on viable bacteria or endotoxins, relatively little is known about the pathophysiological significance of bacterial exotoxins yet. Staphylococcus aureus and Escherichia coli are well known rods to cause sepsis. Some of their isolates produce bacterial exotoxins, which represent potent virulence factors. The most important exotoxins outside the intestinal tract, a-toxin of Staphylococcus aureus and Escherichia coli hemolysin, represent prototypes of bacterial pore-forming exotoxins. Their pathophysiological relevance in sepsis was extensively demonstrated in cell cultures, isolated organs and animal models. The characteristic pathophysiological concept of these toxins seems to be their ability to activate target cells in sublytic doses. Investigations in isolated lungs, intestine and hearts clearly demonstrated the significance of arachidonic acid metabolism followed by the production of vasoactive eicosanoids. The induction of microcirculatory failure by these eicosanoids has already been shown in lung and intestine models, but not clearly in hearts. Therefore, the aim of this investigation was to measure regional myocardial perfusion in the isolated, buffer perfused rat heart challenged with these toxins, using the coloured dye-extraction microsphere-technique. This technique is suitable to quantify changes in microcirculation even in little pieces of tissue. Simultaneously, parameters of heart performance were monitored. Furthermore, the aim was to characterize pathomechanisms of both pore-forming toxins and to look for eventual differences between them. The application of both toxins in the coronary vasculature resulted in a strong vasoconstriction and a loss in contractility of the hearts. Microcirculatory changes resulted from a maldistribution of perfusion between endocardial and epicardial layers of the left ventricular free wall. It is of interest that ECH caused a loss of perfusion in endocardial layers, while a-toxin caused a loss in epicardial layers of the left ventricular myocardium. These findings suggest that different systems of mediators are responsible for the effects of the exotoxins used. They were confirmed with the use of a cyclooxygesase-inhibitor and a lipoxygenase-inhibitor. In the case of a-toxin it was possible to reduce the coronary vasoconstriction, loss in contractility and loss in epicardial perfusion by blocking the cyclooxygenase, which suggests TxA2 as the main acting vasoconstrictory agent. In case of ECH the lipoxygenase-inhibition showed the same effects. Here toxin-effects seem to be mediated by leukotrienes. Synthesis of eicosanoids in response to bacterial exotoxins may be responsible for microcirculatory alterations followed by the loss in myocardial performance. These findings weaken the high status of negative inotropic cytokines in septic cardiomyopathy. They emphasize not only the importance of bacterial exotoxins in sepsis, but demonstrate that microcirculatory alterations, as seen in many other organs in sepsis, contribute to organ failure even in the heart.