Effects of endotoxin-induced inflammation on glucose metabolism and contractility of the rat heart in vivo and in vitro

Acute and chronic inflammations of the myocardium (as induced by sepsis) are often associated with a severe impairment of cardiac contractility. Key players in these events are proinflammatory cytokines, such as Tumor Necrosis Factor (TNFa) and Interleukin-1b (IL-1b). Despite the fact (i) that inflammatory cytokines are known to affect glucose metabolism in other insulin-sensitive tissues and (ii) that the utilisation of fuels by the heart is one of the determinants of its contractile capacity, relatively little is known about metabolic alterations occurring in this organ in the course of an inflammatory response. The aim of this work was therefore to examine the influence of a systemic inflammation in rats on the cardiac utilisation of glucose and its significance for the mechanical function of the myocardium. First, an experimental protocol was established, in which intravenous injection of bacterial lipopolysaccharide (LPS) caused a reproducible generalised inflammatory reaction, as well as clear signs of severe insulin resistance. In addition LPS injection led to a reduction of the left ventricular developed pressure by ~50%, which was demonstrated ex vivo in isolated hearts (Langendorff perfusion) 6 h following the treatment (compared to saline treated rat hearts). In hearts perfused with glucose as sole substrate, the rate of glycolysis between control and LPS group was not different. When the hearts were additionally perfused with the ketone body ß-hydroxybutyrate (ß-HB) (to mimic the in vivo conditions of fat mobilisation, as it is the case after LPS-treatment or sepsis), the glycolytic depression through ß-HB in hearts from LPS-treated rats was 45% significantly greater as in control hearts. In hearts from LPS-rats, ß-HB produced a larger increase of the citrate content (by 40%) compared to controls, which may be the mechanism underlying the stronger glycolytic inhibition in the LPS group, because alternative substrates are known to depress the phosphofructokinase reaction (a major regulatory step of glycolysis) via an increase in this allosteric inhibitor. In control hearts, ß-HB addition reinforced the insulin-dependent increase in glycogen; this effect was not observed in the LPS group, indicating that the endotoxin also causes an insulin resistance at the level of glycogen metabolism. In the search for inflammation-dependent signals, which trigger the higher glycolysis inhibition and known mediators, which are induced by cytokines in heart as well, it was observed, that a stronger cardiac production of nitric oxide does not play any role. Particularly (i) no higher nitrite concentration in coronary effluent of isolated hearts and (ii) no influence of the NOS-Inhibitor L-Nitroarginin-methylester on the LPS-dependent inhibition of the glycolysis through ß-HB were found. In contrast, perfusion (ex vivo) with N-oleyl-ethanolamine (ceramidase inhibitor), NS-398 (COX-2 inhibitor), or the thromboxane A2 receptor antagonist SQ-29548 suppressed the LPS-dependent glycolytic reduction. This data indicates that the effect of LPS on glycolysis may be mediated by a sphingomyelin derivative, and COX-2-derived thromboxane A2. Finally additional non-metabolic factors responsible for the observed cardiodepression were sought. The obtained excitability of the left ventricle developed pressure of isolated hearts and the increase of the coronary flow by the ß-adrenergic agonist Isoproterenol show that the cardiodepression can neither be explained by an irreversible damage to the electromechanical coupling, nor the contractile apparatus or the coronary reserve. Therefore in additional studies were therefore performed on isolated cardiomyocytes the calcium influx through voltage-sensitive Ca2+- channels (L-type channels) was measured. It was found that an incubation of these cells in vitro with LPS (1 µg/ml) for 1-2 h reduced the calcium current by 50%. This effect was prevented by co-incubation with cyclooxygenase inhibitor indomethacin (0.36 µg/ml). These observations suggest that LPS itself may produce a prostaglandin-mediated cardiodepression through inhibition of Ca2+- channels.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2003

Author dc:creator

• Tessier, Jean-Philippe

Contributors dc:contributor

• Fischer, Yvan

• info:eu-repo/classification/ddc/570
• Biowissenschaften, Biologie
• heart
• glucose metabolism
• rat
• contractility

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123560%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:61954