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CLINICAL STUDIES

Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite

Markus Flesch, MD^a, Heiko Kilter, MD^a, Bodo Cremers, MS^a, Ulrich Laufs, MD^a, Michael Südkamp, MD^*, Monika Ortmann, MD, Frank U. Müller, MD and Michael Böhm, MD^a

^a Klinik III für Innere Medizin, der Westfälischen Wilhelms-Universität, Münster, Germany
^* Klinik für Herz- und Thoraxchirurgie, der Westfälischen Wilhelms-Universität, Münster, Germany
Pathologisches Institut, der Universität zu Köln, der Westfälischen Wilhelms-Universität, Münster, Germany
Institut für Pharmakologie und Toxikologie, der Westfälischen Wilhelms-Universität, Münster, Germany

Manuscript received February 27, 1998; revised manuscript received September 1, 1998, accepted December 7, 1998.

Reprint requests and correspondence: Dr. Markus Flesch, Klinik III für Innere Medizin der Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50924 Köln, Germany
markus.flesch{at}medizin.uni-koeln.de

OBJECTIVES

This study examined the effects of endotoxin on cardiac contractility in human myocardium.

BACKGROUND

In animal myocardium, endotoxin and cytokine treatment led to enhanced inducible nitric oxide synthase (iNOS) expression and contractile dysfunction. Effects in human myocardium are unknown.

METHODS

Left ventricular myocardial preparations from failing (n = 18) and nonfailing (n = 5) human hearts were incubated for 6 and 12 h in tyrode solution or in tyrode plus lipopolysaccharides (LPS), with LPS plus N^G-mono-methyl-L-arginine (L-NMMA), with LPS plus hemoglobin or with LPS plus the superoxide scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). Force of contraction in response to isoprenaline (0.001 to 3 µmol/liter) was determined in electrically stimulated muscle preparations. The iNOS mRNA expression was examined by in situ hybridization and by polymerase chain reaction. The cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay.

RESULTS

Isoprenaline concentration dependently increased force of contraction. Six and 12 hours of LPS treatment of failing myocardium decreased maximum inotropic response to isoprenaline by 54% (p = 0.009) and by 69% (p = 0.0023), respectively. In nonfailing myocardium, 12 h of LPS treatment decreased maximum inotropic effect of isoprenaline by 66% (p < 0.001). The LPS effects were attenuated by L-NMMA, hemoglobin and also Tiron. The iNOS mRNA was expressed in all LPS-treated preparations but also in most control myocardial preparations. In situ hybridization revealed iNOS expression within cardiac myocytes. There was no increase in myocardial cGMP content in response to endotoxin.

CONCLUSIONS

Endotoxin exposure of human myocardium leads to a depression of cardiac contractility, which is mediated by enhanced iNOS activity and release of nitric oxide (NO). Consecutive reaction of NO with superoxide and formation of peroxynitrite may contribute to the decrease in force of contraction.

Abbreviations and Acronyms   cGMP = cyclic guanosine monophosphate   iNOS = inducible nitric oxide synthase   NO = nitric oxide   O2– = superoxide   ONOO– = peroxynitrite

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