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

• Published in: Journal of the American College of Cardiology Vol. 33; no. 4; pp. 1062 - 1070
• Main Authors: Flesch, Markus, Kilter, Heiko, Cremers, Bodo, Laufs, Ulrich, Südkamp, Michael, Ortmann, Monika, Müller, Frank U, Böhm, Michael
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15-03-1999; Elsevier Science
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Culture Techniques; Dose-Response Relationship, Drug; Emergency and intensive cardiocirculatory care. Cardiogenic shock. Coronary intensive care; Endotoxins - pharmacology; Female; Heart Failure - physiopathology; Humans; Intensive care medicine; Isoproterenol - pharmacology; Male; Medical sciences; Middle Aged; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Nitrates - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; NO; cGMP; iNOS; ONOO; O2; Shock; Human origin; Pharmacologic test; Isoprenaline; Pathophysiology; Pathogenesis; Septicemia; Contractility; Cardiovascular disease; Heart ventricle; Biosynthesis; Left ventricular failure; Experimental study; Endotoxin; Left ventricle; Isolated organ; Infection; Heart disease; Nitric oxide; Lipopolysaccharide
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/S0735-1097(98)00660-3

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 NG-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.