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

OBJECTIVES This study examined the effects of endotoxin on cardiac contract ility in human myocardium. BACKGROUND In animal myocardium, endotoxin and cytokine treatment led to en hanced inducible nitric oxide synthase (iNOS) expression and contractile dy sfunction. 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 sol ution or in tyrode plus lipopolysaccharides (LPS), with LPS plus N-G-mono-m ethyl-L-arginine (L-NMMA), with LPS plus hemoglobin or with LPS plus the su peroxide scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). Force of contraction in response to isoprenaline (0.001 to 3 mu mol/liter) was d etermined in electrically stimulated muscle preparations. The iNOS mRNA exp ression was examined by in situ hybridization and by polymerase chain react ion. The cyclic guanosine monophosphate (cGMP) levels were determined by ra dioimmunoassay. RESULTS Isoprenaline concentration dependently increased force of contracti on. Six and 12 hours of LPS treatment of failing myocardium decreased maxim um inotropic response to isoprenaline by 54% (p = 0.009) and by 69% (p = 0. 0023), respectively. In nonfailing myocardium, 12 h of LPS treatment decrea sed maximum inotropic effect of isoprenaline by 66% (p < 0.001). The LPS ef fects were attenuated by L-NMMA, hemoglobin and also Tiron. The iNOS mRNA w as expressed in all LPS-treated preparations but also in most control myoca rdial preparations. In situ hybridization revealed iNOS expression within c ardiac myocytes. There nas no increase in myocardial cGMP content in respon se to endotoxin. CONCLUSIONS Endotoxin exposure of human myocardium leads to a depression of cardiac contractility, which is mediated by enhanced iNOS activity and rel ease of nitric oxide (NO). Consecutive reaction of NO with superoxide and f ormation of peroxynitrite may contribute to the decrease in force of contra ction. (J Am Coll Cardiol 1999;33:1062-70) (C) 1999 by the American College of Cardiology.