Negative inotropic effects of cytokines on the heart mediated by nitric oxide.
The direct effects of pro-inflammatory cytokines on the contractility of mammalian heart were studied. Tumor necrosis factor alpha, interleukin-6, and interleukin-2 inhibited contractility of isolated hamster papillary muscles in a concentration-dependent, reversible manner. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) blocked these negative inotropic effects. L-Arginine reversed the inhibition by L-NMMA. Removal of the endocardial endothelium did not alter these responses. These findings demonstrate that the direct negative inotropic effect of cytokines is mediated through a myocardial nitric oxide synthase. The regulation of pro-inflammatory cytokines and myocardial nitric oxide synthase may provide new therapeutic strategies for the treatment of cardiac disease.
Finkel
M S
MS
Department of Medicine, University of Pittsburgh School of Medicine, PA 15213.
Oddis
C V
CV
Jacob
T D
TD
Watkins
S C
SC
Hattler
B G
BG
Simmons
R L
RL
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004699:Endocardium / Q000166:cytology; D004848:Epithelium / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019323:omega-N-Methylarginine
D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine