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1 Section of Critical Care Medicine, Department of Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612; and 2 Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G-2S2
Previous studies have demonstrated the
existence of a circulating myocardial depressant substance during human
septic shock. We have recently identified this substance as a
synergistic combination of tumor necrosis factor-
(TNF-) and
interleukin-1
(IL-1). This study utilized an in vitro cardiac
myocyte assay to evaluate the potential mechanistic role of nitric
oxide (NO) and cGMP in depression of myocyte contractility induced by
TNF-, IL-1, TNF- + IL-1 (at low concentrations), and human
septic shock serum (HSS). TNF-, IL-1, TNF- + IL-1, and each
of 5 sera from patients with acute septic shock caused depression of
both maximum extent and peak velocity of cardiac myocyte shortening and
an increase in intracellular cGMP concentration during 30 min of
exposure (minimum P < 0.01). NO
synthetase (NOS) and guanylate cyclase inhibitors such as
N-methyl-L-arginine
(L-NMA) and methylene blue prevented these effects; an excess of
L-arginine with
L-NMA restored them (minimum
P < 0.01). In contrast,
D-arginine failed to reestablish cytokine-induced myocyte depression and cGMP accumulation prevented by
L-NMA. Exposure of myocytes to
TNF-, IL-1, or TNF- + IL-1 produced a
concentration-dependent increase in intracellular cGMP that paralleled
the depression of cardiac myocyte contractility (minimum
P < 0.001). In addition, TNF-,
IL-1, TNF- + IL-1, or HSS application to cardiac myocytes
resulted in increased NO gas generation, which was inhibited by
L-NMA (minimum
P < 0.01). Furthermore, unstimulated
cardiac myocytes were shown to harbor constitutive but not inducible
NOS activity. These data suggest that the sequential generation of NO
by a constitutive NOS and cGMP by guanylate cyclase represents an
important mechanism of cardiac myocyte depression by TNF-, IL-1,
TNF- + IL-1, and the myocardial depressant substance(s)
of septic shock.
myocardial depressant factor; cytokine; heart contractility; cyclic nucleotide; septicemia
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