© 1995 American Heart Association, Inc.
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Inhibition of Nitric Oxide Synthesis Causes Myocardial Ischemia in Endotoxemic Rats
From the Department of Surgery (J.A.M.A., H.A.B.), University Hospital Rotterdam (Netherlands) and the Department of Anesthesiology (J.A.M.A., C.I.), Academic Medical Center, Amsterdam, Netherlands.
Correspondence to C. Ince, PhD, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
Abstract Inhibitors of nitric oxide (NO) synthesis have been
used in the treatment of septic and endotoxic shock. However, several
studies question the beneficial effect of inhibiting NO production in
sepsis and endotoxemia. We have investigated the effect of inhibition
of NO synthesis after endotoxemia in the isolated perfused rat heart.
In hearts from endotoxin-treated animals, coronary flow was elevated
64% and oxygen consumption was elevated 20% compared with control
hearts. NADH fluorescence imaging was used as an indicator of regional
hypoperfusion. A homogeneous low-surface NADH fluorescence, indicative
of adequate tissue perfusion, was observed in both control and
endotoxin-treated hearts. The increase in coronary flow and oxygen
consumption could only partially be prevented by pretreatment of the
animals with dexamethasone. Addition of
N
-nitro-L-arginine (NNLA), an
inhibitor of NO synthesis, to the perfusion medium eliminated
differences in coronary flow and oxygen consumption between normal and
endotoxin-treated hearts. However, NADH surface fluorescence images of
endotoxin-treated hearts after NNLA revealed areas of high
fluorescence, indicating local ischemia, whereas the control hearts
remained without signs of ischemia. The ischemic areas were
present at various perfusion pressures and disappeared after the
infusion of L-arginine, the natural precursor of NO, or the
exogenous NO donor sodium nitroprusside. Methylene blue (MB), an
inhibitor of soluble guanylate cyclase, the effector enzyme of NO, also
eliminated differences in coronary flow and produced similar areas of
local myocardial ischemia in endotoxin-treated hearts but not in
control hearts. Reducing coronary flow by direct vasoconstriction with
vasopressin resulted in similar patterns of myocardial ischemia as with
NNLA and MB. Our results suggest that the coronary vasodilation in the
isolated rat heart after endotoxemia is caused by an increased release
of NO. Coronary flow reduction with NNLA, MB, or direct
vasoconstriction with vasopressin causes local areas of myocardial
ischemia in endotoxin-treated hearts but not in untreated hearts. These
data suggest that endotoxemia promotes myocardial ischemia in
vulnerable areas of the heart after inhibition of the NO pathway or
direct vasoconstriction.
Key Words: nitric oxide • sepsis • endotoxemia • myocardial ischemia • NADH fluorescence
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