(Circulation. 2000;102:1440.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Congenital Deficiency of Nitric Oxide Synthase 2 Protects Against Endotoxin-Induced Myocardial Dysfunction in Mice
From the Department of Anesthesia and Critical Care (R.U., F.I., W.M.Z., Z.M.N.Q.) and the Cardiology Division (M.S.-C., K.D.B., M.H.P.), Cardiac Ultrasound Laboratory (M.S.-C., M.H.P.), and Cardiovascular Research Center (K.D.B., F.I., H.N., Z.M.N.Q.) of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
Correspondence to Warren M. Zapol, MD, Reginald Jenney Professor of Anaesthesia, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 32 Fruit St, Boston, MA 02114. E-mail zapol{at}etherdome.mgh.harvard.edu
Background—Sepsis can be complicated by severe myocardial dysfunction and is associated with increased nitric oxide (NO) production by inducible NO synthase (NOS2). To investigate the role of NOS2 in endotoxin-induced myocardial dysfunction in vivo, we studied wild-type and NOS2-deficient mice.
Methods and Results—Serial echocardiographic
parameters of myocardial function were measured before and
at 4, 7, 16, and 24 hours after an endotoxin challenge. Seven hours
after challenge with either endotoxin or saline, systemic and left
ventricular pressures were measured, and the first
derivative of left ventricular developed pressure (dP/dt),
slope of the end-systolic pressure–dimension relationship
(SlopeLVESPD), and time constant of isovolumic relaxation
(
) were calculated. Endotoxin challenge in wild-type mice decreased
left ventricular fractional shortening, velocity of
circumferential shortening, dP/dtmax,
SlopeLVESPD, and dP/dtmin and increased time
constant . Endotoxin-induced myocardial dysfunction was associated
with increased ventricular NOS2 gene expression and cGMP
concentrations. Seven hours after endotoxin challenge, NOS2-deficient
mice had greater fractional shortening, dP/dtmax, and
SlopeLVESPD than did endotoxin-challenged wild-type mice.
Measures of diastolic function, dP/dtmin and
time constant , were preserved in endotoxin-challenged
NOS2-deficient mice. After endotoxin challenge in wild-type mice, early
(3-hour) inhibition of NOS2 with
L-N6-(1-iminoethyl)lysine
hydrochloride prevented, whereas later (7-hour) inhibition could not
reverse, endotoxin-induced myocardial dysfunction.
Conclusions—These results suggest that NOS2 is required for the development of systolic and diastolic dysfunction in murine sepsis.
Key Words: echocardiography • heart failure • inflammation • inhibitors • sepsis
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