Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice

Background-Sepsis can be complicated by severe myocardial dysfunction and i s associated with increased nitric oxide (NO) production by inducible NO sy nthase (NOS2). To investigate the role of NOS2 in endotoxin-induced myocard ial dysfunction in vivo, we studied wild-type and NOS2-deficient mice. Methods and Results-Serial echocardiographic parameters of myocardial funct ion were measured before and at 4, 7, 16, and 24 hours after an endotoxin c hallenge. Seven hours after challenge with either endotoxin or saline, syst emic 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 (Slope(LVESPD)), and time constant of isovo lumic relaxation (tau) were calculated. Endotoxin challenge in wild-type mi ce decreased left ventricular fractional shortening, velocity of circumfere ntial shortening, dP/dt(max), Slope(LVESPD) and dP/dt(min) and increased ti me constant tau. Endotoxin-induced myocardial dysfunction was associated wi th increased ventricular NOS2 gene expression and cGMP concentrations. Seve n hours after endotoxin challenge, NOS2-deficient mice had greater fraction al shortening, dP/dt(max), and Slope(LVESPD) than did endotoxin-challenged wild-type mice. Measures of diastolic function, dP/dt(min) and time constan t tau, were preserved in endotoxin-challenged NOS2-deficient mice. After en dotoxin challenge in wild-type mice, early (3-hour) inhibition of NOS2 with L-N-6-(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.