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

Abstract

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. 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 (Slope(LVESPD)), and time constant of isovolumic relaxation (tau) were calculated. Endotoxin challenge in wild-type mice decreased left ventricular fractional shortening, velocity of circumferential shortening, dP/dt(max), Slope(LVESPD), and dP/dt(min) and increased time constant tau. 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/dt(max), and Slope(LVESPD) than did endotoxin-challenged wild-type mice. Measures of diastolic function, dP/dt(min) and time constant tau, were preserved in endotoxin-challenged NOS2-deficient mice. After endotoxin 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. These results suggest that NOS2 is required for the development of systolic and diastolic dysfunction in murine sepsis.