Nitric oxide (NO) produced by the induced NO synthase (NOS) enzyme has been implicated in the mechanisms of the circulatory changes that occur in the later stages of sepsis. As NO produced by the constitutive form of the enzyme is known to play a role in the regulation of normal circulation, we have performed a series of experiments to study the early circulatory effects of inhibition of NOS in a hyperdynamic endotoxemic dog model. Pentobarbital-anesthetized animals were used. Cardiac output (CO) was measured by thermodilution. Myocardial contractility (MC) was estimated from the slope of the left ventricular end-systolic pressure-diameter relationship obtained from sonomicrometer- and catheter-tip manometer signals in closed-chest animals. All animals received a 15 mL/kg/h infusion of Ringer's lactate. A hyperdynamic response was elicited by a 2 h infusion of a total dose of 5.3 μg/kg Escherichia coli O55:B5 endotoxin (ETX). CO increased initially by about 25%, and total peripheral resistance decreased by 35%. These changes subsided in 60-90 min, after which a sustained decrease in CO occurred. MC elevated transiently by 25% after the first 30 min of ETX infusion, then decreased gradually below the control level. Administration of 2 mg/kg of the NOS inhibitor N-nitro-L-arginine (NNA) between the 45th and 55th min of the ETX infusion increased MC to the level in the control group, but accelerated the decline of the initially increased CO and caused a sustained increase in total peripheral resistance to about 50% above the control level. In normal (nonendotoxin treated) dogs, NNA also caused a similar increase in MC which, however, lasted at least 3 h. Left ventricular diameter increased in the NNA-treated groups. This increase also occurred in the endotoxin-only group but with a delay of about 2.5 h. Our results demonstrate the participation of constitutive NOS-produced NO in the early hyperdynamic response of endotoxemia. Suppression of NO is associated with increased myocardial contractility. NNA treatment may be favorable for the restoration of depressed cardiac contractility during endotoxemia, but this treatment is probably detrimental for the compensatory systemic flow (CO) increase.
ASJC Scopus subject areas
- Emergency Medicine
- Critical Care and Intensive Care Medicine