EFFECT OF NITRIC-OXIDE SYNTHASE INHIBITION ON MYOCARDIAL-CONTRACTILITY IN ANESTHETIZED NORMAL AND ENDOTOXEMIC DOGS

Nitric oxide (NO) produced by the induced NO synthase (NOS) enzyme has been implicated in the mechanisms of the circulatory changes that occ ur in the later stages of sepsis. As NO produced by the constitutive f orm 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 ea rly circulatory effects of inhibition of NOS in a hyperdynamic endotox emic 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 cathe ter-tip manometer signals in closed-chest animals. All animals receive d a 15 mL/kg/h infusion of Ringer's lactate. A hyperdynamic response w as elicited by a 2 h infusion of a total dose of 5.3 mu g/kg Escherich ia coil O55:B5 endotoxin (ETX). CO increased initially by about 25%, a nd total peripheral resistance decreased by 35%. These changes subside d in 60-90 min, after which a sustained decrease in CO occurred. MC el evated transiently by 25% after the first 30 min of ETX infusion, then decreased gradually below the control level. Administration of 2 mg/k g of the NOS inhibitor N-nitro-L-arginine (NNA) between the 45th and 5 5th min of the ETX infusion increased MC to the level in the control g roup, but accelerated the decline of the initially increased CO and ca used a sustained increase in total peripheral resistance to about 50% above the control level. In normal (nonendotoxin treated) dogs, NNA al so 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 constitutiv e NOS-produced NO in the early hyperdynamic response of endotoxemia. S uppression of NO is associated with increased myocardial contractility . NNA treatment may be favorable for the restoration of depressed card iac contractility during endotoxemia, but this treatment is probably d etrimental for the compensatory systemic flow (GO) increase.