Detrimental effect of a non-selective nitric oxide synthase inhibitor on the energy state of the liver following acute endotoxemia in rabbits.
BACKGROUND
The effect of nitric oxide synthase (NOS) inhibitors in septic shock is very controversial. It is known that the administration of NOS inhibitors to normal subjects itself increases pulmonary vascular resistance with a concomitant decrease of cardiac output. Therefore, the hypothesis was tested that the detrimental effects of a non-selective NOS inhibitor on liver energetics in a rodent model of endotoxemia are mediated by the adverse pulmonary circulatory effect of the drug itself.


METHODS
Twenty anesthetized rabbits were instrumented and two separate experiments (a magnetic resonance spectroscopic study and a hemodynamic study) were performed under similar conditions. Animals were assigned randomly to either a control group (group 1; animals received lipopolysaccharide (LPS) at a dose of 400 microg/kg alone) or a treatment group (group 2; animals received NG-nitro-L-arginine methyl ester (L-NAME) at a dose of 7.5 mg/kg, 75 min after administration of LPS).


RESULTS
In group 1, slight decreases in hepatic adenosine triphosphate (ATP) value were observed. In group 2, the decreases in ATP values were more prominent than those observed in group 1. LPS produced an acute drop in mean arterial pressure (MAP) with a concomitant increase in pulmonary vascular resistance (PVR) and a reduction in the cardiac output (CO) at 30 min after LPS. The administration of L-NAME caused a transient increase in MAP with a concomitant increase in systemic vascular resistance at 2 h after LPS. However, these changes in PVR and CO were more prominent than in group 1.


CONCLUSIONS
These results suggest that alterations within the pulmonary circulation may be a contributing factor which was responsible for the non-selective NOS inhibitor-induced acute hepatic energy derangement after LPS.
Kaneda
K
K
Department of Anesthesiology and Critical Care Medicine, Tokyo Medical and Dental University, School of Medicine, Japan.
Makita
K
K
Yokoyama
K
K
Toyooka
H
H
Amaha
K
K
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019446:Endotoxemia / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006439:Hemodynamics / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011817:Rabbits
D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester