N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.

Abstract

SllmmaryInhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N~~ (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N~-amino-t-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVKI and PVKI, p ~< 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p -0.046) compared with controls (n = 6). Moreover, N'~ increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of t-arginine did not improve survival or alter the cardiopulmonary effects of N~~ -arginine, which suggests that inhibition of NOS may not have been competitive, In normal animals, N~176 alone (n = 3) increased SVtLI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N~'-amino-L-arginine, or both.

Mechanisms of Brain Injury in Bacterial Meningitis: Workshop Summary

“…However, the higher dose of l-NA resulted in the death of four of five rats between the second and third hour of treatment, whereas none of the rats that were infected and then either left untreated or treated with the lower dose died. Similar increased mortality rates were reported by Cobb et al [52], who administered N G amino-t-arginine to awake dogs after challenge with endotoxin, and by Haberl et al [53], who administered l-NA methyl ester to rats with experimental pneumococcal meningitis. Studies investigating the effect of l-NA in uninfected rats are warranted.…”

Effect of Nitric Oxide Synthase Inhibition during Group B Streptococcal Sepsis in Neonatal Piglets

“…These arginine analogs have been used to determine the extent of ongoing NO production during pathologic conditions. In adult dogs administered a single bolus of endotoxin, L-NAA further augmented the endotoxin-induced increase in PVR, suggesting that NO modulates PVR in this model of Gramnegative sepsis (9). There are no reports on the influence of endogenous NO on pulmonary vascular tone during sepsis produced by Gram-positive organisms.…”

“…Enhanced NO production contributes to endotoxin-mediated systemic hypotension in adult animals (1,2,(5)(6)(7)(8)(9). There are no published reports on the role of endogenous NO in the control of pulmonary arterial pressure in neonatal animal models of sepsis and pulmonary hypertension.…”

“…L-Arginine analogs, such as L-NAME and L-NAA, are competitive antagonists of both isoforms of NOS and inhibit NO synthesis (4,9). These arginine analogs have been used to determine the extent of ongoing NO production during pathologic conditions.…”

The nonspecific inflammatory response to injury

“…It is also clear that therapy aimed at blunting the inflammatory response may paradoxically worsen clinical outcomes. 93,94 This likely represents a delicate balance that exists in which either under or over expression of the inflammatory response may be harmful (e.g. during CPB, either too much NO 77 or insufficient NO ss may be harmful).…”