Protective Role of Pulmonary Nitric Oxide in the Acute Phase of Endotoxemia in Rats

Abstract

We present for the first time direct continuous assay of NO concentration (porphyrinic sensor) in the lung parenchyma of Sprague-Dawley rats in vivo during endotoxemia. Intravenous infusion of lipopolysaccharide (LPS, 2 mg x kg(-1) x min(-1) for 10 minutes) stimulated an acute burst of NO from constitutive NO synthase (NOS) that peaked 10 to 15 minutes after the start of LPS infusion, mirroring a coincident peak drop in arterial pressure. NO concentration declined over the next hour to twice above pre-LPS infusion NO levels, where it remained until the rats died, 5 to 6 hours after LPS infusion. The chronic drop in arterial pressure observed from 70 minutes to 6 hours after the start of LPS infusion was not convincingly mirrored by a chronic increase in NO concentration, even though indirect NO assay (Griess method, assaying NO decay products NO2-/NO3-) showed that NO production was increasing as a result of continuous NO release by inducible NOS. A NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA, 10 mg/kg i.v.) injected 45 minutes before LPS infusion, resulted in sudden death accompanied by macroscopically/microscopically diagnosed symptoms similar to acute respiratory distress syndrome <25 minutes after the start of LPS infusion. Pharmacological analysis of this L-NNA+LPS model by replacing L-NNA with 1-amino-2-hydroxy-guanidine (selective inhibitor of inducible NOS) or by pretreatment with S-nitroso-N-acetyl-penicillamine (NO donor), camonagrel (thromboxane synthase inhibitor), or WEB2170 (platelet-activating factor receptor antagonist) indicated that in the early acute phase of endotoxemia, LPS stimulated the production of cytoprotective NO, cytotoxic thromboxane A2, and platelet-activating factor.

Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat

“…26 The literature concerning the role of NO in endotoxic shock is, however, confusing with reports of both protective and deleterious effects, for example, although infusion of L-nitromonomethyl arginine may transiently improve blood pressure, there may be a marked reduction of survival. 27 Several studies have shown that both Kupffer cells and hepatocytes themselves synthesize NO. 28,29 In LPS treated rats portal and systemic plasma nitrite and nitrate levels (considered markers of NO production) are increased over 40-fold compared with normal rats as a result of iNOS induction by LPS.…”

Platelet-Activating Factor and Bacteremia-Induced Pulmonary Hypertension

“…The fact that NO production occurs by a mechanism independent of PAF might be teleologically advantageous. Others report that prevention of NO synthesis greatly worsens cellular and organ dysfunction attributed to PAF during endotoxemia or bacteremia [33][34][35]. Especially in the lung, NO may exert a protective effect [34].…”

Physiologically Relevant Measurements of Nitric Oxide in Cardiovascular Research Using Electrochemical Microsensors

“…iNOS is thought to play a pivotal role in endotoxemia, and NO concentration has been measured in endotoxemia by insertion of an NO-sensitive porphyrin microelectrode in the lung [110], in the aorta wall [111], or in the pulmonary artery wall [112]. Injection of lipopolysaccharide to induce endotoxemia was followed by a decrease in systemic arterial pressure, and a transient increase in NO (baseline 50 n M , peak 150 n M NO) which lasted 20 min was measured both in the aortic wall [110] and lung tissue [111].…”

“…Injection of lipopolysaccharide to induce endotoxemia was followed by a decrease in systemic arterial pressure, and a transient increase in NO (baseline 50 n M , peak 150 n M NO) which lasted 20 min was measured both in the aortic wall [110] and lung tissue [111]. A second slower rise was recorded in the pulmonary artery at 45 min [112].…”

“…A second slower rise was recorded in the pulmonary artery at 45 min [112]. The increase in NO concentration demonstrated to be protective in the acute phase of endotoxemia, since inhibition of the NO increase by NOS inhibitors shortens survival of the rats with endotoxemia [111]. The low levels of free NO concentration measured in endotoxemia correspond to the levels detected in isolated preparations in vitro as mentioned above [43, 54, 55], and hence, underline that it is possible to obtain reliable measurements of NO concentration in living animals.…”