Ventilatory Response to Hypoxia during Endotoxemia in Young Rats: Role of Nitric Oxide

Abstract

Administration of Escherichia coli endotoxin attenuates the ventilatory response to hypoxia (VRH) in newborn piglets, but the mechanisms responsible for this depression are not clearly understood. Nitric oxide (NO) production increases during sepsis and elevated NO levels can inhibit carotid body function. The role of endothelial NO on the VRH during endotoxemia was evaluated in 26 young rats. Minute ventilation (V E ) and oxygen consumption (VO 2 ) were measured in room air (RA) and during 30 min of hypoxia (10% O 2 ) before and after E. coli endotoxin administration. During endotoxemia, animals received placebo (PL, n ϭ 8); a nonselective nitric oxide synthase (NOS) inhibitor (N G -nitro-L-arginine methyl ester, L-NAME, n ϭ 9), or a neuronal NOS (nNOS) inhibitor (7-nitroindazole, 7-NI, n ϭ 9). During endotoxemia, a larger increase in V E was observed only during the first min of hypoxia in the L-NAME group when compared with PL or 7-NI (p Ͻ 0.001). VRH was similar in the PL and 7-NI groups. A larger decrease in VO 2 at 30 min of hypoxia was observed in L-NAME and 7-NI groups when compared with PL (p Ͻ 0.03). These data demonstrate that the attenuation of the early VRH during endotoxemia is in part mediated by an inhibitory effect of endothelial NO on the respiratory control mechanisms. (Pediatr Res 62: 134-138, 2007) C hanges in breathing pattern and apnea episodes are frequently observed in newborns and infants with sepsis (1). In adult humans, endotoxin administration results in changes in the basal respiratory pattern and dyspnea (2). We previously demonstrated that endotoxin infusion in newborn piglets produced attenuation of the VRH (3). In a pilot study, we also observed similar respiratory behavior in 4-to 6-wkold rats. The interaction of hypoxia, infection, and cytokine abnormalities has been suggested as a possible mechanism of sudden infant death syndrome (SIDS) (4).The mechanisms that explain the changes in breathing pattern during sepsis are not clearly understood. Respiratory muscle fatigue or alterations in lung mechanics and metabolic rate have been associated with the respiratory changes observed during Gram-positive and negative septicemia in piglets (3,5,6). Particularly, the attenuation in the VRH observed after endotoxin administration to unanesthetized newborn piglets was associated with a significant decrease in VO 2 (3). Sepsis can induce the release of inflammatory mediators such as cytokines; prostaglandins, and NO (7,8), which may be responsible for the alterations of the breathing pattern observed during endotoxemia and also may be an important component of many deaths attributed to SIDS (4).It is known that NO is an active participant in the pathophysiology of endotoxemia (9). NO is synthesized from Larginine by three different isoenzymes of NOS: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) (10). Increased eNOS activation and endothelial NO release have been observed shortly after endotoxin administration (11,12). Elevated NO expression has been fou...

Intermittent Hypoxic Episodes in Preterm Infants: Do They Matter?

“…This is associated with an attenuated ventilatory response to hypoxia, both before and after carotid sinus nerve transection [17] . This is consistent with prior data that endotoxemia impairs the ventilatory response to hypoxia in rat pups [18] , and that prostaglandin-mediated respiratory inhibition may be implicated [19] . In summary, as seen in figures 3 and 4 , we speculate that immature or impaired respiratory control and resultant intermittent hypoxia may initiate a proinflammatory and/or prooxidant cascade that, in turn, may further inhibit respiratory neural output and aggravate the problem.…”

Lung inflammation induces IL-1β expression in hypoglossal neurons in rat brainstem

“…We recognize that our model comprising intrapulmonary LPS exposure may initiate inflammation that is compartmentalized to the lung, initiate a blood-borne proinflammatory response, or both. Prior studies have employed injection of E. coli, endotoxin, LPS, or recombinant IL-1β via the intraperitoneal route to simulate neonatal sepsis in rat pups (Ladino et al, 2007, Olsson et al, 2003). As IL-1β does not readily cross the blood brain barrier, a likely mechanism for the resultant apnea was thought to be IL-1β-induced activation of the cyclooxygenase-2 pathway and release of prostaglandin E2 which can cross the blood brain barrier with resultant respiratory depression (Hofstetter et al, 2007).…”

The impact of inflammation on respiratory plasticity

“…The possibility that such differences also contribute to the opposite effects of inflammation induced by LPS versus inspired hypoxia on chemoreflexes (inhibiting vs. facilitating, respectively), remains to be tested. In a number of animal species, the hypoxic or hypercapnic ventilatory responses are actually attenuated by systemic inflammation (Fernández et al, 2008; Ladino et al, 2007; McDeigan et al, 2003). …”