Chemotherapy and Metabolic InhibitorsEffect of nitric oxide donors and nitric oxide synthase inhibitors in neonatal rat endotoxic shock
Section snippets
Animals
All rats used in these experiments were housed in the facilities for laboratory animals provided by the Department of Laboratory Animal Resources. The Medical University of South Carolina laboratory animal care is in accordance with the National Institutes of Health guidelines. The Medical University of South Carolina has full accreditation from the American Association for the Accreditation of Laboratory Animal Care, effective November 5, 1987. Pregnant Sprague–Dawley rats were purchased from
Mortality studies
The percent of mortality of the neonatal pups in response to the various doses of l-NAME and molsidomine was determined (Table 1). The ld50 of endotoxin in 24-hr-old neonatal rat pups was determined previously to be 0.024 mg/kg [17]. Increasing doses of l-NAME given prior to administration of an ld50 of endotoxin did not cause a statistically significant change in mortality. However, the trend was toward a higher mortality with increasing doses of l-NAME pretreatment. Increasing doses of
Discussion
Previous work from our group demonstrated a profound sensitivity of 24-hr-old rats to endotoxic shock compared with adult rats [17]. Zeller et al.[21] also demonstrated an increased susceptibility of 10-day-old rats to endotoxin compared with adult rats. The increased susceptibility of neonates to infection is well established. However, the exact pathophysiologic mechanisms of this increased susceptibility to endotoxin and infection remain unclear. Klein et al.[22] demonstrated decreased
Acknowledgements
This work was supported, in part, by Children’s Hospital Fund Grant CR 21 and by National Institutes of Health Grant GM 27673.
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Is nitric oxide overproduction the target of choice for the management of septic shock?
2001, Pharmacology and TherapeuticsCitation Excerpt :The list of these actions includes the prevention or reversal of the following abnormalities caused by the LPS challenge: depression of cardiac output (Fishman et al., 1997; Liaudet et al., 1996; Rosselet et al., 1998) and venous return (Fishman et al., 1997); altered microvascular permeability, leading to plasma extravasation and hypovolemia (Filep et al., 1997), endothelial dysfunction evaluated ex vivo in the aorta (Szabo et al., 1996a) and the pulmonary circulation (Fischer et al., 1999); loss of pulmonary vasoreactivity to inhaled NO (Holzmann et al., 1999); myocardial hypocontractility (Afulukwe et al., 2000; Ullrich et al., 2000); pulmonary edema (Heremans et al., 2000) and lung injury (Arkovitz et al., 1996; Fatehi-Hassanabad et al., 1996; Wang et al., 1999); liver injury (Kengatharan et al., 1996; Liaudet et al., 1997a, 1998; Ruetten et al., 1996; Szabo et al., 1994; Thiemermann et al., 1995; Wang et al., 1998); kidney dysfunction or injury (Fatehi-Hassanabad et al., 1996; Liaudet et al., 1997a; Schwartz et al., 1997; Szabo et al., 1994; Wu et al., 1996); injury to the gastrointestinal tract (Castaneda et al., 1999; Liaudet et al., 1997a) and pancreas (Liaudet et al., 1998; Ruetten et al., 1996; Wu et al., 1996); bacterial translocation from the gut lumen to the mesenteric lymph nodes (Unno et al., 1997); indications of tissue dysoxia such as systemic lactic acidosis (Liaudet et al., 1996, 1997a, 1997b; Rosselet et al., 1998); and reduced ATP content (Levy et al., 1999; Liaudet et al., 1997a) or mitochondrial respiration (Unno et al., 1997) in various organs. In contrast to observations made with nonselective compounds, administration of selective iNOS inhibitors to endotoxemic rodents decreased (Gryglewski et al., 1998; Liaudet et al., 1998; Szabo et al., 1994, 1996a; Takano et al., 1997; Tunctan et al., 1998; Wu et al., 1995; Yen et al., 1997) or did not change mortality (Cochran et al., 1999; Heremans et al., 2000; Koga et al., 1995; Yen et al., 1997), but never increased it. At least two studies support the finding that in endotoxemia, iNOS-derived NO may inhibit eNOS, leading to an endothelial dysfunction that may be reversed by selective iNOS inhibitors.
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