NO Overproduction (no + overproduction)

Distribution by Scientific Domains


Selected Abstracts


Insulin resistance, a new target for nitric oxide-delivery drugs

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2002
Stéphane Cook
Abstract In the Western hemisphere, the incidence of insulin resistance and its complications has been growing rapidly and is reaching epidemic proportions. Over the past decade, evidence has accumulated, indicating that nitric oxide (NO) plays a key role in the regulation of metabolic and cardiovascular homeostasis. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes insulin resistance, arterial hypertension and dyslipidemia in mice, and characterizes insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction in mice, may also cause metabolic insulin resistance, suggesting a Yin,Yang effect of NO in the regulation of glucose homeostasis. Here, we will review the evidence for this novel concept, and thereby provide the conceptual framework for the use of NO-delivery drugs and pharmacological agents that modulate the bioavailability of endogenously produced NO for the treatment of insulin resistance. [source]


Acceleration of nitric oxide autoxidation and nitrosation by membranes

IUBMB LIFE, Issue 4-5 2007
Matias N. Möller
Abstract The reaction between nitric oxide (,NO) and oxygen yields reactive species capable of oxidizing and nitrosating proteins, as well as deaminating DNA bases. Although this reaction is considered too slow to be biologically relevant, it has been shown that membranes, lipoproteins, mitochondria and possibly proteins can accelerate this reaction. This effect stems from the higher solubility of both ,NO and O2in the hydrophobic phase of these biological particles, leading to a concentration of both reagents and so a higher rate of reaction. It has been determined that this reaction occurs from 30 to 300 times more rapidly within the membrane, while even higher values have been suggested for proteins. The autoxidation of ,NO in membranes is not the main route for cellular ,NO consumption but an important consequence of this phenomenon is to focus the generation of significant amounts of oxidizing and nitrosating molecules (nitrogen dioxide and dinitrogen trioxide) in the small volume comprised by cellular membranes. Even so, these reactive species are diffusible and their ultimate fate will depend on the reactivity towards available substrates rather than on physical barriers. The acceleration of ,NO autoxidation by biological hydrophobic phases may thus be a general phenomenon that increases in importance in cases of ,NO overproduction. IUBMB Life, 59: 243-248, 2007 [source]


Nitric Oxide-Mediated Intestinal Injury Is Required for Alcohol-Induced Gut Leakiness and Liver Damage

ALCOHOLISM, Issue 7 2009
Yueming Tang
Background:, Alcoholic liver disease (ALD) requires endotoxemia and is commonly associated with intestinal barrier leakiness. Using monolayers of intestinal epithelial cells as an in vitro barrier model, we showed that ethanol-induced intestinal barrier disruption is mediated by inducible nitric oxide synthase (iNOS) upregulation, nitric oxide (NO) overproduction, and oxidation/nitration of cytoskeletal proteins. We hypothesized that iNOS inhibitors [NG-nitro- l -arginine methyl ester (l -NAME), l -N6 -(1-iminoethyl)-lysine (l -NIL)] in vivo will inhibit the above cascade and liver injury in an animal model of alcoholic steatohepatitis (ASH). Methods:, Male Sprague,Dawley rats were gavaged daily with alcohol (6 g/kg/d) or dextrose for 10 weeks ± l -NAME, l -NIL, or vehicle. Systemic and intestinal NO levels were measured by nitrites and nitrates in urine and tissue samples, oxidative damage to the intestinal mucosa by protein carbonyl and nitrotyrosine, intestinal permeability by urinary sugar tests, and liver injury by histological inflammation scores, liver fat, and myeloperoxidase activity. Results:, Alcohol caused tissue oxidation, gut leakiness, endotoxemia, and ASH. l -NIL and l -NAME, but not the d -enantiomers, attenuated all steps in the alcohol-induced cascade including NO overproduction, oxidative tissue damage, gut leakiness, endotoxemia, hepatic inflammation, and liver injury. Conclusions:, The mechanism we reported for alcohol-induced intestinal barrier disruption in vitro , NO overproduction, oxidative tissue damage, leaky gut, endotoxemia, and liver injury , appears to be relevant in vivo in an animal model of alcohol-induced liver injury. That iNOS inhibitors attenuated all steps of this cascade suggests that prevention of this cascade in alcoholics will protect the liver against the injurious effects of chronic alcohol and that iNOS may be a useful target for prevention of ALD. [source]


NF-,B involvement in the induction of high affinity CAT-2 in lipopolysaccharide-stimulated rat lungs

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2004
C.-J. Huang
Background:, Endotoxemia stimulates nitric oxide (NO) biosynthesis through induction of inducible NO synthase (iNOS). Cellular uptake of l -arginine, the sole substrate for iNOS, is an important mechanism regulating NO biosynthesis by iNOS. The isozymes of type-2 cationic amino acid transporters, including CAT-2, CAT-2A, and CAT-2B, constitute the most important pathways responsible for trans -membrane l -arginine transportation. Therefore, regulation of CAT-2 isozymes expression may constitute one of the downstream regulatory pathways that control iNOS activity. We investigated the time course of enzyme induction and the role of nuclear factor-,B (NF-,B) in CAT-2 isozymes expression in lipopolysaccharide-(LPS) treated rat lungs. Methods:, Adult male Sprague,Dawley rats were randomly given intravenous injections of normal saline (N/S), LPS, LPS plus NF-,B inhibitor pre-treatment (PDTC, dexamethasone, or salicylate), or an NF-,B inhibitor alone. The rats were sacrificed at different times after injection and enzyme expression and lung injury were examined. Pulmonary and systemic NO production were also measured. Results:, LPS co-induced iNOS, CAT-2, and CAT-2B but not CAT-2A expression in the lungs. Furthermore, NF-,B actively participated in LPS-induction of iNOS, CAT-2, and CAT-2B. LPS induced pulmonary and systemic NO overproduction and resulted in lung injuries. Attenuation of LPS-induced iNOS, CAT-2, and CAT-2B induction significantly inhibited NO biosynthesis and lessened lung injury. Conclusion:, NF-,B actively participates in the induction of CAT-2 and CAT-2B in intact animals. Our data further support the idea that CAT-2 and CAT-2B are crucial in regulating iNOS activity. [source]