Nitric Oxide Synthase Inhibition Aggravates Intestinal Microvascular Vasoconstriction and Hypoperfusion of Bacteremia

Spain, David A.; Wilson, Mark A.; Barnatan, Marcos F.; Garrison, R. Neal

doi:10.1097/00005373-199405000-00021

Cited by 63 publications

(16 citation statements)

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“…In most of these diseases, abnormally high NO production induces profound vasodilation and vasopressor-refractory hypotension. A marked increase in iNOS underlies the elevated NO production in sepsis (49), and nonselective NOS inhibitors increase blood pressure in animal models of sepsis, but have had a mixed effect on sepsis-associated mortality in animals and humans (18,50); this may relate, in part, to inhibition of eNOS leading to microvascular vasoconstriction and decreased tissue and organ perfusion (51)(52)(53)(54)(55). Selective iNOS inhibitors should avoid some of the problems encountered with nonspecific inhibitors, but iNOS expression in some tissues may be functionally important as has been found for myocyte iNOS (11, 56 -59).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Broderick¹,

Veena²,

Zhuang

et al. 2005

Journal of Biological Chemistry

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Nitric oxide (NO) is an important signaling molecule, and a number of NO synthesis inhibitors and scavengers have been developed to allow study of NO functions and to reduce excess NO levels in disease states. We showed previously that cobinamide, a cobalamin (vitamin B 12 ) precursor, binds NO with high affinity, and we now evaluated the potential of cobinamide as a NO scavenger in biologic systems. We found that cobinamide reversed NO-stimulated fluid secretion in Drosophila Malpighian tubules, both when applied in the form of a NO donor and when produced intracellularly by nitricoxide synthase. Moreover, feeding flies cobinamide markedly attenuated subsequent NO-induced increases in tubular fluid secretion. Cobinamide was taken up efficiently by cultured rodent cells and prevented NOinduced phosphorylation of the vasodilator-stimulated phosphoprotein VASP both when NO was provided to the cells and when NO was generated intracellularly. Cobinamide appeared to act via scavenging NO because it reduced nitrite and nitrate concentrations in both the fly and mammalian cell systems, and it did not interfere with cGMP-induced phosphorylation of VASP. In rodent and human cells, cobinamide exhibited toxicity at concentrations >50 M with toxicity completely prevented by providing equimolar amounts of cobalamin. Combining cobalamin with cobinamide had no effect on the ability of cobinamide to scavenge NO. Cobinamide did not inhibit the in vitro activity of either of the two mammalian cobalamin-dependent enzymes, methionine synthase or methylmalonyl-coenzyme A mutase; however, it did inhibit the in vivo activities of the enzymes in the absence, but not presence, of cobalamin, suggesting that cobinamide toxicity was secondary to interference with cobalamin metabolism. As part of these studies, we developed a facile method for producing and purifying cobinamide. We conclude that cobinamide is an effective intra-and extracellular NO scavenger whose modest toxicity can be eliminated by cobalamin.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Broderick¹,

Veena²,

Zhuang

et al. 2005

Journal of Biological Chemistry

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“…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].…”

Section: Discussionmentioning

confidence: 99%

Platelet-Activating Factor and Bacteremia-Induced Pulmonary Hypertension

Clavijo¹,

Carter²,

Matheson³

et al. 2000

Journal of Surgical Research

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“…In contrast, in an acute sepsis model in rats, inhibition of NOS caused an increased vasoconstriction of the small intestine as studied by videomicroscopy and Doppler flowcytometry [55]. Furthermore, the ileum appeared especially dependent on physiological production of NO during the acute phase of lipopolysaccharide-induced sepsis in rats [56].…”

Section: Nitric Oxide Donorsmentioning

confidence: 97%

Opening the microcirculation: can vasodilators be useful in sepsis?

2002

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Prostacyclin and nitric oxide donors are the best studied vasodilating agents in experimental sepsis and have shown improved tissue perfusion and oxygen extraction. In several clinical studies prostacyclin has also been shown to have such beneficial effects. Recent studies using orthogonal polarization spectral imaging have shown microcirculatory recruitment by nitric oxide donors in hemodynamically resuscitated septic patients. Whether such therapeutic modalities aimed at recruitment of the microcirculation improve outcome, however, still has to be determined.

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Nitric Oxide Synthase Inhibition Aggravates Intestinal Microvascular Vasoconstriction and Hypoperfusion of Bacteremia

Cited by 63 publications

References 0 publications

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Platelet-Activating Factor and Bacteremia-Induced Pulmonary Hypertension

Opening the microcirculation: can vasodilators be useful in sepsis?

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