Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

Chen, Luni; He, Hao; Mondéjar, E. Fernández; Hedenstierna, Göran

doi:10.1152/ajpheart.00535.2002

Cited by 4 publications

(2 citation statements)

References 23 publications

(48 reference statements)

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“…Evidence that NOS inhibition may also contribute to the increase in pulmonary arterial pressure exists (43)(44)(45); however, whether inhibition actually occurs is still a matter of debate (46,47). RBCs, in conjunction with other vasoconstrictors (48,49), may mediate the rebound effect seen on termination of NO inhalation therapy.…”

Section: Discussionmentioning

confidence: 99%

Regulation of nitric oxide consumption by hypoxic red blood cells

Han

Qamirani

Nelson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The homeostasis of nitric oxide (NO) is attained through a balance between its production and consumption. Shifts in NO bioavailability have been linked to a variety of diseases. Although the regulation of NO production has been well documented, its consumption is largely thought to be unregulated. Here, we have demonstrated that under hypoxic conditions, NO accelerates its own consumption by increasing its entry into RBCs. When RBCs were exposed to NO (1:400 NO͞heme ratio) under hypoxic conditions to form HbFe(II)NO, the consumption rate of NO increased significantly. This increase in NO consumption converted the bioactivity of serotonin from a vasodilator to a vasoconstrictor in isolated coronary arterioles. We identified HbFe(II)NO as a potential mediator of accelerated NO consumption. Accelerated NO consumption by HbFe(II)NO-bearing RBCs may contribute to hypoxic pulmonary vasoconstriction and the rebound effect seen on termination of NO inhalation therapy. Furthermore, accelerated NO consumption may exacerbate ischemia-mediated vasospasm and nitrate tolerance. Finally, this phenomenon may be an evolved mechanism to stabilize the vasculature in sepsis. N itric oxide (NO) is a signaling molecule produced by three isoforms of NO synthases for a variety of functions, including regulation of vasculature, participation in immune responses, and neuronal signaling͞regulation. Regulation of NO concentration has generated considerable interest, because changes in NO bioavailability have been linked to a variety of disease states (1). The homeostasis of NO is attained through a balance between its production and consumption. In the vasculature, RBCs are the major scavenger of NO, because RBCs contain high concentrations of Hb, an effective NO scavenger. HbFe(II)O 2 converts NO to nitrate, whereas HbFe(II) binds to NO to form HbFe(II)NO. Because Hb efficiently consumes NO at extremely high rates, the consumption of NO has generally been considered to be unregulated.However, when Hb is enclosed within RBCs, its consumption of NO decreases significantly (2-5). This reduction in NO consumption has been attributed to (i) the RBC-free zone near the vessel wall (2), (ii) extracellular diffusion resistance from the bulk solution to the RBC surface (3), and (iii) the intracellular barrier associated with the RBC membrane and membrane skeleton (4). In support of the last mechanism, Huang et al. (4) have demonstrated that chemical modifications to the RBC result in the modulation of NO bioavailability by altering the rate RBCs consume NO. This result suggested that changes to the consumption of NO can potentially be an effective means to regulate NO bioavailability.To investigate the physiological relevance of this potential regulatory mechanism, we tested various molecules that can serve as a physiological modulator of NO consumption. Surprisingly, we found that NO consumption by RBCs can be modulated by NO itself at concentrations found in vivo, but only under hypoxic conditions that allow for the formation of HbFe(II)NO. Th...

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Section: Discussionmentioning

confidence: 99%

Regulation of nitric oxide consumption by hypoxic red blood cells

Han

Qamirani

Nelson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…The phenomenon of the rebound response is one of the major complications of stopping prolonged inhaled NO therapy (27,38,39). Our protocol allowed for monitoring the response of the animal for an interval of only 5 min after stopping ENO 2 inhalation.…”

Section: Discussionmentioning

confidence: 99%

A Novel Inhaled Organic Nitrate That Affects Pulmonary Vascular Tone in a Piglet Model of Hypoxia-Induced Pulmonary Hypertension

et al. 2005

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Persistent pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance after birth leading to right-to-left shunting and systemic arterial hypoxemia. Inhaled nitric oxide (NO) is effective in reducing the need for extracorporeal membrane oxygenation, but it has potential toxicities, especially in an oxygen-rich environment. A number of other NO-based molecules have been given by inhalation, but their structure-function relationships have not been established. Recent studies have raised the idea that toxic and beneficial properties can be separated. We synthesized a novel organic nitrate [ethyl nitrate (ENO 2 )], tested it in vitro, and administered it to hypoxic piglets. ENO 2 lowered pulmonary artery pressure and raised the PO 2 in arterial blood but did not alter systemic vascular resistance or methemoglobin levels. In addition, we tested the effect of ENO 2 in the presence of the thiol glutathione, both in vivo and in vitro, and found its action to be enhanced. Although ENO 2 is less potent than inhaled NO on a doseequivalency basis, pretreatment of hypoxic animals with glutathione, which may be depleted in injured lungs, led to a markedly enhanced effect (largely mitigating the difference in potency). The disease entity persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR) after birth leading to extrapulmonary right-to-left shunting through the patent foramen ovale and patent ductus arteriosus with resulting systemic arterial hypoxemia. These patients are frequently treated with inhaled nitric oxide (NO) and may require extracorporeal membrane oxygenation; those with severe respiratory failure are at increased risk for neurodevelopmental impairment (1,2). NO's clinical effectiveness has been well documented (3-6), although some reports suggest that it may exacerbate lung inflammation (7), raising the concern that it may have toxic properties in some clinical settings. Infants who receive inhaled NO for PPHN are often treated with high inspired oxygen, and in the O 2 -rich environment of the lung, higher oxides of nitrogen (NO x ) including peroxynitrite may form (8), which can cause hemorrhage, inflammation, and edema (9,10). Airways of animal and human subjects who have received inhaled NO showed the same patterns of oxidative injury found in animals and humans who were exposed to NO x or hyperoxia (11,12).Inhaled, exogenous NO is delivered to well-ventilated parts of the lung and will stimulate guanylate cyclase activity, leading to vascular smooth muscle relaxation. Thus, NO has been effective in lowering pulmonary artery pressure (PAP)

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Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

Szabó

2010

Burger's Medicinal Chemistry and Drug Discovery

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Nitric oxide ( NO ), carbon monoxide ( CO ), and hydrogen sulfide ( H 2 S ) are the main endogenous gasotransmitters. These gases are produced by the body by enzymatic reactions and serve physiological regulatory purposes including vasodilatation and anti‐inflammatory effects. Over the past decades, multiple approaches have been identified for the therapeutic exploitation of these three gasotransmitters, based on inhalation of the gases and/or the parenteral or enteral administration of various formulations of these molecules or their prodrugs. Here we overview the medicinal chemistry and the therapeutic applications of NO, CO, and H 2 S and their prodrugs. Inhaled NO is used clinically to selectively dilate the pulmonary vasculature in the therapy of the primary pulmonary hypertension of the newborn. Organic nitrates such as glyceryl trinitrate or nitroglycerin are used in the therapy of acute and chronic angina. Sodium nitroprusside is used to counteract acute hypertensive crisis. Another class of clinical‐stage NO donor drugs is the sydnonimines (molsidomine, linsidomine). Additional classes of NO donors include diazeniumdiolates (NONOates) and S ‐nitrosothiols, with beneficial effects in various preclinical models of disease. With respect to CO, the main therapeutic approaches are CO inhalation (currently in clinical trials for the experimental therapy of delayed graft function associated with kidney transplantation) and carbon monoxide releasing compounds of various classes (in preclinical stage). With respect to H 2 S, a parenteral injectable formulation of the gas is currently is Phase I trials. Several classes of H 2 S donor molecules have also been identified, which are used in preclinical studies.

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Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

Cited by 4 publications

References 23 publications

Regulation of nitric oxide consumption by hypoxic red blood cells

Regulation of nitric oxide consumption by hypoxic red blood cells

A Novel Inhaled Organic Nitrate That Affects Pulmonary Vascular Tone in a Piglet Model of Hypoxia-Induced Pulmonary Hypertension

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

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Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

Cited by 4 publications

References 23 publications

Regulation of nitric oxide consumption by hypoxic red blood cells

Regulation of nitric oxide consumption by hypoxic red blood cells

A Novel Inhaled Organic Nitrate That Affects Pulmonary Vascular Tone in a Piglet Model of Hypoxia-Induced Pulmonary Hypertension

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs

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Product

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Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs