Evidence for the Extrapulmonary Localization of Inhaled Nitric Oxide

Lecour, Sandrine; Clermont, Gaëlle; E, du Toit; Gilson, L. E.; Maupoil,; Lowe, Stephen L.; Dupuis, Pierce; Girard, Claude; Rochette, Luc

doi:10.1097/01.hdx.0000098613.53486.08

Cited by 9 publications

(5 citation statements)

References 32 publications

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“…Lecour and colleagues reported that breathing 100 or 200 ppm NO increased nitric oxide concentrations in peripheral tissues, as detected by electron spin resonance spectroscopy combined with a spin-trapping technique19. However, in contrast to our observations demonstrating that NO-heme levels increased as early as 5 min after the start of 80 ppm NO inhalation, Lecour and colleagues did not detect an increase in cardiac nitric oxide concentrations in rats breathing 100 ppm NO for 45 min.…”

Section: Discussioncontrasting

confidence: 99%

“…One possibility is that exposure of leukocytes and platelets to high nitric oxide concentrations as they transit the lung may inhibit their activation in peripheral tissues. On the other hand, multiple research groups have observed that inhalation of nitric oxide leads to the formation of NO-metabolites in the bloodstream12,16 and tissues19. To better understand the mechanisms responsible for the extrapulmonary effects of inhaled nitric oxide, we quantitatively assessed the fate of inhaled nitric oxide in whole body extracts, as well as in blood and representative tissues.…”

Section: Discussionmentioning

confidence: 99%

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Brief Periods of Nitric Oxide Inhalation Protect against Myocardial Ischemia–Reperfusion Injury

Nagasaka¹,

Fernandez

García-Saura

et al. 2008

Anesthesiology

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Background Prolonged breathing of nitric oxide reduces myocardial ischemia-reperfusion injury but the precise mechanisms responsible for the cardioprotective effects of inhaled nitric oxide are incompletely understood. Methods We investigated the fate of inhaled nitric oxide (80 parts per million) in mice, and quantified the formation of nitric oxide metabolites (NO-metabolites) in blood and tissues. We tested whether the accumulation of NO-metabolites correlated with the ability of inhaled nitric oxide to protect against cardiac ischemia-reperfusion injury. Results Mice absorbed nitric oxide in a nearly linear fashion (0.19±0.02 μmol/g·h). Breathing nitric oxide rapidly increased a broad spectrum of NO-metabolites. Levels of erythrocytic S-nitrosothiols, N-nitrosamines and nitrosyl-hemes exceeded nitrite within 30 sec of commencing nitric oxide inhalation. Marked increases of lung S-nitrosothiols and liver N-nitrosamines levels were measured, as well as elevated cardiac and brain NO-metabolite levels. Breathing hypoxic concentrations potentiated the ability of inhaled nitric oxide to increase cardiac NO-metabolite levels. Concentrations of each NO-metabolite, except nitrate, rapidly reached a plateau and were similar after 5 and 60 minutes. Studying a murine cardiac ischemia-reperfusion injury model, breathing nitric oxide for either 5 or 60 min before reperfusion decreased MI/AAR by 31 and 32%, respectively. Conclusions Breathing nitric oxide leads to the rapid accumulation of a variety of NO-metabolites in blood and tissues, contributing to the ability of brief periods of nitric oxide inhalation to provide cardioprotection against ischemia-reperfusion injury. The NO-metabolite concentrations achieved in a target tissue may be more important than the absolute amounts of nitric oxide absorbed.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Brief Periods of Nitric Oxide Inhalation Protect against Myocardial Ischemia–Reperfusion Injury

Nagasaka¹,

Fernandez

García-Saura

et al. 2008

Anesthesiology

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“…Alternatively, accumulating evidence shows that breathing NO increases plasma levels of NO metabolites including nitrite. 11,14,31 Nitrite has been implicated as a potential mediator of the systemic vasodilation induced by tissue hypoxia, 18,19,32,33 and nitrite formed during NO inhalation could be responsible for the ability of inhaled NO pretreatment to prevent HBOC-induced systemic hypertension. We observed that sodium nitrite infusion increased plasma nitrite levels and prevented the systemic hypertension caused by the subsequent infusion of HBOC.…”

Section: Discussionmentioning

confidence: 99%

Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension

et al. 2008

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Background-One of the major obstacles hindering the clinical development of a cell-free, hemoglobin-based oxygen carrier (HBOC) is systemic vasoconstriction. Methods and Results-Experiments were performed in healthy mice and lambs by infusion of either murine tetrameric hemoglobin (0.48 g/kg) or glutaraldehyde-polymerized bovine hemoglobin (HBOC-201, 1.44 g/kg). We observed that intravenous infusion of either murine tetrameric hemoglobin or HBOC-201 induced prolonged systemic vasoconstriction in wild-type mice but not in mice congenitally deficient in endothelial nitric oxide (NO) synthase (NOS3). Treatment of wild-type mice by breathing NO at 80 ppm in air for 15 or 60 minutes or with 200 ppm NO for 7 minutes prevented the systemic hypertension induced by subsequent intravenous administration of murine tetrameric hemoglobin or HBOC-201 and did not result in conversion of plasma hemoglobin to methemoglobin. Intravenous administration of sodium nitrite (48 nmol) 5 minutes before infusion of murine tetrameric hemoglobin also prevented the development of systemic hypertension. In awake lambs, breathing NO at 80 ppm for 1 hour prevented the systemic hypertension caused by subsequent infusion of HBOC-201. Conclusions-These findings demonstrate that HBOC can cause systemic vasoconstriction by scavenging NO produced by NOS3. Moreover, in 2 species, inhaled NO administered before the intravenous infusion of HBOC can prevent systemic vasoconstriction without causing methemoglobinemia.

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“…Yet, the sustained physiological activity of inhaled NO gas36, 37, the limited ability of phosphodiesterase inhibitors to dramatically alter blood pressure38, 39, and the number of major human diseases associated with states of “NO insufficiency” of undefined origin40, 41 are compelling evidence that additional regulatory pathways must limit NO/cGMP signaling. One of these pathways is mediated by the secreted protein thrombospondin-1 (TSP1).…”

Section: What Limits Physiological No Signaling?mentioning

confidence: 99%

Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies

et al. 2009

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In addition to long term regulation of angiogenesis, angiogenic growth factor signaling through nitric oxide (NO) acutely controls blood flow and hemostasis. Inhibition of this pathway may account for the hypertensive and prothrombotic side effects of vascular endothelial growth factor antagonists currently used for cancer treatment. The first identified endogenous angiogenesis inhibitor, thrombospondin-1, also controls tissue perfusion, hemostasis, and radiosensitivity by antagonizing NO signaling. We examine the role of these and other emerging activities of thrombospondin-1 in cancer. Clarifying how endogenous and therapeutic angiogenesis inhibitors regulate vascular NO signaling could facilitate development of more selective inhibitors.The insight that tumor growth requires angiogenesis led to the development and clinical use of angiogenesis inhibitors as cancer therapeutics. The drugs bevacizumab, sorafenib, and sunitinib, which are approved by the US Food and Drug Administration for the treatment of several cancers, act specifically or in part by blocking the angiogenic activity of the vascular endothelial growth factor (VEGF) pathway. These targeted drugs significantly extend survival of cancer patients but have cardiovascular side effects that include hypertension [G] and thrombosis [G] [1][2][3] . Although most attempts to define the etiology of their hypertensive activity have focused on long term changes in vessel architecture, VEGF signaling via nitric oxide (NO) also has acute effects on vessel tone [G] 4,5 , and hypertension induced by the experimental VEGF receptor kinase inhibitor cediranib was recently shown to be caused by acute disruption of NO synthesis in vascular endothelium 6 . Recent studies of the first identified endogenous angiogenesis inhibitor, thrombospondin-1 (TSP1), reveal that it also inhibits NO-mediated signaling to acutely control tissue perfusion [G] and hemostasis [G] 7,8 .Interestingly, the pioneering work of Folkman and colleagues showed that tumors can produce circulating angiogenesis inhibitors 9 , and circulating TSP1 levels are elevated in people and mice with certain cancers [10][11][12] . The benefit to the tumor of circulating angiogenesis inhibitors, which in some cases are produced by stromal rather than tumor cells, is unclear. We propose that elevated plasma TSP1 can enhance tumor perfusion through its hypertensive activity. This review synthesizes emerging evidence that hemostasis and tissue blood flow are acute targets of both endogenous and therapeutic angiogenesis inhibitors and explores ways that this insight can be used to improve anti-angiogenic therapy. Nitric oxidePhysiological activity of NO was first described by Davy in 1800 13 , but its production by mammalian tissues and role as a signaling molecule in vascular cells was not discovered until the 1980s 14 . The primary endogenous source of NO in endothelial cells is the endothelial isoform of nitric oxide synthase [G] (eNOS, also known as NOS3). eNOS is a highly regulated enzyme th...

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Evidence for the Extrapulmonary Localization of Inhaled Nitric Oxide

Cited by 9 publications

References 32 publications

Brief Periods of Nitric Oxide Inhalation Protect against Myocardial Ischemia–Reperfusion Injury

Brief Periods of Nitric Oxide Inhalation Protect against Myocardial Ischemia–Reperfusion Injury

Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension

Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies

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