Hemoglobin Effects on Nitric Oxide Mediated Hypoxic Vasodilation

Abstract Nitrite was once thought to be inert in human physiology. However, research over the past few decades has established a link between nitrite and the production of nitric oxide (NO) that is potentiated under hypoxic and acidic conditions. Under this new role nitrite acts as a storage pool for bioavailable NO. The NO so produced is likely to play important roles in decreasing platelet activation, contributing to hypoxic vasodilation and minimizing blood-cell adhesion to endothelial cells. Researchers have proposed multiple mechanisms for nitrite reduction in the blood. However, NO production in blood must somehow overcome rapid scavenging by hemoglobin in order to be effective. Here we review the role of red blood cell hemoglobin in the reduction of nitrite and present recent research into mechanisms that may allow nitric oxide and other reactive nitrogen signaling species to escape the red blood cell.

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Nitric Oxide Involvement in Hypoxic Dilation of Pial Arteries in the Cat

Anesthesiology ◽

10.1097/00000542-199612000-00016 ◽

1996 ◽

Vol 85 (6) ◽

pp. 1350-1356. ◽

Cited By ~ 11

Author(s):

Naoko Ishimura ◽

Katsuyasu Kitaguchi ◽

Kazuyuki Tatsumi ◽

Hitoshi Furuya

Keyword(s):

Nitric Oxide ◽

Cerebral Arteries ◽

Video Recording ◽

Vessel Diameter ◽

Pial Arteries ◽

Nitric Oxide Synthase Inhibitor ◽

Cranial Window ◽

Hypoxic Conditions ◽

Hypoxic Vasodilation ◽

Synthase Inhibitor

Background The reactivity of cerebral arteries to different stimuli varies according to vessel size. Whether nitric oxide mediates hypoxic vasodilation is controversial. The authors considered this question by measuring the diameter of pial arteries and arterioles with or without exposure to the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME). Methods The cranial window technique, combined with microscopic video recording, was used in an experiment involving 20 cats anesthetized with fentanyl and midazolam. The diameters of pial arteries and arterioles were measured under the following conditions: (1) normoxia (PaO2 > 100 mmHg); (2) hypoxia (PaO2 < 45 mmHg); (3) normoxia with L-NAME infusion; and (4) hypoxia with L-NAME infusion. Changes in vessel diameter were analyzed with respect to artery size. Results Under hypoxic conditions, arteries and arterioles smaller than 200 microns were dilated significantly (P < 0.05). In arterioles smaller than 200 microns, L-NAME attenuated this hypoxic vasodilation (P < 0.05). In contrast, under normoxic conditions, L-NAME caused significant vasoconstriction in arteries larger than 100 microns but not in arteries smaller than 100 microns. Conclusions Arteries and arterioles smaller than 200 microns are dilated by hypoxia, and nitric oxide contributes to this process. Nitric oxide synthesis may also be related to the regulation of resting vascular tone in arteries larger than 100 microns.

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Role of Nitric Oxide Carried by Hemoglobin in Cardiovascular Physiology

Circulation Research ◽

10.1161/circresaha.119.315626 ◽

2020 ◽

Vol 126 (1) ◽

pp. 129-158 ◽

Cited By ~ 7

Author(s):

Richard T. Premont ◽

James D. Reynolds ◽

Rongli Zhang ◽

Jonathan S. Stamler

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Oxygen Delivery ◽

Tissue Oxygenation ◽

Common Factor ◽

Well Being ◽

Therapeutic Interventions ◽

Oxygen Binding ◽

Metabolic Demand ◽

Hypoxic Vasodilation

A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide—the three-gas respiratory cycle—that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)–replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery—steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.

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Dilation of rat diaphragmatic arterioles by flow and hypoxia: roles of nitric oxide and prostaglandins

Journal of Applied Physiology ◽

10.1152/jappl.1999.86.5.1644 ◽

1999 ◽

Vol 86 (5) ◽

pp. 1644-1650 ◽

Cited By ~ 18

Author(s):

Michael E. Ward

Keyword(s):

Nitric Oxide ◽

Methyl Ester ◽

Nitric Oxide Synthase ◽

Concurrent Treatment ◽

Nitric Oxide Release ◽

Luminal Flow ◽

Hypoxic Vasodilation ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

The in vitro responses to ACh, flow, and hypoxia were studied in arterioles isolated from the diaphragms of rats. The endothelium was removed in some vessels by low-pressure air perfusion. In endothelium-intact arterioles, pressurized to 70 mmHg in the absence of luminal flow, ACh (10−5 M) elicited dilation (from 103 ± 10 to 156 ± 13 μm). The response to ACh was eliminated by endothelial ablation and by the nitric oxide synthase antagonists N G-nitro-l-arginine (l-NNA; 10−5 M) and N G-nitro-l-arginine methyl ester (l-NAME, 10−5 M) but not by indomethacin (10−5 M). Increases in luminal flow (5–35 μl/min in 5 μl/min steps) at constant distending pressure (70 mmHg) elicited dilation (from 98 ± 8 to 159 ± 12 μm) in endothelium-intact arterioles. The response to flow was partially inhibited byl-NNA,l-NAME, and indomethacin and eliminated by endothelial ablation and by concurrent treatment withl-NAME and indomethacin. The response to hypoxia was determined by reducing the periarteriolar[Formula: see text] from 100 to 25–30 Torr by changing the composition of the gas used to bubble the superfusing solution. Hypoxia elicited dilation (from 110 ± 9 to 165 ± 12 μm) in endothelium-intact arterioles but not in arterioles from which the endothelium had been removed. Hypoxic vasodilation was eliminated by treatment with indomethacin and was not affected byl-NAME orl-NNA. In rat diaphragmatic arterioles, the response to ACh is dependent on endothelial nitric oxide release, whereas the response to hypoxia is mediated by endothelium-derived prostaglandins. Flow-dilation requires that both nitric oxide and cyclooxygenase pathways be intact.

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Faculty Opinions recommendation of Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717952963.793458510 ◽

2012 ◽

Author(s):

Paul Sanders

Keyword(s):

Nitric Oxide ◽

Hypoxic Vasodilation

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Dual role of the L-arginine–ADMA–NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction

Pulmonary Circulation ◽

10.1177/2045894020918850 ◽

2020 ◽

Vol 10 (1_suppl) ◽

pp. 23-30 ◽

Cited By ~ 2

Author(s):

Rainer Böger ◽

Juliane Hannemann

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Vascular Endothelium ◽

Asymmetric Dimethylarginine ◽

Hypoxic Pulmonary Vasoconstriction ◽

Systemic Circulation ◽

Pulmonary Vasoconstriction ◽

Hypoxic Vasodilation ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

In healthy vascular endothelium, nitric oxide acts as a vasodilator paracrine mediator on adjacent smooth muscle cells. By activating soluble guanylyl cyclase, nitric oxide stimulates cyclic guanosine monophosphate (cGMP) which causes relaxation of vascular smooth muscle (vasodilation) and inhibition of platelet aggregation. This mechanism is active in both, the systemic and pulmonary circulation. In the systemic circulation, hypoxia results in local vasodilation, which has been shown to be brought about by stabilization of hypoxia-inducible factor-1α (HIF1α) and concomitant upregulation of endothelial nitric oxide synthase. By contrast, the physiological response to hypoxia in the pulmonary circulation is vasoconstriction. Hypoxia in the lung primarily results from hypoventilation of circumscript areas of the lung, e.g. by bronchial tree obstruction or inflammatory infiltration. Therefore, hypoxic pulmonary vasoconstriction is a mechanism preventing distribution of blood to hypoventilated areas of the lungs, thereby maintaining maximal oxygenation of blood. The exact molecular mechanism of hypoxic pulmonary vasoconstriction is less well understood than hypoxic vasodilation in the systemic circulation. While alveolar epithelial cells may be key in sensing low oxygen concentration, and pulmonary vascular smooth muscle cells obviously are the effectors of vasoconstriction, the pulmonary vascular endothelium plays a crucial role as an intermediate between these cell types. Indeed, dysfunctional endothelial nitric oxide release was observed in humans exposed to acute hypoxia, and animal studies suggest that hypoxic pulmonary vasoconstriction is enhanced by nitric oxide synthase inhibition. This may be caused, in part, by elevation of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthesis. High asymmetric dimethylarginine levels are associated with endothelial dysfunction, vascular disease, and hypertension.

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