The Nature of Circulatory Collapse Induced by Sodium Nitrite 1

Weiss, Soma; Wilkins, Robert W.; Haynes, Florence W.

doi:10.1172/jci100840

Cited by 142 publications

(33 citation statements)

References 11 publications

(13 reference statements)

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“…56 59 ; and Ignarro and Gruetter 60 ). However, the high micromolar to millimolar concentrations of nitrite necessary to achieve these effects contrasted with the low nanomolar concentrations of authentic NO needed to vasodilate aortic rings.…”

Section: Physiologic Effects Of Nitrite Reactions With Hemoglobinmentioning

confidence: 99%

The functional nitrite reductase activity of the heme-globins

Gladwin

Kim‐Shapiro

2008

Blood

258

195

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Hemoglobin and myoglobin are among the most extensively studied proteins, and nitrite is one of the most studied small molecules. Recently, multiple physiologic studies have surprisingly revealed that nitrite represents a biologic reservoir of NO that can regulate hypoxic vasodilation, cellular respiration, and signaling. These studies suggest a vital role for deoxyhemoglobin-and deoxymyoglobindependent nitrite reduction. Biophysical and chemical analysis of the nitritedeoxyhemoglobin reaction has revealed unexpected chemistries between nitrite and deoxyhemoglobin that may contribute to and facilitate hypoxic NO generation and signaling. The first is that hemoglobin is an allosterically regulated nitrite reductase, such that oxygen binding increases the rate of nitrite conversion to NO, a process termed R-state catalysis. The second chemical property is oxidative denitrosylation, a process by which the NO formed in the deoxyhemoglobinnitrite reaction that binds to other deoxyhemes can be released due to heme oxidation, releasing free NO. Third, the reaction undergoes a nitrite reductase/anhydrase redox cycle that catalyzes the anaerobic conversion of 2 molecules of nitrite into dinitrogen trioxide (N 2 O 3 ), an uncharged molecule that may be exported from the erythrocyte. We will review these reactions in the biologic framework of hypoxic signaling in blood and the heart. IntroductionNitric oxide (NO) is a diatomic gas molecule that is a critical regulator of basal blood vessel tone and vascular homeostasis (antiplatelet activity, modulation of endothelial and smooth muscle proliferation, and adhesion molecule expression). [1][2][3][4][5] NO is a paracrine signaling molecule, as it is produced in endothelium and then diffuses to vicinal smooth muscle to activate soluble guanylyl cyclase that produces cGMP, and ultimately produces smooth muscle relaxation. Nitric oxide is subject to rapid inactivation reactions with hemoglobin that greatly limit its lifetime in blood, however recent studies suggest that NO formed from endothelial NO synthases is also oxidized by oxygen or plasma ceruloplasmin to form nitrite. 6 Nitrite transport in blood provides an endocrine form of NO that is shuttled from the lungs to the periphery, while limiting the exposure of authentic NO to the scavenging red cell environment. Then during the rapid hemoglobin deoxygenation from artery to vein the nitrite is reduced back to NO. Such a cycle conserves NO in the one electron oxidation state. In this model, the nitrite pool represents the "live payload," only one electron away from NO.We have hypothesized that nitrite and the heme-globin family subserve a critical NO signaling function in blood, smooth muscle cells, the cardiomyocyte, and skeletal muscle cells. In these environments, NO is conserved by oxidation, allowing nitrite storage and free nitrite diffusion. As oxygen tensions decrease, nitrite reactions with deoxygenated hemoglobin, myoglobin, neuroglobin, cytoglobin, and other heme proteins may generate NO to regulate physiologic h...

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Section: Physiologic Effects Of Nitrite Reactions With Hemoglobinmentioning

confidence: 99%

The functional nitrite reductase activity of the heme-globins

Gladwin

Kim‐Shapiro

2008

Blood

258

195

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“…Some studies have suggested that the vasodilatation seen in neurally mediated syncope results from a withdrawal of sympathetic tone (14)(15)(16). Consistent with this view, there is evidence of reduced cardiac and renal norepinephrine (NorEpi) 1 spillover in patients who fainted during cardiac catheterization (17).…”

Section: Introductionmentioning

confidence: 99%

Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt.

et al. 1997

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The pathophysiology of neurally mediated syncope is poorly understood. It has been widely assumed that excessive sympathetic activation in a setting of left ventricular hypovolemia stimulates ventricular afferents that trigger hypotension and bradycardia. We tested this hypothesis by determining if excessive sympathetic activation precedes development of neurally mediated syncope, and if this correlates with alterations in baroreflex function. We studied the changes in intraarterial blood pressure (BP), heart rate (HR), central venous pressure (CVP), muscle sympathetic nerve activity (MSNA), and plasma catecholamines evoked by upright tilt in recurrent neurally mediated syncope patients (SYN, 5 Ϯ 1 episodes/mo, n ϭ 14), age-and sex-matched controls (CON, n ϭ 23), and in healthy subjects who consistently experienced syncope during tilt (FS ϩ , n ϭ 20). Baroreflex responses were evaluated from changes in HR, BP, and MSNA that were obtained after infusions of phenylephrine and sodium nitroprusside. Compared to CON, patients with SYN had blunted increases in MSNA at low tilt levels, followed by a progressive decrease and ultimately complete disappearance of MSNA with syncope. SYN patients also had attenuation of norepinephrine increases and lower baroreflex slope sensitivity, both during tilt and after pharmacologic testing. FS ϩ subjects had the largest decrease in CVP with tilt and had significant increases in MSNA and heart rate baroreflex slopes. These data challenge the view that excessive generalized sympathetic activation is the precursor of the hemodynamic abnormality underlying recurrent neurally mediated syncope. ( J. Clin. Invest. 1997. 99:2736-2744.)

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“…An experimental study of the vasomotor collapse induced by sodium nitrite in normal subjects in the upright position has revealed that the state of collapse is accompanied by a fall in venous pressure and an inadequate return of venous blood to the heart from the lower half of the body (1).…”

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confidence: 99%

The Rôle of the Venous System in Circulatory Collapse Induced by Sodium Nitrite 1

Wilkins¹,

Haynes²,

Weiss³

1937

J. Clin. Invest.

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An experimental study of the vasomotor collapse induced by sodium nitrite in normal subjects in the upright position has revealed that the state of collapse is accompanied by a fall in venous pressure and an inadequate return of venous blood to the heart from the lower half of the body (1).As long as the subject remains in the prone position, a small dose of sodium nitrite will produce no symptoms and only slight, if any, measurable circulatory changes in terms of blood pressure. heart rate, arterial blood flow or venous pressure. When the subject is raised from the horizontal to the upright position after the same dose of nitrite, however, he soon develops signs and symptoms of collapse. After nitrite has been given, the peripheral circulation is unable to adjust itself to the strain of the orthostatic position.Our purpose in the present work was further to clarify the mechanism of the nitrite collapse. On rising to the upright position, the greatest relative change in the circulation is on the venous side of the vascular system in the lower half of the body. Here the venous pressure is normally raised from an average prone value of 5 cm. of water to about 100 cm. of water in the feet and 50 cm. in the abdomen. This consideration, as well as the fact that previous studies revealed no appreciable dilatation of the arterioles or change in the cardiac output after nitrite (2), turned our attention to the venous side of the circulation as possibly one of the most important sites of action of sodium nitrite. We therefore undertook to test the effect of nitrite on the distensibility of the peripheral vascular beds under increases in venous pressure.WVe were particularly interested to know whether the effect of nitrite on the venous systemi is generalized or limited to certain vascular areas, such as the splanchnics.In the present study, the hands of normal sub- ' This investigation was aided in part by a grant from the Josiah Macy, Jr., Foundation. jects were placed under known increases in venous pressure, anid the corresponding increases in hand volume were measured both before and after the administration of nitrite. The subject remained in the prone position and in this way other factors, such as changes in arterial blood pressure, pulse or blood flow, were eliminated. Capps, working in this laboratory, developed this method as a means of measuring the tone or " resistance to stretch " of the capillaries. venules and veins of the hands in both normal and diseased states (3). WVe have used this procedure, with minor modifications, with satisfactory results. METHODThe subject rested in a comfortable horizontal position for at least 45 minutes after all apparatus had been adjusted before any observations were begun, and remained in this position throughout an experiment. Arterial blood pressure was determined in the arm by the usual auscultatory method, using a mercury manometer. The heart rate was counted by arterial palpation or from the plethysmographic tracings. The rate of blood flow was determined by Freeman'...

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The Nature of Circulatory Collapse Induced by Sodium Nitrite 1

Cited by 142 publications

References 11 publications

The functional nitrite reductase activity of the heme-globins

The functional nitrite reductase activity of the heme-globins

Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt.

The Rôle of the Venous System in Circulatory Collapse Induced by Sodium Nitrite 1

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