Umbilical Arterial S-nitrosothiols in Stressed Newborns: Role in Perinatal Circulatory Transition

Gaston, Benjamin; Fry, Emory; Sears, Stephen T.; Heroman, William M.; Ignarro, Louis J.; Stamler, Jonathan S.

doi:10.1006/bbrc.1998.9865

Cited by 23 publications

(11 citation statements)

References 17 publications

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“…1), and maintaining these lines, particularly the βC93A line, was a significant challenge. This finding is consistent with previous studies that have suggested a role for SNO-Hb in the regulation of fetal blood flow (21) and in the perinatal circulatory transition (22).…”

Section: Resultssupporting

confidence: 93%

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Zhang

Hess

Qian

et al. 2015

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

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Oxygen delivery by Hb is essential for vertebrate life. Three amino acids in Hb are strictly conserved in all mammals and birds, but only two of those, a His and a Phe that stabilize the heme moiety, are needed to carry O2. The third conserved residue is a Cys within the β-chain (βCys93) that has been assigned a role in S-nitrosothiol (SNO)-based hypoxic vasodilation by RBCs. Under this model, the delivery of SNO-based NO bioactivity by Hb redefines the respiratory cycle as a triune system (NO/O2/CO2). However, the physiological ramifications of RBC-mediated vasodilation are unknown, and the apparently essential nature of βCys93 remains unclear. Here we report that mice with a βCys93Ala mutation are deficient in hypoxic vasodilation that governs blood flow autoregulation, the classic physiological mechanism that controls tissue oxygenation but whose molecular basis has been a longstanding mystery. Peripheral blood flow and tissue oxygenation are decreased at baseline in mutant animals and decline excessively during hypoxia. In addition, βCys93Ala mutation results in myocardial ischemia under basal normoxic conditions and in acute cardiac decompensation and enhanced mortality during transient hypoxia. Fetal viability is diminished also. Thus, βCys93-derived SNO bioactivity is essential for tissue oxygenation by RBCs within the respiratory cycle that is required for both normal cardiovascular function and circulatory adaptation to hypoxia.

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Section: Resultssupporting

confidence: 93%

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Zhang

Hess

Qian

et al. 2015

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

Self Cite

100

112

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“…It has been speculated that these S-nitrosylation reactions are adapted to provide NO bioactivity in the lung, and, in support of this proposition, we have shown that human airways are relaxed in vitro by endogenous concentrations of GSNO (14). The case for physiological relevance is further strengthened by studies demonstrating that airway GSNO may be depleted in human conditions associated with impairments in V͞Q matching, including asthma (28), cystic fibrosis (38), and hypoxemic respiratory failure (14,39), and by the finding that aerosolized GSNO can reverse the V͞Q matching impairment associated with SNO deficiency (40). Here, we report that selective repletion of indigenous species of SNO is linked to improvements in lung function.…”

Section: Resultssupporting

confidence: 68%

S -nitrosothiol repletion by an inhaled gas regulates pulmonary function

Moya

Gow

McMahon

et al. 2001

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

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NO synthases are widely distributed in the lung and are extensively involved in the control of airway and vascular homeostasis. It is recognized, however, that the O2-rich environment of the lung may predispose NO toward toxicity. These Janus faces of NO are manifest in recent clinical trials with inhaled NO gas, which has shown therapeutic benefit in some patient populations but increased morbidity in others. In the airways and circulation of humans, most NO bioactivity is packaged in the form of S-nitrosothiols (SNOs), which are relatively resistant to toxic reactions with O 2͞O2 ؊ . This finding has led to the proposition that channeling of NO into SNOs may provide a natural defense against lung toxicity. The means to selectively manipulate the SNO pool, however, has not been previously possible. Here we report on a gas, O-nitrosoethanol (ENO), which does not react with O2 or release NO and which markedly increases the concentration of indigenous species of SNO within airway lining fluid. Inhalation of ENO provided immediate relief from hypoxic pulmonary vasoconstriction without affecting systemic hemodynamics. Further, in a porcine model of lung injury, there was no rebound in cardiopulmonary hemodynamics or fall in oxygenation on stopping the drug (as seen with NO gas), and additionally ENO protected against a decline in cardiac output. Our data suggest that SNOs within the lung serve in matching ventilation to perfusion, and can be manipulated for therapeutic gain. Thus, ENO may be of particular benefit to patients with pulmonary hypertension, hypoxemia, and͞or right heart failure, and may offer a new therapeutic approach in disorders such as asthma and cystic fibrosis, where the airways may be depleted of SNOs.

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“…Human foetal NOS2 immunoreactivity in large cartilaginous airways during the second trimester is not significantly different from that seen postnatally [8]. Near term, however, changes in NOS3 activation may have an additional role in mediating the transition from foetal to newborn circulation patterns [48,49]. There is little direct evidence for postnatal changes in NOS distribution in humans.…”

Section: Nitric Oxide and Lung Developmentmentioning

confidence: 92%

Measurement of exhaled nitric oxide in children, 2001: E. Baraldi and J.C. de Jongste on behalf of the Task Force

Baraldi¹,

Jongste²,

Gaston³

et al. 2002

European Respiratory Journal

288

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Umbilical Arterial S-nitrosothiols in Stressed Newborns: Role in Perinatal Circulatory Transition

Cited by 23 publications

References 17 publications

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

S -nitrosothiol repletion by an inhaled gas regulates pulmonary function

Measurement of exhaled nitric oxide in children, 2001: E. Baraldi and J.C. de Jongste on behalf of the Task Force

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