Hypoxia inhibits nitric oxide synthesis in isolated rabbit lung

Kantrow, Stephen P.; Huang, Y.-C. T.; Whorton, A. R.; Grayck, Eva Nozik; Knight, Jennifer M.; Millington, David S.; Piantadosi, Claude A.

doi:10.1152/ajplung.1997.272.6.l1167

Cited by 28 publications

(31 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our K m value is consistent with the NO-dependent increase in fetal pulmonary blood flow when pulmonary arterial PO 2 was increased from 25 to 55 mmHg (42) and with the decrease in NO synthesis during hypoxia (mean PO 2 in perfusate of 25 mmHg) in isolated perfused rabbit lung (22). However, it does not explain the decreased ACh-induced relaxations we observed during HBO exposure, suggesting a more complex relation between oxygen concentration and eNOS-derived NO in the intact cellular environment during HBO exposure.…”

Section: Ach Relaxation and Enos Activity During Hbo Exposuresupporting

confidence: 86%

Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure

Hink¹,

Thom²,

Simonsen³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

. Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure. Am J Physiol Heart Circ Physiol 291: H1988 -H1998, 2006. First published April 28, 2006 doi:10.1152/ajpheart.00145.2006.-Accumulating evidence suggests that hyperbaric oxygen (HBO) stimulates neuronal nitric oxide (NO) synthase (NOS) activity, but the influence on endothelial NOS (eNOS) activity and vascular NO bioavailability remains unclear. We used a bioassay employing rat aortic rings to evaluate vascular NO bioavailability. HBO exposure to 2.8 atm absolute (ATA) in vitro decreased ACh relaxation. This effect remained unchanged, despite treatment with SOD-polyethylene glycol and catalase-polyethylene glycol, suggesting that the reduction in endothelium-derived NO bioavailability was independent of superoxide production. In vitro HBO induced contraction of resting aortic rings with and without endothelium, and these contractions were reduced by the NOS inhibitor N -nitro-L-arginine. In addition, in vitro HBO attenuated the vascular contraction produced by norepinephrine, and this effect was reversed by N -nitro-L-arginine, but not by endothelial denudation. These findings indicate stimulation of extraendothelial NO production during HBO exposure. A radiochemical assay was used to assess NOS activity in rat aortic endothelial cells. Catalytic activity of eNOS in cell homogenates was not decreased by HBO, and in vivo HBO exposure to 2.8 ATA was without effect on eNOS activity and/or vascular NO bioavailability in vitro. We conclude that HBO reduces endothelium-derived NO bioavailability independent of superoxide production, and this effect seems to be unrelated to a decrease in eNOS catalytic activity. In addition, HBO increases the resting tone of rat aortic rings and attenuates the contractile response to norepinephrine by endothelium-independent mechanisms that involve extraendothelial NO production. nitric oxide synthase; acetylcholine relaxation; autooxidation HYPERBARIC OXYGEN (HBO) is used in clinical medicine in the management of different diseases and conditions, because it mediates some useful actions, such as stimulation of angiogenesis and inhibition of leukocyte adhesion. However, the underlying biochemical mechanisms have not been fully elucidated.Nitric oxide (NO) bioavailability in rat and mouse cerebral cortex, measured by NO-specific microelectrodes, is increased early during HBO exposure and paralleled by an increase in regional blood flow (40). Thom et al. (40) reported that cerebral NO production was increased much more in knockout mice lacking genes for endothelial NO synthase (eNOS) than in those lacking genes for neuronal NO synthase (nNOS), suggesting that changes in eNOS activity during HBO exposure are minimal compared with changes in nNOS activity. However, because of the predominance of nNOS in the central nervous system (20), this might not be the case in the systemic circulation. Increased nNOS-but not eNOS-derived NO was also observed at the abluminal side of th...

show abstract

Section: Ach Relaxation and Enos Activity During Hbo Exposuresupporting

confidence: 86%

Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure

Hink¹,

Thom²,

Simonsen³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…These results suggest that hypoxic enhancement of Ca 2ϩ sensitivity in IPA was due to hypoxic inhibition of NO production or activity in smooth muscle. Consistent with this possibility, all three NOS isoforms (neuronal, inducible, and endothelial) have been detected in PASMC (12, 17, 49, 67, 71, 76, 78 -80), and hypoxic inhibition of NO production or its transduction pathways has been reported in isolated pulmonary arteries (19,28,55,63) and isolated (1,7,9,11,20,24,29,44) and intact (1,13,60) lungs.…”

Section: Discussionmentioning

confidence: 59%

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Weigand

Shimoda

Sylvester

2011

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

(37,40,48,51,52,54,56,62,72,77,82). The increased [Ca 2ϩ ] i leads in turn to calmodulin-dependent activation of myosin light chain (MLC) kinase (MLCK), MLCK-dependent phosphorylation of the 20-kDa regulatory MLC (P-MLC 20 ), P-MLC 20 -dependent activation of the actin-myosin interaction, and PASMC contraction (38,42,74,75,83 ] i during the slowly developing phase 2 contraction (52). Endothelial denudation did not alter the [Ca 2ϩ ] i response to hypoxia but abolished phase 2 contraction (51). These results suggest that phase 2 contraction resulted from an increase in PASMC Ca 2ϩ sensitivity and that this sensitization was due to release of factors from endothelial cells, rather than direct effects of hypoxia on smooth muscle. The identities of these factors remain unknown; however, antagonists of endothelin-1 (ET-1) had no effect on phase 2 HPV in endothelium-intact IPA, suggesting that ET-1 played no role (51). Although the nitric oxide/guanylate cyclase/protein kinase G (NO/GC/PKG) transduction pathway can alter Ca 2ϩ sensitivity in pulmonary arteries (27, 57), its effect on Ca 2ϩ sensitivity during acute hypoxia has not been examined.Consistent with endothelium dependence, hypoxia did not change steady-state isometric force achieved during normoxia at [Ca 2ϩ ] i ϭ 3-1,000 nM in endothelium-denuded rat extrapulmonary arteries permeabilized with ␤-escin and exposed to phorbol-12,13-dibutyrate, a protein kinase C activator, at 30°C (58); however, an effect of hypoxia may have been precluded in these experiments by use of proximal pulmonary arteries, which have weak contractile responses to hypoxia (39,40,61,65); phorbol-12,13-dibutyrate, which enhances Ca 2ϩ sensitivity on its own (30, 59); and low temperature, which inhibits HPV (4,21,36). Hypoxia also did not alter the relation between increases in [Ca 2ϩ ] i and decreases in cell length induced by the Ca 2ϩ ionophore 4-bromo-A-23187 in freshly isolated porcine distal PASMC at 37°C (62); however, since these cells were variably attached to glass coverslips, uneven loading among cells and the absence of isotonic conditions may have obscured possible effects of hypoxia.Many stimuli increase myofilament Ca 2ϩ sensitivity by decreasing activity of MLC phosphatase (MLCP), the enzyme responsible for dephosphorylation and inactivation of P-MLC 20 . Decreased MLCP activity leads to [Ca 2ϩ ] i -independent increases in P-MLC 20 concentration ([P-MLC 20 ]), actin-myosin interaction, and contraction (66), and can be achieved by upregulation of signals causing MLCP inhibition, such as those generated by Rho kinase (31, 66), or downregulation of signals causing MLCP activation, such as those generated by NO/GC/PKG (35,66). Among these possibilities, Rho kinase has been the most studied in PASMC during hypoxia.

show abstract

“…The endothelium of the pulmonary artery is a rich source of NO (30). Thus, NO scavenging by RBCs does not increase PVR unless NO synthesis is reduced by hypoxia (3,31). RBCs thereby prevent blood from perfusing poorly ventilated alveolar units in HPV (27) (decrease in V͞Q mismatch).…”

Section: Discussionmentioning

confidence: 99%

A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension

McMahon

Ahearn

Moya

et al. 2005

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

118

138

View full text Add to dashboard Cite

The mechanism by which hypoxia [low partial pressure of O2 (pO2)] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO 2-governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). hemoglobin ͉ red blood cell vasodilation ͉ S-nitrosylation I n the systemic microcirculation, blood flow is regulated by physiological O 2 gradients that couple the O 2 content of blood to regulated vasodilation and vasoconstriction (1-3). Blood flow is thereby matched to tissue O 2 demand. An analogous mechanism operates in the lungs, where O 2 uptake (ventilation) is optimized through regulated vasodilation and vasoconstriction (perfusion). Blood flow is thereby matched to alveolar ventilation (2). Because it is Hb O 2 saturation, not the partial pressure of O 2 (pO 2 ), that is coupled to blood flow in vivo (1, 3) it has been deduced that RBCs may serve as O 2 sensors within the integrated vascular system. In support of this idea, it has been shown recently that RBCs can act as O 2 -responsive transducers of vasodilator and vasoconstrictor activity (4-10), at least partly by modulating the availability of [6][7][8]10,11). According to these studies, RBCs release NO bioactivity under hypoxia and sequester it at hyperoxia. The release of NO bioactivity would facilitate hypoxic vasodilation in peripheral tissues and oppose hypoxic pulmonary vasoconstriction (HPV) in the lungs. S-nitrosothiol (SNO)-deficientThe mechanism by which NO bioactivity escapes from RBCs is incompletely understood. It is generally accepted that the rapid reaction of NO with the hemes of Hb produces a heme-iron nitrosyl adduct (Hb [FeNO]) that exhibits no vasodilator activity (4,7,12). Hb also sustains S-nitrosylation at two cysteine residues conserved in all mammals and birds. Biochemical and mutational analyses (␤93Cys3Ala) indicate that S-nitrosohemoglobin (SNO-Hb) is formed upon oxygenation of Hb [FeNO] by means of heme-to-Cys NO transfer (13-15) and by transnitrosylative transfer from low-mass S-nitrosothiols (SNOs) (16,17). SNO-Hb is very stable in the oxygenated (or R) structure and thus cannot effectively dilate blood vessels (5, 10, 18). However, upon deoxygenation [or with change in the spin state of the hemes (3)], the vasodilator potency of SNO-Hb is markedly potentiated (5,16,18). Crystal structures and molecular models show that the ␤-Cys NO gains solvent access in the deoxygenated (or T) state (3, 19). Solvent-exposed NO can exchange with acceptor thiols within the N-terminal cytoplasmic domain of the RBC membrane anion exchange protein (AE1; band 3) (4, 15). Transnitrosylation of AE1 by SNO-Hb involves a direct protein-protein interaction. The st...

show abstract

Hypoxia inhibits nitric oxide synthesis in isolated rabbit lung

Cited by 28 publications

References 20 publications

Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure

Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension

Contact Info

Product

Resources

About