Endothelium-dependent and -independent responses to severe hypoxia in rat pulmonary artery

Greenberg, Barry; Kishiyama, Shirley S.

doi:10.1152/ajpheart.1993.265.5.h1712

Cited by 30 publications

(29 citation statements)

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“…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

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(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.

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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

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“…: 410-955-1530; Fax: 410-955-0485. 1 The abbreviations used are: NO, nitric oxide; NOS, nitric-oxide synthase; ecNOS, endothelial nitric-oxide synthase; BAEC, bovine aortic endothelial cells; MOPS, 4-morpholinepropanesulfonic acid.…”

Section: Methodsmentioning

confidence: 99%

“…Possible mechanisms include direct relaxation of smooth muscle cells induced by changes in pH, ion channel conductance changes, and decreases in ATP levels. Endothelial cells may also release lower amounts of vasoconstrictors, such as endothelin or thromboxane, or may release increased amounts of vasodilators such as adenosine, prostacyclin, endothelial hyperpolarizing factor, and nitric oxide (NO) 1 (1)(2)(3). NO is made in endothelial cells by endothelial nitric-oxide synthase (ecNOS), which converts arginine and oxygen into citrulline and NO (4 -12).…”

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confidence: 99%

Regulation of Endothelial Nitric-oxide Synthase during Hypoxia

Arnet

McMillan

Dinerman

et al. 1996

Journal of Biological Chemistry

180

106

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The mechanism by which nitric-oxide (NO) production increases during hypoxia is unknown. To explore the effect of hypoxia upon endothelial nitric-oxide synthase (ecNOS) activity and expression, we exposed bovine aortic endothelial cells (BAEC) to hypoxia (1% O 2 ) for 0 -24 h and measured levels of ecNOS mRNA, protein, and activity. The amount of ecNOS mRNA increases to more than twice the basal level after 6 h of hypoxia. Incubation of BAEC with actinomycin D during hypoxia prevents this increase, demonstrating that higher levels of mRNA observed during hypoxia are due to increased synthesis, not to increased stability of ecNOS mRNA. Levels of ecNOS protein increase throughout 24 h of hypoxia to more than twice normoxic levels. Although ecNOS expression increases within 2 h of hypoxia, total activity remains unchanged. To explore the transcriptional regulation of ecNOS, we constructed a reporter plasmid containing the ecNOS promoter region upstream of the luc gene and transfected this reporter plasmid into BAEC. In this system, hypoxia induces a linear increase over time in the expression of luciferase driven by the ecNOS promoter. It is concluded that hypoxia induces an increase in transcription of ecNOS in endothelial cells, activating the regulatory region of ec-NOS by undefined transcription factors.Systemic arteries vasodilate in response to hypoxia, delivering more blood to peripheral tissues. This dilation occurs within seconds after hypoxia, and is maintained for hours. The molecular basis of hypoxic vasodilation is not completely understood. Possible mechanisms include direct relaxation of smooth muscle cells induced by changes in pH, ion channel conductance changes, and decreases in ATP levels. Endothelial cells may also release lower amounts of vasoconstrictors, such as endothelin or thromboxane, or may release increased amounts of vasodilators such as adenosine, prostacyclin, endothelial hyperpolarizing factor, and nitric oxide (NO) 1 (1-3). NO is made in endothelial cells by endothelial nitric-oxide synthase (ecNOS), which converts arginine and oxygen into citrulline and NO (4 -12). Although ecNOS is expressed constitutively in resting endothelial cells, the level of ecNOS expression can be altered by various stimuli. Shear-stress and estrogen can increase ecNOS expression both in vitro and in vivo (13-23). Tumor necrosis factor-␣ decreases expression of ecNOS (17, 24 -27). Thus, although ecNOS is called a "constitutive" isoform of NOS, its expression can be altered.Several studies have shown that hypoxia increases the synthesis of NO from systemic arteries both ex vivo (28 -30) and in vivo (31, 32). The effect of hypoxia on NO synthesis from endothelial cells in vitro is less clear; some studies report an increase, decrease, or no change (33-35). These studies exposed cells isolated from systemic vessels to hypoxia for different periods of time, which may explain the different effects of hypoxia. An increase in NO synthesis during hypoxia could be due to increased levels of calcium prolonging the ...

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“…This hypothesis arises from different lines of evidence. Firstly, in vitro studies in pulmonary artery rings have shown that endothelium-derived NO modulates the increase in tone induced by hypoxic stimuli [29,30]. Secondly, in healthy individuals inhaled NO inhibits the increase in pulmonary artery pressure induced by hypoxia [14], a feature that in COPD worsens pulmonary gas exchange [16].…”

Section: Discussionmentioning

confidence: 99%

Effect of nitric oxide synthesis inhibition with nebulized L-NAME on ventilation-perfusion distributions in bronchial asthma

Gómez

Barberà²,

Roca³

et al. 1998

Eur Respir J

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Patients with clinically stable asthma may show ventilation-perfusion (V'A/Q') mismatch. Nitric oxide (NO), a potent endogenous vasodilator, is increased in exhaled air of asthmatics. Such an increased NO production may be detrimental for optimal V'A/Q' balance owing to the potential inhibition of hypoxic pulmonary vasoconstriction. This study was undertaken to investigate the relationship between the concentration of NO in exhaled air and the degree of gas-exchange impairment and to assess the effect of nebulized N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthesis, on gas exchange in patients with asthma. Twelve patients (four females and eight males, aged 31+/-5 yrs) with clinically stable asthma (forced expiratory volume in one second (FEV1) 80+/-5%) not treated with glucocorticoids and increased exhaled NO (58+/-9 parts per billion (ppb)) were studied. Exhaled NO, respiratory system resistance (Rrs), arterial blood gases and V'A/Q' distributions were measured before and 30, 60, 90 and 120 min after placebo or L-NAME (10(-1) M) nebulization; in eight patients pulmonary haemodynamics were also measured. At baseline no relationships between exhaled NO and gas-exchange measurements were shown. Nebulized L-NAME induced a significant decrease in exhaled NO (p< 0.001), which was maximal at 90 min (-55+/-5%). However, after L-NAME no changes in Rrs, arterial oxygen tension, the alveolar-arterial pressure difference in oxygen or V'A/Q' distributions were shown and nebulized L-NAME did not modify pulmonary artery pressure. In conclusion, the degree of gas-exchange impairment in stable asthma is not related to nitric oxide concentration in exhaled air and nitric oxide synthesis inhibition with N(G)-nitro-L-arginine methyl ester does not alter gas exchange or pulmonary haemodynamics, such that ventilation-perfusion disturbances do not appear to be related to an increased synthesis of nitric oxide in the airways.

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Endothelium-dependent and -independent responses to severe hypoxia in rat pulmonary artery

Cited by 30 publications

References 0 publications

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

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

Regulation of Endothelial Nitric-oxide Synthase during Hypoxia

Effect of nitric oxide synthesis inhibition with nebulized L-NAME on ventilation-perfusion distributions in bronchial asthma

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