Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung

Cras, Timothy D Le; Cheng, Xue; Rengasamy, Appavoo; Johns, Roger A.

doi:10.1152/ajplung.1996.270.1.l164

Cited by 170 publications

(193 citation statements)

References 21 publications

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“…In our study, the apparent discrepancy between the increase in NOS III immunoreactivity observed at the end of ischemia and the diminished activity of Ca ϩϩ -dependent NOS in muscle homogenates may result from ischemia-induced oxidative inactivation of the transiently increased amounts of constitutive NOS protein. The increase in NOS III immunoreactivity during ischemia is consistent with recent studies showing that both acute and chronic hypoxia are stimuli for NOS III expression (Gess et al, 1997;Lecras et al, 1996). As reperfusion progressed a large proportion of vasculature became NOS III negative.…”

Section: Messina Et Alsupporting

confidence: 90%

Localization of Inducible Nitric Oxide Synthase to Mast Cells During Ischemia/Reperfusion Injury of Skeletal Muscle

Messina

Knight

Dowsing

et al. 2000

Laboratory Investigation

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SUMMARY:Nitric oxide contributes to tissue necrosis after ischemia-reperfusion (IR). A biochemical and immunohistochemical study was made of the amounts and localization of both Ca ϩϩ -independent nitric oxide synthase (NOS) II and Ca ϩϩ -dependent (NOS I and NOS III) in rat skeletal muscle after ischemia and 0.5, 2, 8, 16, and 24 hours reperfusion. NOS II was not detectable in control muscle or during ischemia, was first detected after 2 hours reperfusion, increased further by 8 hours, and remained elevated at 24 hours. Both NOS II and nitrotyrosine, a marker of peroxynitrite formation, were localized exclusively to mast cells except after 24 hours reperfusion when some macrophages and neutrophils also showed positive immunoreactivity. Mast cells underwent extensive degranulation during reperfusion. NOS I was not detected in injured or control muscle. The level of NOS III, which was localized to the endothelium of blood vessels of all sizes in control muscle, decreased progressively during ischemia and reperfusion to reach undetectable levels after 16 hours reperfusion. These findings indicate that most of the nitric oxide formed during IR injury is generated by NOS II located almost exclusively in mast cells. (Lab Invest 2000, 80:423-431).

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Section: Messina Et Alsupporting

confidence: 90%

Localization of Inducible Nitric Oxide Synthase to Mast Cells During Ischemia/Reperfusion Injury of Skeletal Muscle

Messina

Knight

Dowsing

et al. 2000

Laboratory Investigation

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“…Western blotting of lung homogenates revealed increased eNOS expression after 2 weeks of hypoxia exposure and a maintained baseline eNOS expression (similar to normoxia controls) after 4 weeks of hypoxia exposure. Preserved or increased lung eNOS expression after hypoxia exposure has also been reported by the other groups, [27][28][29] which contrasts with the impairment of NO bioavailability in pulmonary hypertension. One possibility is a decrease in eNOS activity, as observed in isolated pulmonary arteries from rats exposed to hypoxia.…”

Section: Discussionsupporting

confidence: 61%

Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

et al. 2014

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Endothelial nitric oxide synthase (eNOS) plays a major role in maintaining pulmonary vascular homeostasis. Tetrahydrobiopterin (BH 4 ), an essential cofactor that stabilizes the dimerization of eNOS and balances nitric oxide (NO) and superoxide production, may have therapeutic potential in pulmonary hypertension. In the isolated perfused lung, we demonstrated a direct effect of exogenous administration of BH 4 on pulmonary NO production, leading to acute vasorelaxation during the plateau phase of hypoxia-induced pulmonary vasoconstriction. In the chronic hypoxia-induced pulmonary hypertension rat model, chronic BH 4 oral administration attenuated the pressor response to hypoxia (mean pulmonary artery pressure AE standard error of the mean, 31.8 AE 0.5 mmHg at 100 mg/kg/day; placebo group, 36.3 AE 0.6 mmHg; P < 0.05). During telemetric monitoring, right ventricular systolic pressure was reduced by approximately 50% after 1 week of BH 4 treatment at 100 mg/kg/day. BH 4 at 100 mg/kg/day reduced right ventricular hypertrophy (from 0.55 AE 0.01 to 0.50 AE 0.01; P < 0.05) and pulmonary vascular muscularization (from 79.2% AE 2% to 65.2% AE 3%; P < 0.01). BH 4 treatment enhanced lung eNOS activity and reduced superoxide production, with a net increase in cyclic guanosine monophosphate levels. BH 4 is effective in attenuating pulmonary hypertension in the hypoxic rat model when given as a rescue therapy.

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“…This comparison suggests heterogeneity of NO activity throughout the pulmonary arterial bed in the fetal rabbit, with 5-HT-sensitive, endogenous NO activity being present in the large conduit arteries but not in the small muscular pulmonary arteries. Such heterogeneity has been observed in the adult rat where eNOS can be detected in large conduit arteries but not small muscular vessels (Le Cras et al, 1996). In our previous study on fetal rabbit conduit pulmonary arteries, these were exposed to relatively low oxygen tensions, hence this excludes the possibility that these low oxygen tensions had inhibited NO production in the present study.…”

Section: The In¯uence Of No On Responses To 5-htmentioning

confidence: 52%

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

Morecroft

MacLean

1998

British J Pharmacology

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1 Vasoconstrictor responses to 5-HT, 5-carboxamidotryptamine (5-CT, 5-HT 1 receptor agonist), amethyl-5-HT (5-HT 2 receptor agonist) and sumatriptan (5-HT 1D/1B receptor agonist) were studied in fetal, 0 ± 24 h, 4 day, 7 day and adult rabbit pulmonary resistance arteries (PRAs), alone and in the presence of the NO synthase inhibitor N o -nitro-L-arginine methylester (L-NAME). The e ect of the selective 5-HT receptor antagonists ketanserin (5-HT 2A receptor) and GR55562 (5-HT 1B/1D receptor) on vasoconstrictor responses to 5-HT were studied in the presence of L-NAME. Vasodilator responses to 5-CT were also studied in pre-contracted PRAs. 3 5-HT and a-methyl-5-HT were equipotent in causing contraction in the PRAs at each age (e.g. pEC 50 s for 5-HT and a-methyl-5-HT were 6.74+0.13 and 6.63+0.22 respectively in adult vessels). In the perinatal PRAs, sumatriptan and 5-CT produced negligible contractions, but in adult PRAs, 5-CT and sumatriptan were potent agonists with pEC 50 s of 6.05+0.3 and 5.70+0.20 respectively. 4 L-NAME markedly increased the maximum response to 5-HT in the 0 ± 24 h, 4 day and 7 day vessels and increased 5-HT potency in the 4-, 7-day-old and adult rabbit vessels. 5 In perinatal vessels, responses to 5-HT, with L-NAME present, were antagonized by ketanserin (30 nM and 0.1 mM) but not GR55562 (1 mM). A small ketanserin-resistant, GR55562-sensitive component was observed at 0 ± 24 h. In adult vessels, both ketanserin and GR55562 inhibited 5-HTinduced responses. 7 Vasodilator responses to 5-CT were observed in pre-contracted PRAs from 4-and 7-day-old rabbits but not in the fetus, 0 ± 24 h old or adult rabbit vessels. At 4 days the vasodilator response was inhibited both by L-NAME and GR55562. At 7 days the response was only partly blocked by L-NAME and resistant to GR55562. The L-NAME resistant component was antagonized by the 5-HT 7 receptor antagonist spiperone (1 mM). 8 The results suggest that 5-HT 2A -receptors mediate vasoconstriction in perinatal vessels whilst the 5-HT 1D or 5-HT 1B receptor contributes in adult rabbit vessels. The 5-HT 1D or 5-HT 1B receptor mediates NO-dependent vasodilation in vessels from rabbits at 4 days of age whilst 5-HT 7 receptors mediate NOindependent vasodilation by 7 days.

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Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung

Cited by 170 publications

References 21 publications

Localization of Inducible Nitric Oxide Synthase to Mast Cells During Ischemia/Reperfusion Injury of Skeletal Muscle

Localization of Inducible Nitric Oxide Synthase to Mast Cells During Ischemia/Reperfusion Injury of Skeletal Muscle

Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

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