Activity of Endothelium-Derived Hyperpolarizing Factor Is Augmented in Monocrotaline-Induced Pulmonary Hypertension of Rat Lungs

Morio, Yoshiteru; Homma, Noriyuki; Takahashi, Hideki; Yamamoto, Akihito; Nagaoka, Tetsutaro; Sato, Koichi; Matsushima, Masashi; Fukuchi, Yoshinosuke

doi:10.1159/000101778

Cited by 13 publications

(10 citation statements)

References 97 publications

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“…These findings suggest that EETs do not contribute to endothelium-dependent NS309 relaxation in rat pulmonary arteries. Recent studies have reported that cytochrome P450 epoxygenase derivatives are involved in hypoxic vasoconstriction (39), and the present results do not exclude EETs contributing to endothelium-dependent relaxations in arteries from animals with pulmonary hypertension (36). K ϩ (5-22.5 mM) induces relaxation through activation of Na ϩ -K ϩ -ATPase and K ir channels in the vascular smooth muscle (14), and it was suggested that K ϩ ions released from IK Ca and SK Ca channels in the endothelium accumulate in the intercellular space and thereby activate K ir channels and Na ϩ -K ϩ -ATPase leading to EDHF-type relaxation in rat mesenteric arteries (14).…”

Section: Discussioncontrasting

confidence: 99%

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

Kroigaard

Dalsgaard

Simonsen

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Kroigaard C, Dalsgaard T, Simonsen U. Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHFtype relaxation in rat pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 298: L531-L542, 2010. First published January 29, 2010 doi:10.1152/ajplung.00220.2009.-This study investigated the mechanisms underlying epithelium-derived hyperpolarizing factor (EpDHF)-type relaxation in rat bronchioles. Immunohistochemistry was performed, and rat bronchioles and pulmonary arteries were mounted in microvascular myographs for functional studies. An opener of small (SKCa) and intermediate (IKCa)-conductance calcium-activated potassium channels, NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime) was used to induce EpDHF-type relaxation. IK Ca and SKCa3 positive immunoreactions were observed mainly in the epithelium and endothelium of bronchioles and arteries, respectively. In 5-hydroxytryptamine (1 M)-contracted bronchioles (828 Ϯ 20 m, n ϭ 84) and U46619 (0.03 M)-contracted arteries (720 Ϯ 24 m, n ϭ 68), NS309 (0.001-10 M) induced concentration-dependent relaxations that were reduced by epithelium/endothelium removal and by blocking IK Ca channels with charybdotoxin and in bronchioles also by blocking SK Ca channels with apamin. Inhibition of cyclooxygenase, nitric oxide synthase, and cytochrome 2C isoenzymes, or blockade of large (BK Ca)-conductance calciumactivated potassium channels with iberiotoxin, failed to reduce NS309 relaxation. In contrast to the pulmonary arteries, relaxations to a ␤ 2-adrenoceptor agonist, salbutamol, were reduced in bronchioles by removing the epithelium or blocking IK Ca and/or SK Ca channels. Extracellular K ϩ (2-20 mM) induced relaxation in both bronchioles and arteries. An inhibitor of Na ϩ -K ϩ -ATPase, ouabain, abolished relaxations to NS309, salbutamol, and K ϩ . These results suggest that IK Ca and SKCa3 channels are located in the epithelium of bronchioles and endothelium of pulmonary arteries. Analog to the endotheliumderived hyperpolarizing factor (EDHF)-type relaxation in pulmonary arteries, these channels may be involved in EpDHF-type relaxation of bronchioles caused by epithelial K ϩ efflux followed by activation of Na ϩ -K ϩ -ATPase in the underlying smooth muscle layer.NS309; salbutamol; potassium; endothelium; GEA 3175 THE RESPIRATORY EPITHELIUM releases factors that regulate bronchial smooth muscle relaxations (20), and removal of the bronchial epithelium in larger airways has been shown to enhance the effect of contractile agonists and reduce the relaxing response in bronchioles (50, 51). Nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) are mediators of human bronchiole smooth muscle epithelium-dependent relaxations (22). In addition, a non-NO nonprostanoid epithelium-dependent hyperpolarizing factor (EpDHF) is also involved in epitheliumdependent relaxations. Epoxyeicosatrienoic acids (EETs) have been suggested to account for EpDHF-mediated relaxation in guinea pig airways (3). In comparison, opening of intermediate (IK Ca ) and endothelial subt...

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Section: Discussioncontrasting

confidence: 99%

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

Kroigaard

Dalsgaard

Simonsen

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Alternatively, it is plausible to suggest that in humans, some mechanisms may exist to compensate for the deficiency of BH4 in the pulmonary vessels, as was seen in the systemic endothelium that do not exist in the mice. For example, other endothelial mediators such as endothelium-derived hyperpolarizing factor 30 or prostacyclins 31 may have been upregulated in the pulmonary as well as the systemic vasculature. Similarly, downregulation of endothelins 32 or a reduction in sympathetic response may have reduced the physiological antagonism of the pulmonary arterial bed.…”

Section: Discussionmentioning

confidence: 99%

Endothelial, Sympathetic, and Cardiac Function in Inherited (6 R )- l -Erythro-5,6,7,8-Tetrahydro- l -Biopterin Deficiency

Mayahi

Mason

Bleasdale-Barr

et al. 2010

Circ Cardiovasc Genet

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Background-(6R)-5,6,7,8-Tetrahydro-L-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by GCH1. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in GCH1 in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans. Methods and Results-In 16 DOPA-responsive dystonia patients with mutations predicted to affect GTPCH-1 expression or function and in age-and sex-matched control subjects, we measured plasma biopterin and nitrogen oxides by highperformance liquid chromatography and the Griess reaction, respectively, endothelial function by brachial artery flowmediated dilation (FMD), sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response. Cardiac function and structure were assessed by echocardiography. 9%, Pϭ0.91). In patients but not control subjects, FMD was insensitive to nitric oxide synthase inhibition (FMD at baseline, 6.7Ϯ2.1%; FMD during L-NMMA infusion, 6.2Ϯ2.5, Pϭ0.68). The heart rate at rest was higher in patients, but the heart rate and blood pressure response to sympathetic stimulation did not differ in patients and control subjects despite lower concentrations of norepinepherine (264Ϯ8 pg/mL versus 226Ϯ9 pg/mL, Pϭ0.006) and epinephrine (33.8Ϯ5.2 pg/mL versus 17.8Ϯ4.6 pg/mL, Pϭ0.03) in patients. There was also no difference in cardiac function and structure. Conclusions-Sympathetic, cardiac, and endothelial functions are preserved in patients with GCH1 mutations despite a neurological phenotype, reduced plasma biopterin, and norepinepherine and epinephrine concentrations. Lifelong endogenous BH4 deficiency may elicit developmental adaptation through mechanisms that are inaccessible during acquired BH4 deficiency in adulthood. (Circ Cardiovasc Genet. 2010;3:513-522.)Key Words: endothelium Ⅲ sympathetic function Ⅲ tetrahydrobiopterin Ⅲ DOPA-responsive dystonia T etrahydrobiopterin (BH4), synthesized from GTP by the rate-limiting enzyme GTP cyclohydrolase I (GTPCH-1) and encoded by the GCH1 gene, is an essential cofactor for the aromatic amino acid hydroxylases (phenylalanine, tyrosine, and tryptophan hydroxylase), which are responsible for the synthesis of the central and sympathetic neurotransmitters dopamine (DA), norepinephrine (NE), epinephrine, and 5-hydroxytryptamine (5HT), as well as the nitric oxide synthases (eNOS, iNOS, and nNOS). The Michaelis constant (K m ) for BH4 of the aromatic amino acid hydroxylases (100 mol/L) 1 is higher than that for the NOSs (100 nmol/ L), 2 suggesting that they may be more sensitive to the effect of inherited or acquired BH4 deficiency. Clinical Perspective on p 522In the absence of a specific, potent inhibitor of GTPCH-1 for use in humans, it has been difficult to evaluate the precise physiological role of BH4 in sympathetic, endothelial, and cardiac functions....

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“…Endothelial cell adhesion molecules play a pivotal role in the recruitment and binding of inflammatory cells to the vascular endothelium during the development of vascular disease. Since several reports suggested that elevated VCAM-1 levels reflect the impairment of endothelial function (26), VCAM-1 has been regarded as a marker of endothelial dysfunction. In this study, we demonstrated the augmentation of lung VCAM-1 expression and plasma ET-1 levels, and reduction of lung eNOS expression, suggesting endothelial dysfunction characterized by downregulation of eNOS expression and upregulation of ET-1 levels in the PE rat.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, although vascular endothelial dysfunction may exist during the development of vascular disease, there are no studies that have determined the contribution of pulmonary vascular endothelial dysfunction in the pathogenesis of PE. We thus investigated the expression of vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) to evaluate the pulmonary vascular endothelial dysfunction in the PE rats (22,24,26). We also tested whether Rho kinase inhibitor is capable of attenuating the degree of pulmonary hypertension and hypoxemia in the PE rats in vivo.…”

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confidence: 99%

Involvement of Rho kinase in the pathogenesis of acute pulmonary embolism-induced polystyrene microspheres in rats

Toba

Nagaoka

Morio

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute pulmonary embolism (PE) is a life-threatening disease, and several vasoconstrictors, including endothelin-1 (ET-1), play a key role in vasoconstriction and hypoxemia during the development of PE. Rho kinase is activated by various vasoconstrictors resulting in vascular contraction and remodeling. Recent evidence has revealed an important role of Rho kinase in the pathogenesis of systemic and pulmonary vascular diseases. However, contribution of Rho kinase in PE remains unclear. We thus investigated the role of Rho kinase in the PE rat model induced by intrajugular administration of polystyrene microspheres (mean diameter, 26 microm). At 6 h following the administration of microspheres (1.5 ml/kg), right ventricular systolic pressure (RVSP) was higher in the PE than in the control rats (15.8 +/- 1.6 vs. 32.9 +/- 7.5 mmHg). Arterial oxygen tension was lower (92.3 +/- 12.5 vs. 66.0 +/- 17.7 Torr), and alveolar-arterial difference in oxygen partial pressure was higher (3.9 +/- 3.8 vs. 36.5 +/- 26.9 Torr) in the PE rats. Western blotting analysis revealed upregulation and downregulation in expression of vascular cell adhesion molecule-1 and endothelial nitric oxide synthase in lungs from the PE rats, respectively, and radioimmunoassay demonstrated an increase in plasma ET-1 levels. Lung Rho kinase alpha expression was greater in the PE rats. At 5 h following administration of microspheres (0.75 ml/kg), intravenous Rho kinase inhibitors HA1077 and Y27632 (3 mg/kg each) attenuated elevation of RVSP (22.0 +/- 3.7, 17.1 +/- 3.2, 14.3 +/- 2.6 mmHg, PE, PE+HA1077, PE+Y27632) and the severity of hypoxemia (66.3 +/- 16.2, 94.9 +/- 23.0, 89.1 +/- 8.5 Torr, PE, PE+HA1077, PE+Y27632) in the PE rats. These results suggest that pulmonary endothelial dysfunction and activation of Rho kinase may contribute to the potentiation of vasoconstriction and hypoxemia in the PE rats.

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Activity of Endothelium-Derived Hyperpolarizing Factor Is Augmented in Monocrotaline-Induced Pulmonary Hypertension of Rat Lungs

Cited by 13 publications

References 97 publications

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

Endothelial, Sympathetic, and Cardiac Function in Inherited (6 R )- l -Erythro-5,6,7,8-Tetrahydro- l -Biopterin Deficiency

Involvement of Rho kinase in the pathogenesis of acute pulmonary embolism-induced polystyrene microspheres in rats

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