The NO donor molsidomine reduces endothelin-1 gene expression in chronic hypoxic rat lungs

Blumberg, Friedrich C.; Wolf, Karl; Sandner, Peter; Lorenz, Cornelia; Riegger, Günter A.J.; Pfeifer, Michael

doi:10.1152/ajplung.2001.280.2.l258

Cited by 26 publications

(20 citation statements)

References 30 publications

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“…This increased ET-1 release was associated with an increase in ET-1 transcription (36). Conversely, treatment with the NO donor molsidomine reduced the hypoxia-induced increase in ET-1 release in the lungs of rats (7). Although the exact mechanism of the interaction was not resolved, these data indicate that NO and ET-1 have an inverse relationship and provide important information in the context of the regulation of the two vascular mediators.…”

Section: Discussionmentioning

confidence: 84%

Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase

Kelly¹,

Wedgwood²,

Steinhorn³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase. Am J Physiol Lung Cell Mol Physiol 286: L984-L991, 2004. First published December 24, 2003; 10.1152/ajplung.00224.2003.-The use of exogenous nitric oxide (NO) has been shown to alter the regulation of other endothelially derived mediators of vascular tone, such as endothelin-1 (ET-1). However, the interaction between NO and ET-1 appears to be complex and remains incompletely understood. One of the major actions of NO is the activation of soluble guanylate cyclase (sGC) with the subsequent generation of cGMP. Therefore, we undertook this study to test the hypothesis that NO regulates ET-1 production via the activation of the sGC/cGMP pathway. The results obtained indicated that the exposure of primary cultures of 4-wk-old ovine pulmonary arterial endothelial cells (4-wk PAECs) to the long-acting NO donor DETA NONOate induced both a dose-and time-dependent decrease in secreted ET-1. This decrease in ET-1 secretion occurred in the absence of changes in endothelin-converting enzyme-1 or sGC expression but in conjunction with a decrease in prepro-ET-1 mRNA. The changes in ET-1 release were inversely proportional to the cellular cGMP content. Furthermore, the NO-independent activator of sGC, YC-1, or treatment with a cGMP analog also produced significant decreases in ET-1 secretion. Conversely, pretreatment with the sGC inhibitor ODQ blocked the NO-induced decrease in ET-1. Therefore, we conclude that exposure of 4-wk PAECs to exogenous NO decreases secreted ET-1 resulting from the activation of sGC and increased cGMP generation. guanosine 3Ј,5Ј-cyclic monophosphate PERSISTENT PULMONARY HYPERTENSION of the newborn (PPHN) is a disease characterized by a failure of the normal pulmonary vascular transition at birth, leading to increased pulmonary vascular resistance, decreased pulmonary blood flow, and severe hypoxemia (23). PPHN affects between 2 and 6/1,000 live born term infants and continues to have significant morbidity and mortality despite recent advances in therapy (23). Important among these advances is the use of inhaled nitric oxide (NO), which has been shown in several multicenter randomized controlled trials to improve oxygenation and decrease the need for extracorporeal membrane oxygenation in term and near-term infants (16,24).Endogenous NO is an endothelially derived regulator of vascular tone that is formed by nitric oxide synthase (NOS; see Ref. 13). NO can then freely diffuse to the smooth muscle cell and activate soluble guanylate cyclase (sGC), increasing the conversion of GTP to the intracellular signaling molecule cGMP (39). cGMP works, at least in part, by activating cGMP-dependent protein kinase (PKG), another important intracellular signaling enzyme (1). It is presumed that, when NO is given by inhalation, it freely diffuses through the pulmonary epithelium to the vascular smooth muscle where it exerts its vascular dilating effect in a similar fashion (13).Approximately 40% of the infants with P...

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Section: Discussionmentioning

confidence: 84%

Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase

Kelly¹,

Wedgwood²,

Steinhorn³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…After 4 weeks, right ventricular systolic pressure was determined in all animals with the closed‐chest technique as previously described (Blumberg et al . ).…”

Section: Methodsmentioning

confidence: 97%

Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin‐treated rats

et al. 2013

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Simvastatin prevents the development of pulmonary fibrosis, but fails to attenuate already established pulmonary fibrosis. In contrast, it ameliorates pulmonary hypertension and thereby exercise capacity in the prevention and the treatment group regardless of its effects on pulmonary fibrosis. Whether statins are a treatment option in humans with pulmonary fibrosis needs to be investigated by further study.

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“…Indeed (Nakanishi et al 1999), found in a model of hypobaric hypoxia-induced PH increased ET-1 mRNA and protein by in situ hybridization and immunohistochemistry in smooth muscle cells, yet unchanged in endothelial cells of pulmonary arteries, implicating an autocrine role for ET-1 in the remodeling process. Other studies report elevations or reductions of modulating factors in hypoxic vasoconstriction and vascular remodeling, for example the ET B receptor, NO synthase protein and NO (Blumberg et al 2001;Ivy et al 2001;Muramatsu et al 1999), as well as invoking a role for ET-3 (Pfeifer et al 1998).…”

Section: Ph Associated With Disorders Of the Respiratory System And (mentioning

confidence: 99%

The endothelin system in pulmonary hypertension

Michel

Langleben²,

Dupuis³

2003

Can. J. Physiol. Pharmacol.

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Pulmonary hypertension (PH) may result from numerous clinical entities affecting the pulmonary circulation primarily or secondarily. It is recognized that vascular endothelial dysfunction contributes to the development and perpetuation of PH by creating an imbalance between vasodilating and antiproliferative forces and between vasoconstrictive and proliferative forces. In that context, endothelin-1 (ET-1) overproduction was rapidly targeted as a plausible contributor to the pathogenesis of PH. The lung is recognized as the major site for ET production and clearance. In all animal models of PH studied, circulating plasma ET-1 levels are elevated, accompanied by an increase in lung tissue expression of the peptide. The use of selective ETA and dual ETA-ETB receptor antagonists in these models both in prevention and in therapeutic studies have confirmed the contribution of ET-1 to the rise in pulmonary vascular tone, pulmonary medial hypertrophy, and right ventricular hypertrophy. This is found consistently in models affecting the pulmonary circulation primarily or producing PH secondarily. Recent clinical trials in patients with pulmonary arterial hypertension have confirmed the therapeutic effectiveness of ET-receptor antagonists in humans. We offer a systematic review of the pathogenic role of the ET system in the development of PH as well as the rationale behind the preclinical and ongoing clinical trials with this new class of agents.

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The NO donor molsidomine reduces endothelin-1 gene expression in chronic hypoxic rat lungs

Cited by 26 publications

References 30 publications

Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase

Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase

Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin‐treated rats

The endothelin system in pulmonary hypertension

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