Nitric Oxide Stimulates Adrenomedullin Secretion and Gene Expression in Endothelial Cells

Dötsch, J.; Schoof, Ellen; Hänze, Jörg; Dittrich, Katalin; Opherk, P.; Dumke, K; Rascher, Wolfgang

doi:10.1159/000056162

Cited by 10 publications

(4 citation statements)

References 22 publications

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“…Under physiological conditions, the ADM effect on pulmonary vascular resistance can be attenuated by NOS inhibitor administration to fetal sheep (Takahashi et al, 1999). The close interaction of ADM and nitric oxide in vascular cells also becomes obvious by an increase of ADM gene expression and peptide synthesis after incubation of human umbilical venous cells with different NO donors (Dötsch et al, 2002). In our present series of experiments, L-NAME did not attenuate the beneficial effect of inhaled ADM on pulmonary vasodilation and oxygenation.…”

Section: Discussioncontrasting

confidence: 46%

Pilot Intervention: Aerosolized Adrenomedullin Reduces Pulmonary Hypertension

Kandler¹,

Hardt²,

Mahfoud³

et al. 2003

J Pharmacol Exp Ther

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In pulmonary hypertension, systemic infusion of adrenomedullin (ADM), a potent vasodilator peptide, leads to pulmonary vasodilatation. However, systemic blood pressure declines alike. The present study investigated the effect of aerosolized ADM on pulmonary arterial pressure in surfactant-depleted newborn piglets with pulmonary hypertension. Animals randomly received aerosolized ADM (ADM, n ϭ 6), aerosolized ADM combined with intravenous application of N G -nitro-L-arginine methylester to inhibit nitric-oxide (NO) synthases (ADM ϩ L-NAME, n ϭ 5), or aerosolized normal saline solution (control, n ϭ 6). Aerosol therapy was performed in 30-min intervals for 5 h. After a total experimental period of 8 h, mRNA expression of endothelial and inducible NO synthase and endothelin-1 (ET-1) in lung tissue was quantified using TaqMan real-time polymerase chain reaction. Aerosolized ADM reduced mean pulmonary artery pressure (MPAP) compared with control (p Ͻ 0.001; at the end of the study, ⌬-MPAP Ϫ13.5 Ϯ 1.4 versus Ϫ6.2 Ϯ 2.4 mm Hg). PaO 2 significantly increased in the ADM (⌬PaO 2 243.3 mm Hg) and the ADM ϩ L-NAME group (⌬PaO 2 217.4 mm Hg) compared with the control group (⌬PaO 2 82.9 mm Hg; p Ͻ 0.001). Aerosolized ADM did not influence mean systemic arterial pressure (baseline 63.2 Ϯ 2.7 versus end of the study 66.3 Ϯ 6.5 mm Hg; not significant). NO synthases gene expressions were 20 to 30% lower with ADM compared with control. ET-1 gene expression was significantly reduced (Ͼ50%) after ADM aerosol therapy (p Ͻ 0.001). Aerosolized adrenomedullin significantly reduced MPAP without lowering the systemic arterial pressure and improved profoundly the arterial oxygen tension. This effect seems to be mediated at least in part by the reduction of ET-1.

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Section: Discussioncontrasting

confidence: 46%

Pilot Intervention: Aerosolized Adrenomedullin Reduces Pulmonary Hypertension

Kandler¹,

Hardt²,

Mahfoud³

et al. 2003

J Pharmacol Exp Ther

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“…ADM biology is closely related to nitric oxide synthase-2 (NOS2) and the NO cascade. NO has been shown to stimulate ADM production in endothelial and smooth muscle cell lines (6,13). Furthermore, in transgenic mice overexpressing ADM in their vasculature, NO production is highly augmented (34).…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS

Agorreta¹,

Zulueta²,

Montuenga³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Adrenomedullin (ADM) is upregulated independently by hypoxia and LPS, two key factors in the pathogenesis of acute lung injury (ALI). This study evaluates the expression of ADM in ALI using experimental models combining both stimuli: an in vivo model of rats treated with LPS and acute normobaric hypoxia (9% O2) and an in vitro model of rat lung cell lines cultured with LPS and exposed to hypoxia (1% O2). ADM expression was analyzed by in situ hybridization, Northern blot, Western blot, and RIA analyses. In the rat lung, combination of hypoxia and LPS treatments overcomes ADM induction occurring after each treatment alone. With in situ techniques, the synergistic effect of both stimuli mainly correlates with ADM expression in inflammatory cells within blood vessels and, to a lesser extent, to cells in the lung parenchyma and bronchiolar epithelial cells. In the in vitro model, hypoxia and hypoxia + LPS treatments caused a similar strong induction of ADM expression and secretion in epithelial and endothelial cell lines. In alveolar macrophages, however, LPS-induced ADM expression and secretion were further increased by the concomitant exposure to hypoxia, thus paralleling the in vivo response. In conclusion, ADM expression is highly induced in a variety of key lung cell types in this rat model of ALI by combination of hypoxia and LPS, suggesting an essential role for this mediator in this syndrome.

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“…Although we did not measure peptide concentration directly, these data are indicative of ADM production in human adipose tissue containing adipocytes and stromal cells, since Vasoactive systems in adipose tissue I Knerr et al that ADM stimulates NO synthesis and vice versa. 27 In mice, deficiency of ADM leads to hypertension and a reduced lifespan; the reactive oxygen species in muscle are found to be increased whereas the insulin-stimulated glucose uptake was decreased in muscle. 28 ADM may therefore be considered as an endogenous peptide preserving insulin sensitivity with aging and the associated increased oxidative stress parameters.…”

Section: Discussionmentioning

confidence: 99%

Maturation of the expression of adrenomedullin, endothelin-1 and nitric oxide synthases in adipose tissues from childhood to adulthood

et al. 2005

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OBJECTIVE:To investigate if the vasoactive systems adrenomedullin (ADM) and endothelin-1 (ET-1) are expressed in human adipose tissues in children and in adults and to determine the distribution pattern of nitric oxide synthases (NOS). DESIGN AND SUBJECTS: Subcutaneous, mesenterial and omental adipose tissue specimens taken from 15 children (age 0.5-16 y, median 6 y) and 13 adults (age 43-79 y, median 60 y) were analyzed. The body mass indices (BMI) were within the normal range. All patients were normotensive, and were free of infectious disease, and metabolic or endocrine disorders. The specimens were taken during elective laparotomies after informed consent was obtained. MEASUREMENTS: ADM, ET-1, the endothelial (eNOS) and inducible (iNOS) NOS as well as two housekeeping genes were measured using quantitative real-time PCR. RESULTS: ADM gene expression was found at all locations, and was significantly higher in adults than in children (Po0.01 for subcutaneous and omental adipose tissue). ET-1 mRNA was distributed in a similar way, showing significantly higher levels in the subcutaneous and mesenterial adipose tissue sections of adults than of children. For eNOS, the adult patients exhibited a higher expression in subcutaneous and mesenterial specimens than the children (Po0.01 and Po0.05). The iNOS mRNA was increased in subcutaneous, mesenterial and omental adipose tissues in the adult cohort compared to the children's levels (Po0.05 to Po0.01). CONCLUSION: Human adipose tissue expresses many vasoactive substances including ADM and ET-1. In adults, the amounts of ET-1 and ADM as well as eNOS and iNOS mRNA are higher, possibly due to a physiological upregulation with increasing age. Although there are differences depending on the locations of the tissues, the expression patterns of the antagonists ADM and ET-1 are quite similar, indicative of a well-balanced pattern of local gene expression in normotensive individuals with normal body weight.

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Nitric Oxide Stimulates Adrenomedullin Secretion and Gene Expression in Endothelial Cells

Cited by 10 publications

References 22 publications

Pilot Intervention: Aerosolized Adrenomedullin Reduces Pulmonary Hypertension

Pilot Intervention: Aerosolized Adrenomedullin Reduces Pulmonary Hypertension

Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS

Maturation of the expression of adrenomedullin, endothelin-1 and nitric oxide synthases in adipose tissues from childhood to adulthood

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