Activation of adenylate cyclase and phosphodiesterase inhibition enhance neutral endopeptidase activity in human endothelial cells

Graf, Kristof; Kunkel, Kerstin; Zhang, Minzhong; Gräfe, Michael; Schultz, K D; Schudt, Christian; Biroc, Sandra L.; Fleck, Eckart; Kunkel, G.

doi:10.1016/0196-9781(95)00077-w

Cited by 22 publications

(18 citation statements)

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“…13 In addition, activation of adenylate cyclase in tissue culture has been shown to increase neutral endopeptidase activity, which would be expected to enhance metabolism of BNP. 38 However, ADM-induced reductions in natriuretic peptide levels were small and nonsignificant, whereas the reductions in plasma cGMP were more substantial, which suggests that ADM in some way impaired the ability of the natriuretic peptides to generate second messenger. A final possibility is that interactions between second messengers at the level of cyclic nucleotide phosphodiesterases accounted for the attenuated cGMP response to BNP when coinfused with ADM. 39 Such interactions require further study, especially because other workers, using bovine aortic endothelial cells, reported ADM stimulated (rather than suppressed) cGMP through activation of nitric oxide synthase.…”

Section: Discussionmentioning

confidence: 81%

Bioactivity and Interactions of Adrenomedullin and Brain Natriuretic Peptide in Patients With Heart Failure

et al. 1999

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Abstract-Plasma concentrations of the recently discovered hormones adrenomedullin (ADM), from vascular tissue, and brain natriuretic peptide (BNP), secreted by myocardium, are elevated in patients with heart failure. We tested the hypotheses that short-term increments in circulating levels of these hormones, within the pathophysiological range, would have biological effects and that the 2 hormone systems interact. Eight patients with heart failure (left ventricular ejection fractions Ͻ35%) received 4-hour infusions of BNP (3.0 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) alone, ADM (2.7 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 and 5.4 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 for 2 hours each) alone, ADM and BNP combined, and placebo. BNP and ADM infusions raised plasma levels of the respective peptide within the pathophysiological range. Arterial blood pressure fell (PϽ0.05) with all peptide infusions, but cardiac output was unchanged. Heart rate increased with ADM and combined infusions (PϽ0.01). Sodium excretion rose (PϽ0.05), and creatinine clearance was sustained during both BNP and combined infusions. Urine volume increased in response to BNP alone (Pϭ0.02). Despite a Ͼ2-fold increase in plasma renin with both ADM and combined infusions (PϽ0.05), plasma aldosterone remained lower than time-matched placebo levels. Plasma noradrenaline was increased by combined, BNP, and higher dose ADM infusions (PϽ0.05). ADM suppressed plasma cGMP (PϽ0.05) and inhibited the plasma cGMP response to BNP (PϽ0.05). The vascular hormones ADM and BNP, produced by myocardium, at plasma concentrations within the pathophysiological range have hemodynamic, renal, and hormonal effects and measurable interactions in patients with heart failure. (Hypertension. 1999;34:70-75.) Key Words: heart failure Ⅲ adrenomedullin Ⅲ natriuretic peptides Ⅲ arterial pressure N eurohormonal activation plays a crucial role in the pathophysiology of heart failure. 1 Adrenomedullin (ADM), discovered in 1993, 2 and brain natriuretic peptide (BNP) are peptides with vasodilator, natriuretic, and aldosterone-inhibitory actions. 3-5 Plasma levels of both peptides are increased in proportion to the degree of hemodynamic compromise. 6,7 BNP is secreted predominantly from the left ventricle in response to increases in wall stress, whereas production of ADM from cultured endothelial and vascular smooth muscle cells suggests that blood vessels may be a major source of circulating ADM. 8,9 It is likely that ADM functions in an autocrine or paracrine fashion in addition to any role it may have as a circulating hormone because tissues with ADM receptors are also those with ADM synthetic capability. 10,11 Preliminary data suggest that there may be interactions between ADM, produced primarily in the peripheral circulation, and the cardiac natriuretic peptides produced in the heart. 12,13 Currently, however, there is no information regarding the effects of infused ADM in patients with heart failure and no data directly comparing the biological actions of ADM and BNP. Furthermore, the effects of coadministration of ADM and BNP in ...

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Section: Discussionmentioning

confidence: 81%

Bioactivity and Interactions of Adrenomedullin and Brain Natriuretic Peptide in Patients With Heart Failure

et al. 1999

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“…The different conditions may influence cyclic AMP and cyclic GMP levels. It has been reported that cyclic AMP affect angiotensin converting enzyme and neutral endopeptidase in endothelial cells (Iwai et al ., 1987; Dasarathy & Fanburg, 1991; Graf et al ., 1995). It is of interest to determine how the signal from the B 2 ‐receptor regulates the pathways of both the cyclo‐oxygenase and NO‐synthase systems in endothelial cells and why relaxant response was first evoked before contractile response.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of bradykinin B₂‐receptors on endothelial cells induces relaxation and contraction in porcine basilar artery in vitro

Miyamoto¹,

Ishiguro²,

Nishio³

1999

British J Pharmacology

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1 The aim of the present study was to characterize the subtypes of bradykinin (BK) receptors that evoke the relaxation and contraction induced by BK and to identify the main contracting and relaxing factors in isolated porcine basilar artery by measuring changes in isometric tension and a thromboxane (TX) metabolite. 2 Endothelial denudation completely abolished both responses. [Thi 5,8 , ]-BK (a B 2 -receptor antagonist) inhibited the BK-induced relaxation and contraction, whereas des-Arg 9 , [Leu 8 ]-BK (a B 1 -receptor antagonist) had no e ect. 3 L-nitro-arginine (L-NA, a nitric oxide synthase inhibitor) completely inhibited BK-induced relaxation. Indomethacin (a cyclo-oxygenase inhibitor) completely and ONO-3708 (a TXA 2 / prostaglandin H 2 receptor antagonist) partially inhibited BK-induced contraction, whereas OKY-046 (a TXA 2 synthase inhibitor) and nordihydroguaiaretic acid (a lipoxygenase inhibitor) did not. 4 In the presence of L-NA, the contractile response to BK was inhibited by indomethacin or ONO-3708 and was competitively antagonized by [Thi 5,8 , D-Phe 7 ]-BK (pA 2 =7.50). In the presence of indomethacin, the relaxant response to BK was inhibited by L-NA and was competitively antagonized by [Thi 5,8 , ]-BK (pA 2 =7.59). 5 TXA 2 release was not induced by BK-stimulation. 6 These results suggest that the endothelium-dependent relaxation and contraction to BK in the porcine basilar artery is mediated via activation of endothelial B 2 -receptors. The main relaxing factor may be NO and the main contracting factor may be prostaglandin H 2 .

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“…Despite the significant role of NEP in reducing Ab levels in brain, little is known about factors that regulate its neural expression. In non-neural cells, various factors have been reported to increase NEP activity and expression, including opioids in monocytes (Wang et al 1998), transforming growth factor b in renal smooth muscle cells (Tharaux et al 1997), phorbol ester in choriocarcinoma cells (Suzuki et al 2002), substance P in bone marrow cells (Joshi et al 2001), and cAMP in endothelial cells (Graf et al 1995). Notably, androgens are known to increase NEP expression in prostate cancer cell lines (Papandreou et al 1998;Shen et al 2000a,b).…”

Section: Discussionmentioning

confidence: 99%

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Yao

Nguyen

Rosario

et al. 2008

Journal of Neurochemistry

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Age‐related testosterone depletion in men is a risk factor for Alzheimer’s disease. Prior studies suggest that androgens affect Alzheimer’s disease risk by regulating accumulation of β‐amyloid protein (Aβ) by an undefined mechanism. In this study, we investigated the role of the Aβ‐catabolizing enzyme neprilysin (NEP) in this process. First, we observed that androgens positively regulate neural expression of NEP in adult male rats. Next, we investigated androgen regulatory effects on both NEP expression and Aβ levels using cultured hippocampal neurons and neuronally differentiated rat pheochromocytoma cell 12 with or without androgen receptor (AR). Dihydrotestosterone (DHT) induced a time‐dependent increase in NEP expression. DHT also significantly decreased levels of Aβ in AR‐expressing cells transfected with amyloid precursor protein, but did not affect levels of either full‐length or non‐amyloidogenic, soluble amyloid precursor protein. Importantly, the DHT induced decrease of Aβ was blocked by pharmacological inhibition of NEP. The DHT‐mediated increase in NEP expression and decrease in Aβ levels were (i) not observed in rat pheochromocytoma cell 12 lacking AR and (ii) blocked in AR‐expressing cells by the antagonists, cyproterone acetate and flutamide. Together, these findings suggest that androgen regulation of Aβ involves an AR‐dependent mechanism requiring up‐regulation of the Aβ catabolizing enzyme NEP.

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Activation of adenylate cyclase and phosphodiesterase inhibition enhance neutral endopeptidase activity in human endothelial cells

Cited by 22 publications

References 21 publications

Bioactivity and Interactions of Adrenomedullin and Brain Natriuretic Peptide in Patients With Heart Failure

Bioactivity and Interactions of Adrenomedullin and Brain Natriuretic Peptide in Patients With Heart Failure

Stimulation of bradykinin B₂‐receptors on endothelial cells induces relaxation and contraction in porcine basilar artery in vitro

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

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Activation of adenylate cyclase and phosphodiesterase inhibition enhance neutral endopeptidase activity in human endothelial cells

Cited by 22 publications

References 21 publications

Bioactivity and Interactions of Adrenomedullin and Brain Natriuretic Peptide in Patients With Heart Failure

Bioactivity and Interactions of Adrenomedullin and Brain Natriuretic Peptide in Patients With Heart Failure

Stimulation of bradykinin B2‐receptors on endothelial cells induces relaxation and contraction in porcine basilar artery in vitro

Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

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Stimulation of bradykinin B₂‐receptors on endothelial cells induces relaxation and contraction in porcine basilar artery in vitro