Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats

Kobayashi, Noboru; Mori, Yoshihide; Nakano, Shigefumi; Tsubokou, Yusuke; Shirataki, Hiromichi; Matsuoka, Hiroaki

doi:10.1097/00004872-200104000-00017

Cited by 35 publications

(25 citation statements)

References 35 publications

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“…However, they increased the protective eNOS mRNA expression in the endothelial system, and therefore increased the release of NO from endothelial cells, which increased the blood supply to damaged areas of the heart. Several studies have reported that eNOS could improve cardiac remodeling [17,18] , which supports our present results. However, ET-1 enhances cardiac remodeling and promotes the development of HF [19] .…”

Section: Differences In Pharmacological Mechanisms Between the Sur2b/supporting

confidence: 93%

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

Wang

Long

Cui³

et al. 2016

Acta Pharmacol Sin

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Both iptakalim (Ipt) and natakalim (Nat) activate the SUR2B/Kir6.1 channel, an ATP-sensitive potassium channel (K ATP ) subtype, with high selectivity. In this study we investigated the therapeutic effects of Ipt and Nat against isoproterenol-induced chronic heart failure (ISO-CHF) in rats, and demonstrated a new therapeutic approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells. In ISO-CHF rats, oral administration of Nat (1, 3, 9 mg·kg -1 ·d -1 ) or Ipt (3 mg·kg -1 ·d -1 ) for 60 days significantly improved cardiac dysfunction, reversed cardiac remodeling, significantly attenuated the pathological increases in BNP levels, and improved endothelial dysfunction by adjusting the balance between endothelin and NO systems. The therapeutic effects of Nat were prevented by the selective K ATP blocker glibenclamine (Gli, 50 mg·kg -1 ·d -1 ), confirming that these effects were mediated through activation of the SUR2B/Kir6.1 channel in endothelial cells. The molecular mechanisms underlying the therapeutic effects of Nat were further addressed using proteomic methods. We identified 724 proteins in the plasma of ISO-CHF rats; 55 proteins were related to Nat. These differentially expressed proteins were mainly involved in single-organism processes and the regulation of biological quality relative to CHF, including proteasome (Psm) and ATP protein clusters. We screened out PRKAR2β, GAS6/eNOS/NO and NO/PKG/VASP pathways involved in the amelioration of CHF among the 24 enriched pathways. We further confirmed 6 protein candidates, including PRKAR2β, GAS6 and VASP, which were involved in the endothelial mechanisms, and ATP, TIMP3 and AGT, which contributed to its cardiovascular actions. This study demonstrates a new pharmacological approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells, and that the eNOS/VASP pathways are involved in its signaling mechanisms.

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Section: Differences In Pharmacological Mechanisms Between the Sur2b/supporting

confidence: 93%

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

Wang

Long

Cui³

et al. 2016

Acta Pharmacol Sin

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“…16 Rats received weekly subcutaneous injections of DOCA (30 mg/kg) after right nephrectomy and were given 1% saline as drinking water (DOCA-V, nϭ7). Eight of the 14 remaining DOCA-salt rats were treated with celiprolol (Nippon Shinyaku Co, Ltd) in their drinking water for 5 weeks, and a fresh drug solution was prepared daily (DOCA-Ce, nϭ8).…”

Section: Animal Models and Experimental Designmentioning

confidence: 99%

“…The drug was given at an average dose of 10 mg · kg Ϫ1 · d Ϫ1 (subpressor dose), which was adjusted weekly to the drinking habits of the animals. 16 The remaining 6 DOCA-salt rats were treated with celiprolol plus wortmannin, a PI3K inhibitor (DOCA-CeϩWo, nϭ6). An osmotic minipump (model 2ML4, Alzet Corp) containing wortmannin (1 mg · kg Ϫ 1 · d Ϫ1 ) dissolved in 8% dimethyl sulfoxide was implanted.…”

Section: Animal Models and Experimental Designmentioning

confidence: 99%

“…15,21 Western Blot Analysis VCAM-1; eNOS; and NAD(P)H oxidase p22phox, p47phox, and gp91phox proteins were measured as described previously. 16,22 Activity of eNOS, Akt, p65NF-B, p60c-Src, ERK1/2, and p90RSK eNOS, Akt, p65NF-B, p60c-Src, p44/p42 extracellular signalregulated kinase (ERK1/2), and p90 ribosomal S6 kinase (p90RSK) phosphorylation was measured as described in detail previously. 23 …”

Section: Reverse Transcription-pcrmentioning

confidence: 99%

“…16 Kakoki et al 17 reported that celiprolol augmented endothelium vasodilation in rat aortas and that this action was attenuated by treatment with NAN-190, a 5-hydroxytryptamine 1A (5-HT 1A ) antagonist. Noda et al 18 also reported that celiprolol showed vasodilatory action by way of an NO-cGMP system in porcine coronary arteries by acting on other ␤-adrenoceptor sites in the endothelium.…”

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confidence: 99%

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Celiprolol Activates eNOS Through the PI3K-Akt Pathway and Inhibits VCAM-1 Via NF-κB Induced by Oxidative Stress

et al. 2003

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Abstract-Vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species play critical roles in early atherogenesis, and nitric oxide (NO) is an important regulator of the cardiovascular system. Although celiprolol, a specific ␤ 1 -antagonist with weak ␤ 2 -agonistic action, stimulates endothelial nitric oxide synthase (eNOS) production, the mechanisms remain to be determined. Because it was recently reported that phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt are implicated in the activation of eNOS and that regulation of VCAM-1 expression is mediated via nuclear factor-B (NF-B), we hypothesized that celiprolol activates phosphorylation of eNOS through the PI3K-Akt signaling pathway; that celiprolol modulates VCAM-1 expression, which is associated with inhibiting NF-B phosphorylation; and that celiprolol suppresses NAD(P)H oxidase p22phox, p47phox, gp91phox, and nox1 expression in the left ventricle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. eNOS and Akt phosphorylation upregulated by celiprolol alone were suppressed by treatment with celiprolol plus wortmannin. Increased expression of VCAM-1, p22phox, p47phox, gp91phox, nox1, activated p65 NF-B, c-Src, p44/p42 extracellular signal-regulated kinases, and their downstream effector p90 ribosomal S6 kinase phosphorylation in DOCA rats was inhibited by celiprolol. Celiprolol administration resulted in a significant improvement in cardiovascular remodeling and suppression of transforming growth factor-␤1 gene expression. Key Words: receptors, adrenergic, ␤ Ⅲ adrenergic receptor blockers Ⅲ kinase Ⅲ nitric oxide Ⅲ oxidative stress Ⅲ cell adhesion molecules L eukocyte adhesion to the endothelium and infiltration into tissue have been found to contribute to the tissue damage and impairment of vascular perfusion in a broad array of systemic diseases, including atherosclerosis and hypertension. 1 Localized accumulation of leukocytes is mediated by the endothelial expression of specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, or plateletendothelial cell adhesion molecule-1. 2 VCAM-1 is an early marker of endothelial activation and dysfunction, leukocyte infiltration, and vascular remodeling, and a recent study demonstrated that VCAM-1 plays a key role in early atherogenesis. 3 Endothelium-derived relaxing factor, nitric oxide (NO), is an important component of vascular homeostasis. 4 Recently, some investigators 5,6 have shown that the serine/ threonine kinase Akt, a downstream effector of phosphatidylinositol 3-OH kinase (PI3K), phosphorylates human endothelial NO synthase (eNOS) on serine 1177 in response to varied stimuli, such as growth factors and shear stress. Furthermore, expression of adhesion molecules, including VCAM-1, can be regulated by NO, and increased levels of NO are associated with decreased leukocyte adhesion molecule expression. 7 The mechanisms by which NO modulates expression of VCAM-1 are unclear. However, regulation of VCAM-1 expression...

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Extracellular matrix fibrotic markers in heart failure

2009

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Given the importance of fibrous tissue in leading to myocardial dysfunction, non-invasive assessment of fibrosis could prove a clinically useful tool in heart failure (HF) patients. Biomarkers may be used for early detection of otherwise subclinical disease, diagnostic assessment of an acute or chronic clinical syndrome, risk stratification of patients with a suspected or confirmed diagnosis, selection of an appropriate therapeutic intervention and monitoring the response to therapy. Extracellular matrix (ECM) biomarkers in HF are promising biomarkers. They are able to detect early changes in heart and large vessel structure and function and transition to HF. High ECM biomarker levels have been associated with poor outcome. The ability of treatment to reduce myocardial fibrosis in HF patients may be monitored by the measurement of various serum peptides arising from the metabolism of collagen types. Biomarkers may be selectively influenced by pharmacological agents.

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Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats

Abstract: Myocardial remodeling of DOCA-salt hypertensive rats was significantly ameliorated by subdepressor doses of celiprolol, which may be due to increased eNOS expression in the left ventricle.

Cited by 35 publications

References 35 publications

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

Celiprolol Activates eNOS Through the PI3K-Akt Pathway and Inhibits VCAM-1 Via NF-κB Induced by Oxidative Stress

Extracellular matrix fibrotic markers in heart failure

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