Carvedilol Inhibits Endothelin-1 Biosynthesis in Cultured Human Coronary Artery Endothelial Cells

Ohlstein, Eliot H.; Arleth, Anthony J.; Storer, Barbara; Romanic, Anne M.

doi:10.1006/jmcc.1997.0582

Cited by 44 publications

(19 citation statements)

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“…16,17 A similar mode of action might be proposed for carvedilol in the present experiments, because there is evidence of increased superoxide anion production by endothelial cells after aortic banding, 32 and of increased ET-1 production stimulated by free radicals in myocardium. 33 Further experiments are needed to test this hypothesis in a specific manner.…”

Section: Discussionsupporting

confidence: 81%

“…15 Unlike other ␤-blockers, carvedilol reduces ET-1 biosynthesis in cultured endothelial cells. 16,17 Recently, carvedilol, at doses that do not reduce systemic blood pressure, has been reported to prevent cardiac growth and remodeling in SHRSP maintained on 1% NaCl drinking solution and highfat diet. 18 In SHRSP, the calcium channel blocker lacidipine also prevents salt-dependent cardiac hypertrophy at doses that only minimally affect hypertension, and this effect could be related to a concomitant reduction in myocardial levels of preproendothelin-1 (preproET-1) mRNA.…”

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confidence: 99%

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Carvedilol and Lacidipine Prevent Cardiac Hypertrophy and Endothelin-1 Gene Overexpression After Aortic Banding

Massart

Donckier²,

Kyselovič³

et al. 1999

Hypertension

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Abstract-Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; PϽ0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; PϽ0.05) and skeletal ␣-actin (3.6 times; PϽ0.05), but the expression of cardiac ␣-actin was not modified. Oral administration of carvedilol at a dose of 30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal ␣-actin gene expression. Carvedilol at a lower dose (7.5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) and lacidipine 1 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (PϽ0.01) and preproendothelin-1 overexpression (PϽ0.05). Labetalol (60 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 did not prevent myocardial overexpression of skeletal ␣-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy. ndothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells, 1 is endowed with remarkable growth-promoting properties. In cultured neonatal cardiac myocytes, ET-1 induces hypertrophy, 2,3 whereas other stimuli, such as mechanical stretch or angiotensin II (Ang II), may evoke hypertrophic growth by increasing ET-1 biosynthesis. 4,5 ET-1 has also been shown to play an important role in some in vivo models of cardiac hypertrophy. ET-1 receptor antagonists prevent, at least transiently, left ventricular (LV) hypertrophy evoked by suprarenal aortic banding. 6 ET-1 receptor blockade has been reported to attenuate cardiac hypertrophy in strokeprone spontaneously hypertensive rats (SHRSP) fed a high-salt diet, 7,8 in uninephrectomized rats receiving deoxycorticosterone acetate and a high-salt diet, 9,10 in renovascular hypertensive rats, 11 and in rats infused with Ang II 12 or norepinephrine. 13 Carvedilol is a nonselective, vasodilating ␤-blocker with potent antioxidant and free radical-scavenging properties 14 that is used in the treatment of hypertension, angina, and congestive heart failure. 15 Unlike other ␤-blockers, carvedilol reduces ET-1 biosynthesis in cultured endothelial cells. 16,17 Recently, carvedilol, at doses that do not reduce systemic blood pressure, has been re...

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Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

Carvedilol and Lacidipine Prevent Cardiac Hypertrophy and Endothelin-1 Gene Overexpression After Aortic Banding

Massart

Donckier²,

Kyselovič³

et al. 1999

Hypertension

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“…21,22 Antioxidants such as probucol 23 and pyrrolidine dithiocarbamate could inhibit in vitro endothelial VCAM-1 expression by downregulating NF-B activation 16,19,24 and prevent in vivo atherogenesis. 7,22 Recent evidence also sug- gested that carvedilol might exert endothelial protection via multiple mechanisms such as inhibiting low-density lipoprotein oxidation by scavenging ROS, 7,14 preserving intracellular mitochondrial function by reducing excessive oxidative stress, 25 inhibiting xanthine-xanthine oxidase-induced LDH release, 26 enhancing vasodilatation by inhibition of endothelin-1 biosynthesis, 27 stimulating endothelial nitric oxide release through ATP efflux, 28 and preventing endothelial apoptosis through modulation of Fas/Fas ligand and caspase-3 pathway. 29,30 Our findings further indicated that carvedilol could inhibit redox-sensitive transcription factor NF-B and AP-1 activation in HAECs.…”

Section: Discussionmentioning

confidence: 99%

Carvedilol Inhibits Tumor Necrosis Factor-α–Induced Endothelial Transcription Factor Activation, Adhesion Molecule Expression, and Adhesiveness to Human Mononuclear Cells

Chen

Lin

Chen

et al. 2004

ATVB

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Objective-We tested the hypothesis that carvedilol, a ␤-adrenoceptor and ␣-adrenoceptor antagonist with potent antioxidant property, could inhibit tumor necrosis factor-␣ (TNF-␣)-induced endothelial adhesiveness to human mononuclear cells (MNCs), an early sign of atherogenesis. Methods and Results-Circulating MNCs were isolated from the peripheral blood of healthy subjects. Compared with control condition, pretreatment of carvedilol (10 mol/L for 18 hours) or probucol (5 mol/L for 18 hours), but not propanolol, prazosin, or both propanolol and prazosin significantly decreased TNF-␣-stimulated adhesiveness of cultured human aortic endothelial cells (HAECs) to MNCs. Carvedilol inhibited TNF-␣-stimulated endothelial vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (66.0Ϯ2.0% and 55.60Ϯ1.0% of control, PϽ0.05, respectively) expression, whereas probucol inhibited only VCAM-1 expression (79.0Ϯ5.0% of control, PϽ0.05). Propanolol, prazosin, or both did not alter the expression of adhesion molecules. Further, pretreatment with carvedilol significantly inhibited TNF-␣-stimulated intracellular reactive oxygen species (ROS) production and the activation of redox sensitive nuclear factor kappa B and activator protein-1 transcription pathways. Conclusions-Carvedilol reduced TNF-␣-stimulated endothelial adhesiveness to human MNCs by inhibiting intracellular ROS production, transcription factor activation, and VCAM-1 as well as E-selectin expression, suggesting its potential role in clinical atherosclerosis disease. Key Words: antioxidant Ⅲ atherosclerosis Ⅲ carvedilol Ⅲ cell adhesion molecules Ⅲ endothelium I n the early phase of atherogenesis, cell surface adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and endothelial cell selectin (E-selectin) could express on endothelial cells to recruit circulating mononuclear cells (MNCs), mainly monocytes, and facilitate their binding to endothelium and migrating to subendothelial space. 1-3 Reactive oxygen species (ROS) may serve as a common intracellular messenger for various redox-sensitive transcription pathways that lead to adhesion molecule expression in vascular endothelial cells. 1,4,5 Accumulating in vitro and in vivo evidence showed that substances with antioxidant activity such as probucol and ginkgo biloba extract could scavenge intracellular ROS and inhibit endothelial adhesiveness to monocytes by reducing the expression of various adhesion molecules. 6,7 However, because of the presence of significant side effects or lack of clinical evidence, these drugs are rarely used for human atherosclerosis disease. 8 Carvedilol, 1-[carbazolyl-4-oxy]-3-[(2-methoxyphenoxyethyl)-amino]-propanol-2, a nonselective ␤-adrenoceptor antagonist with ␣1 adrenoceptor blocking and potent antioxidant activity, is currently used for treatment of hypertension or symptomatic heart failure. 9,10 Previous in vitro evidence showed that carvedilol, as an oxidant scavenger, could inhibit cardiomyocyte membrane lipid perox...

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“…El paciente estudiado en dos ocasiones distintas (con y sin carvedilol) tuvo un aumento de la RFC con carvedilol desproporcionado al aumento de la fracción de eyección. El carvedilol es un antagonista beta y alfa-1 adrenérgi-co, que además tiene propiedades antioxidantes 32 y antiendotelina-1 33 . Estas propiedades pueden explicar, al menos en parte, la RFC ligeramente más alta en el grupo 3.…”

Section: Carvedilolunclassified

Disminución de la reserva de flujo coronario en pacientes con insuficiencia cardíaca no isquémica

et al. 2003

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Introducción y objetivos. La reserva de flujo coronario (RFC) se reduce no sólo en la cardiopatía isquémica, sino también en otras cardiopatías, con o sin insuficiencia cardíaca. El objetivo del estudio fue comprobar si la gravedad de la insuficiencia cardíaca influye en el deterioro de la RFC.Métodos. Se estudió a 40 pacientes diagnosticados de cardiopatía no isquémica e insuficiencia cardíaca, en 41 ocasiones distintas. Fueron repartidos en 4 grupos: 1. 10 pacientes en grado funcional III-IV; 2. 10 pacientes en grado funcional II sin tratamiento con bloqueadores beta; 3. 11 pacientes en grado funcional II tratados con carvedilol, y 4. 10 pacientes en grado funcional I, que previamente habían tenido insuficiencia cardíaca por disfunción sistólica. El flujo miocárdico (FM) se midió mediante tomografía por emisión de positrones (PET) y N-13 amonio: en condiciones basales y durante la infusión de trifosfato de adenosina (ATP).Resultados. El FM máximo y la RFC fueron significativamente más altos en el grupo 4 (1,95 ± 0,58 y 2,40 ± 0,95 ml/min/g) que en el grupo 1 (1,02 ± 0,52 y 1,46 ± 0,48 ml/min/g). La RFC tuvo tendencia a ser mayor en los grupos 2 (1,73 ± 0,72) y 3 (1,89 ± 0,75) que en el grupo 1. No hubo correlación significativa entre la RFC y las siguientes variables: edad, presión arterial sistólica, índice de masa ventricular, índices de volumen y fracción de eyección de ventrículo izquierdo.Conclusiones. La función microvascular coronaria está alterada en la insuficiencia cardíaca no isquémica, y dicha alteración se relaciona con la situación funcional, cualquiera que sea la cardiopatía subyacente.

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Carvedilol Inhibits Endothelin-1 Biosynthesis in Cultured Human Coronary Artery Endothelial Cells

Cited by 44 publications

References 0 publications

Carvedilol and Lacidipine Prevent Cardiac Hypertrophy and Endothelin-1 Gene Overexpression After Aortic Banding

Carvedilol and Lacidipine Prevent Cardiac Hypertrophy and Endothelin-1 Gene Overexpression After Aortic Banding

Carvedilol Inhibits Tumor Necrosis Factor-α–Induced Endothelial Transcription Factor Activation, Adhesion Molecule Expression, and Adhesiveness to Human Mononuclear Cells

Disminución de la reserva de flujo coronario en pacientes con insuficiencia cardíaca no isquémica

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