The role of ET<sub>B</sub> receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET<sub>B</sub> receptor antagonist Ro 46‐8443

Clozel, Martine; Breu, Volker

doi:10.1016/0014-5793(96)00212-8

Cited by 46 publications

(24 citation statements)

References 18 publications

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“…Blockade of the ET B receptor resulted in further increase in blood pressure in hypertensive animals. This finding is in line with previous findings (5,15,23,30) and supports a protective role for ET-1 signaling through the ET B receptor in this model of hypertension. The pressor effect of A-192621 may occur as a result of the inhibition of nitric oxide release mediated by the ET B receptor.…”

Section: Discussionsupporting

confidence: 93%

“…This assumption is based on previous findings using the same experimental model in which the pressor effect of another selective ET B antagonist (Ro46-8443) was abolished by pretreatment with N -nitro-L-arginine methyl ester (5). The activation of the ET A receptors by increased ET-1 could also contribute to the elevation of blood pressure after the administration of a selective ET B antagonist although the pressor effect of the selective ETB antagonist Ro 46-8443 was reported to be unaffected by the administration of a selective ETA antagonist (5). A more recent study however, showed that the administration of ABT-627 (ET A selective antagonist) decreased mean arterial pressure in rats in a high-salt diet treated with the ET B antagonist A-192621 (31).…”

Section: Discussionmentioning

confidence: 99%

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Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor

Bianciotti

Bold

2002

American Journal of Physiology-Heart and Circulatory Physiology

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Bianciotti, Liliana G., and Adolfo J. de Bold. Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor. Am J Physiol Heart Circ Physiol 282: H1127-H1134, 2002; 10.1152/ ajpheart.00468.2001.-We investigated the effect of longterm in vivo blockade of the ET-1 receptor subtype B (ET B) with A-192621, a selective ET B antagonist, on atrial and ventricular natriuretic peptide (NP) gene expression in deoxycorticosterone acetate (DOCA)-salt hypertension. In this model, stimulation of the cardiac natriuretic peptide (NP) and the endothelin system and suppression of the reninangiotensin system is observed. DOCA-salt induced significant hypertension, cardiac hypertrophy and increased NP plasma and left atrial and right and left ventricular NP gene expression. ET B blockade per se produced hypertension and left ventricular hypertrophy but induced little change on the levels of ventricular NP and only increased left atrial natriuretic factor (ANF) mRNA levels. Combined ET B blockade/ DOCA-salt treatment worsened hypertension, increased left ventricular hypertrophy and induced right ventricular hypertrophy. All animals so treated had increased ventricular NP gene expression. Collagen III and ␤-myosin heavy chain gene expression were enhanced in both the right and the left ventricle of DOCA-salt hypertensive rats. The results of this study suggest that the ET B receptor does not participate directly in the modulation of atrial or ventricular NP gene expression and that this receptor mediates a protective cardiovascular function. ET B blockade can induce significant ventricular hypertrophy without an increase in ANF or brain NP gene expression. deoxycorticosterone acetate THE LEVEL OF EXPRESSION OF the cardiac natriuretic peptides (NP), atrial natriuretic factor (ANF), and brain natriuretic peptide (BNP), as well as circulating plasma levels, is increased by hemodynamic overload through mechanisms that are believed to involve both mechanical and neuroendocrine stimuli (7). The activation of the cardiac NP system serves to counterbalance the activity of systems that tend to increase extracellular fluid volume and blood pressure such as the renin-angiotensin-aldosterone and sympathetic systems (6). Although much information has been gathered regarding the regulation of NP gene expression and release through in vitro approaches, comparatively little is known regarding the long-term regulation of NP in the heart. Using a model of renovascular hypertension in the rat, we have previously found that there are two components that contribute to chronic increased NP gene expression. One component is independent of load and is concurrent with the hypertrophic process of chronically overloaded hearts whereas the other is dependent on hemodynamic load (26). We also reported that the expression of ANF and BNP in the ventricles and atria is differentially regulated. That is, in the atria, NP expression appears to be governed by mechanical stimuli (atrial muscle stretch) whereas in the ventr...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor

Bianciotti

Bold

2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…29 Similar findings were observed using Ro 46 -8443, the nonpeptide selective ET B receptor antagonist. 31 In separate experiments, intravenous administration of A-192621 (3 mg/kg) to DOCA-salt hypertensive rats produced increases of 10 to 15 mm Hg in BP and decreases of about 60% in renal blood flow, changes that were greater than those observed in uninephrectomized control normotensive animals (increases of 5 to 10 mm Hg in BP and decreases of about 40% in renal blood flow) (Y.M. et al, unpublished data, 1998).…”

Section: Matsumura Et Al February 1999 763mentioning

confidence: 99%

Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats

et al. 1999

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Abstract-We investigated the involvement of actions mediated by endothelin-A (ET A ) and endothelin-B (ET B ) receptors in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Two weeks after the start of DOCA-salt treatment, rats were given ABT-627 (10 [mg/kg]/d), a selective ET A receptor antagonist; A-192621 (30 [mg/kg]/d), a selective ET B receptor antagonist; or their vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Treatment with DOCA and salt for 2 weeks led to a mild but significant hypertension; in vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3 to 4 weeks. Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was histochemically evaluated at 4 weeks, there were significant increases in wall thickness, wall area, and wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with uninephrectomized control rats. The development of vascular hypertrophy was markedly suppressed by ABT-627. In contrast, treatment with A-192621 significantly exaggerated these vascular changes. In vehicle-treated DOCA-salt rats, renal blood flow and creatinine clearance decreased, and urinary excretion of protein, blood urea nitrogen, fractional excretion of sodium, and urinary N-acetyl-␤-glucosaminidase activity increased. Such damage was overcome by treatment with ABT-627 but not with A-192621; indeed, the latter agent led to worsening of the renal dysfunction. Histopathologic examination of the kidney in vehicle-treated DOCA-salt rats revealed tubular dilatation and atrophy as well as thickening of small arteries. Such damage was reduced in animals given ABT-627, whereas more severe histopathologic changes were observed in A-192621-treated animals. These results strongly support the view that ET A receptor-mediated action plays an important role in the pathogenesis of DOCA-salt-induced hypertension. On the other hand, it seems likely that the ET B receptor-mediated action protects against vascular and renal injuries in this model of hypertension. A selective ET A receptor antagonist is likely to be useful for treatment of subjects with mineralocorticoid-dependent hypertension, whereas ET B -selective antagonism alone is detrimental to such cases. (Hypertension. 1999;33:759-765.)Key Words: receptors, endothelin Ⅲ hypertension, DOCA-salt Ⅲ renal function Ⅲ vascular hypertrophy T here is accumulating evidence indicating that endothelin-1 (ET-1) plays an important role in the development and/or maintenance of hypertension in animal models such as the deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rat 1-6 and Dahl salt-sensitive rat. 7,8 This view is based on findings indicating that acute administration of an endothelin-A (ET A )-selective receptor antagonist or nonselective ET A /ET B receptor antagonist to DOCAsal...

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“…Overall, its non-peptidic nature, potency and ETB receptor selectivity make Ro 46-8443 a unique tool which may make it possible to explore the role of ETB receptors in different animal models such as hypertension [32].…”

Section: Discussionmentioning

confidence: 99%

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

Breu¹,

Clozel²,

Burri³

et al. 1996

FEBS Letters

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The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

Cited by 46 publications

References 18 publications

Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor

Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor

Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

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The role of ETB receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ETB receptor antagonist Ro 46‐8443

Cited by 46 publications

References 18 publications

Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor

Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor

Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ETB receptor

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The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor