Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: <i>ex vivo</i> and <i>in vivo</i> studies

Wessale, Jerry L.; Adler, Andrew; Novosad, Eugene I.; Calzadilla, Samuel V.; Dayton, Brian D.; Marsh, Kennan C.; Winn, Martin; Jae, Hwan-Soo; Geldern, Thomas W von; Opgenorth, Terry J.; Wu-Wong, Jinshyun R.

doi:10.1042/cs103s112s

Cited by 54 publications

(44 citation statements)

References 16 publications

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“…The potency and the selectivity of ABT-627 for the ETA receptor and that of A-192621 for the ETB receptor are among the highest of any known ET receptor antagonist both in vivo and in vitro (20,24,25). The IC 50 of ABT-627 for ETA and ETB are 0.055 and 84.4 nM, respectively; A-192621 for ETA and ETB are 4280 and 4.54 nM, respectively.…”

Section: Experimental Drugsmentioning

confidence: 83%

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Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Chang¹,

Parker²,

Nahas³

et al. 2007

Journal of the American Society of Nephrology

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease that causes kidney failure and accounts for 10% of all patients who are on renal replacement therapy. However, the marked phenotypic variation between patients who carry the same PKD1 or PKD2 mutation suggests that nonallelic factors may have a greater influence on the cystic phenotype. Endothelin-1 (ET-1) transgenic mice have been reported to develop profound renal cystic disease and interstitial fibrosis without hypertension. The hypothesis that ET-1 acts as a modifying factor for cystic disease progression was tested in an orthologous mouse model of ADPKD (Pkd2 WS25/؊ ). Four experimental groups (n ‫؍‬ 8 to 11) were treated from 5 to 16 wk of age with the highly selective orally active receptor antagonists ABT-627 (ETA) and A-192621 (ETB) singly or in combination. Unexpected, ETB blockade led to accelerated cystic kidney disease. Of significance, this was associated with a reduction in urine volume and sodium excretion and increases in urine osmolarity and renal cAMP and ET-1 concentrations. The deleterious effect of chronic ETB blockade was neutralized by simultaneous ETA blockade. ETA blockade alone resulted in a significant increase in tubular cell proliferation but did not alter the cystic phenotype. It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney. These results implicate ET, acting via vasopressin-dependent and independent pathways, as a major modifying factor for cystic disease progression in human ADPKD. A utosomal dominant polycystic kidney disease (AD-PKD) causes kidney failure in 10% of all patients who are on renal replacement therapy and is caused by mutations in PKD1 or PKD2 (1). The ADPKD proteins polycystin-1 and polycystin-2 function as a complex and regulate multiple signaling pathways to maintain normal tubular structure and function (2). Although a weak phenotype-genotype correlation for renal survival has been reported for PKD1, it is apparent that nonallelic factors such as genetic modifying loci and/or environmental factors have a greater influence on the cystic phenotype (3,4). These factors probably account for the marked intrafamilial phenotypic variability that sometimes is seen in PKD1 or PKD2 pedigrees (5,6).The endothelins (ET-1, ET-2, and ET-3) are a family of multifunctional peptides with potent effects on BP, renal function, and cellular behavior. Although ET-1 originally was purified as a highly potent endothelial-derived vasoconstrictor (7), many other cell types, especially in the kidney, can synthesize and bind ET-1, suggesting a range of other functions (8,9). Two ET receptor subtypes, ETA and ETB, have been shown to mediate ET-1 action but often with opposing effects (10,11). During development, ET-1 (acting via ETA receptors) and ET-3 (acting via ETB receptors) are essential for the development of neural crest-derived tissues (12,13).Several lines of evidence had suggested that ET-1 might pa...

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Section: Experimental Drugsmentioning

confidence: 83%

“…The dosages chosen were based on the ED 50 values for each compound in blocking ET-1 or SX6c induced pressor responses in the rat (24,25). On the day of the experiment, mice were anesthetized and the trachea was cannulated.…”

Section: In Vivo Antagonism Of the Pressor Effect Of Et-1 And Sarafotmentioning

confidence: 99%

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Chang¹,

Parker²,

Nahas³

et al. 2007

Journal of the American Society of Nephrology

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“…The general contractile capacities of pulmonary arteries from both groups were evaluated with: a high potassium solution (127 mmol l −1 ), a concentration-response curve to ET-1 (0. . In order to test potential improvement in efficacy of the ET receptor antagonists in PAH, the concentrations of the antagonists were chosen based on concentration-response curves for normal pulmonary resistance arteries [17,18] as these concentrations caused no or minimal effects on the normal response. The basilar arteries were subjected to ET-1-induced vasoconstriction in the absence and presence of the dual antagonist bosentan.…”

Section: Vascular Reactivity Studiesmentioning

confidence: 99%

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

Sauvageau¹,

Thorin²,

Villeneuve³

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Background and purpose-The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension.Experimental approach-ET-1 levels were quantified by ELISA. PreproET-1, ET A and ET B receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ET A (A-147627), ET B (A-192621) and dual ET A/B (bosentan) receptor antagonists.Key results-In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced (p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ET B receptor (p < 0.001) gene expressions were reduced, as were ET B receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ET A or the ET B receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ET A receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01).

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“…Blood pressure was monitored either by telemetric method (as previously reported) (6) or via the tailcuff method (Kent Scientific, Torrington, CT), which we have previously validated on telemetry-implanted animals (5). After the spontaneous onset of diabetes, starting at 14 weeks of age, animals were divided into groups and treated for 4 weeks as follows: ET A receptor blockade, atrasentan (Abbott Labs) 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water; ET B receptor blockade, A-192621 (Abbott Labs) 15 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 by oral gavage split into two daily doses; or vehicle as recommended by the manufacturer (6,16,17). Daily water consumption was measured for atrasentan treatment arm (6).…”

Section: Methodsmentioning

confidence: 99%

Evidence for Vasculoprotective Effects of ETB Receptors in Resistance Artery Remodeling in Diabetes

et al. 2007

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OBJECTIVE-Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/l) ratio, contributes to the development of microvascular complications in diabetes. Matrix metalloproteinases (MMPs) play an important role in the regulation of extracellular matrix (ECM) turnover and vascular remodeling. Vasoactive factor endothelin (ET)-1 not only causes potent vasoconstriction but also exerts profibrotic and proliferative effects that change vessel architecture, which makes it a likely candidate for a key role in vascular complications of diabetes. Thus, this study investigated the regulation of MMP activity of resistance arteries under mild-to-moderate diabetes conditions, as seen in type 2 diabetes, and the relative role of ET receptors in this process. C ardiovascular complications contribute to the increased morbidity and mortality in type 2 diabetes. Pathological changes in vascular function and structure underlie these complications. Vasoactive factor endothelin (ET)-1 not only causes potent vasoconstriction but also exerts profibrotic and proliferative effects that change vessel architecture, which make it a likely candidate for a key role in vascular complications of diabetes. A significant correlation has been observed between plasma ET-1 levels and diabetes complications (1,2). ET A receptor antagonism prevents mesenteric vascular hypertrophy in type 1 diabetes (3). Fukuda et al. (4) reported that blockade of ET-1 action inhibits aortic extracellular matrix (ECM) deposition. We showed that ET-1 levels are elevated and that an ET A antagonist prevents ECM deposition and MMP activation in middle cerebral arteries but not in the kidney of Goto-Kakizaki (GK) rats-a nonobese type 2 diabetes model (5,6). ET-1 mediates its diverse effects via distinct G protein-coupled receptor subtypes ETB AB and ETB BB . While these past studies indicate the involvement of the ET A receptor subtype in mediating detrimental effects of ET-1, the role of ET B receptors in diabetes-induced changes in the vasculature remains unknown. ETB AB receptors, localized mainly on vascular smooth muscle cells (VSMCs), are responsible for the vasocontractile and proliferative response to ET-1 (7). Endothelial ETB B receptors mediate vasodilatation, whereas VSMC ET B receptors can also lead to vasoconstriction in certain vascular beds (7). This duality of function of ETB B receptors underscores the importance of binding and function of both ET receptor subtypes. Especially given that inhibition of the ETB BB receptor system in a knockout mouse model or pharmacological blockade by an ETB BB antagonist leads to enhanced intimal hyperplasia observed in carotid arteries after injury induced by ligation, suggesting a vasculoprotective effect (8), the question remains whether ET B receptors contribute to or balance detrimental effects of ET A receptor activation in diabetic vascular remodeling. RESEARCH DESIGN AND METHODS-VesselVascular ECM displays a very dynamic equilibrium where there is constant synthesis, degra...

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Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: ex vivo and in vivo studies

Cited by 54 publications

References 16 publications

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

Evidence for Vasculoprotective Effects of ETB Receptors in Resistance Artery Remodeling in Diabetes

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