Design of a functional hexapeptide antagonist of endothelin

Cody, Wayne L.; Doherty, Anne M.; He, John X.; DePue, Patricia L.; Rapundalo, Stephen T.; Hingorani, Gary; Major, Terry C.; Panek, Robert L.; Dudley, David T.; Haleen, Stephen J.

doi:10.1021/jm00095a029

Cited by 92 publications

(33 citation statements)

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“…Here, the proarrhythmic role of this subtype was confirmed and a role for the ETB receptor was excluded. Expectedly therefore, the subtype non-selective antagonist PD 142893 [21] showed a similar antiarrhythmic potency as the ETA selective antagonist PD 155080 (Fig. 4).…”

Section: Discussionmentioning

confidence: 69%

Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Brünner

Doherty²

1996

FEBS Letters

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The effects of two endothelin (ET) receptor antagonists, PD 155080 (ETA selective) and BQ-788 (ETB selective), on cardiac function and ET-1 release were studied in isolated rat hearts. In normoxic hearts, infusion of PD 155080 (50 nM-5 oM) reduced coronary resistance, but had no effect on ET-1 release. Low concentrations of BQ-788 (2 and 20 nM) had no effect on coronary resistance; high concentrations (0.2 and 2 gM) increased it ,-.2-fold; all concentrations increased ET-1 release (up to 24-fold). Similar results were obtained in reperfused hearts. Although concentrations of ET-1 were higher in interstitial fluid than coronary effluent, levels never exceeded the low pg/ml range. These results indicate that (1) ETA receptors mediate coronary constriction, whereas ETB receptors bind and sequester ET-1, and (2) ET-1 displaced by ETB antagonist accesses ETA receptors resulting in coronary constriction.

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Section: Discussionmentioning

confidence: 69%

Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Brünner

Doherty²

1996

FEBS Letters

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“…The generated curve showed an appropriate sigmoidal shape, and the IC 50 generated from the curve (17.5 nM) showed good correlation to that reported in the literature for this inhibitor. 37,38 These data indicate that CDS responses can be used to conduct pharmacological evaluations of receptor activity. Because this receptor was endogenous to this cell line, these data also indicate that overexpression of receptors by transfection is not necessary using this system.…”

Section: Quantitative Analyses: Hit Confirmation Physiological Perfomentioning

confidence: 95%

Cellular Dielectric Spectroscopy: A Powerful New Approach to Label-Free Cellular Analysis

Ciambrone¹,

Liu²,

Lin³

et al. 2004

SLAS Discovery

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The past decade has seen a number of significant changes in identifying higher quality lead compounds earlier in the drug discovery process. Cell-based assay technologies yielding high-content information have emerged to achieve this goal. Although most of these systems are based on fluorescence detection, this article describes the development and application of an innovative cellular assay technology based on radio frequency spectrometry and bioimpedance measurements. Using this technique, the authors have discovered a link between cellular bioimpedance changes and receptor-mediated signal transduction events. By performing dielectric spectroscopy of cells across a spectrum of frequencies (1 KHz to 110 MHz), a series of receptorspecific, frequency-dependent impedance patterns is collected. These raw data patterns are used to determine the identity of the cellular receptor-signaling pathway being tested and to quantify stimulation endpoints and kinetics. The authors describe the application of this technology to the analysis of ligand-induced cellular responses mediated by the 3 major classes of Gprotein-coupled receptors (GPCRs) and protein tyrosine kinase receptors. This single assay platform can be used with ease to monitor G s , G i , and G q GPCRs without the need for chimeric or promiscuous G-proteins, fluorophors, or tagged proteins. In contrast to other methods of monitoring cellular signal transduction, this approach provides high information content in a sim-

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“…These results indicate that the Ca¥ ripples are generated via inositol 1,4,5-trisphosphate-induced Ca¥ release from the intracellular Ca¥ stores. We then looked for a receptor upstream of phospholipase C. The effect of PD-142893 (10 ìÒ), an endothelin receptor antagonist (Cody et al 1992), was studied because our preparation had an intact endothelium. However, this drug had no effect on Ca¥ ripples (Fig.…”

Section: Characterization Of Ca¥ Ripplesmentioning

confidence: 99%

Dynamic Ca²⁺ signalling in rat arterial smooth muscle cells under the control of local renin‐angiotensin system

Asada

Yamazawa

Hirose

et al. 1999

The Journal of Physiology

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Intracellular Ca¥ signals exhibit characteristic spatiotemporal patterns in various cell types and regulate a vast array of cell functions including cell movement, secretion, cell differentiation, cell death, gene expression and synaptic plasticity (Berridge, 1993). In vascular smooth muscle cells, the best known cell function regulated by the intracellular Ca¥ concentration ([Ca¥]é) is contraction, which controls blood pressure. Recent studies indicate that [Ca¥]é may also have a role in cell growth with activation of a phosphorylation cascade via the Ca¥-dependent prolinerich tyrosine kinase (PYK2) (Brinson et al. 1998;Sabri et al. 1998). Vascular smooth muscle cell proliferation is implicated in vascular diseases such as atherosclerosis. Although Ca¥ signalling mechanisms are often studied in isolated or cultured cells, it is also important to study Ca¥ signals within the context of the organized cell structure of tissues, because there exist intercellular interactions which may not yet be fully understood. With the above idea in

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Design of a functional hexapeptide antagonist of endothelin

Cited by 92 publications

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Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Cellular Dielectric Spectroscopy: A Powerful New Approach to Label-Free Cellular Analysis

Dynamic Ca²⁺ signalling in rat arterial smooth muscle cells under the control of local renin‐angiotensin system

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Design of a functional hexapeptide antagonist of endothelin

Cited by 92 publications

References 0 publications

Role of ETB receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Role of ETB receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Cellular Dielectric Spectroscopy: A Powerful New Approach to Label-Free Cellular Analysis

Dynamic Ca2+ signalling in rat arterial smooth muscle cells under the control of local renin‐angiotensin system

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Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Dynamic Ca²⁺ signalling in rat arterial smooth muscle cells under the control of local renin‐angiotensin system