W276 Mutation in the Endothelin Receptor Subtype B Impairs GqCoupling but Not Gior GoCoupling†

The potent vasoconstrictor endothelin-1 (ET-1) is a paracrine, but also autocrine, factor for some types of cells. The goal of our study was to evaluate whether the receptor population in cells expressing endothelin receptor subtype A (rat mesangial cells) or endothelin receptor subtype B (human and rat endothelial cells) was affected by the autocrine production of ET-1. We therefore studied maximal binding capacity of 125I-labeled ET-1 in the presence or absence of the metalloprotease inhibitors phosphoramidon, which blocks the intracellular processing of Big ET-1 to ET-1, and thiorphan, which does not block this conversion. Phosphoramidon inhibited the release of ET-1 by human umbilical vein endothelial cells, rat aortic endothelial cells, and rat mesangial cells, and increased 1.4- to 17-fold the maximal binding capacity in the three types of cells. Thiorphan affected neither ET-1 release nor binding. The increase in receptor binding by phosphoramidon was associated with an increase in the functional effect of ET-1, as measured by arachidonic acid release in rat mesangial cells. We conclude that autocrine production of ET-1 decreases, either by binding or by downregulation, the number of binding sites available for ET-1 of paracrine or systemic sources. This aspect of modulation of the vasoconstrictor effect of endothelin should be considered in pathological situations or after endothelin-converting-enzyme inhibition.

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Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells.

Journal of Clinical Investigation ◽

10.1172/jci116338 ◽

1993 ◽

Vol 91 (4) ◽

pp. 1367-1373 ◽

Cited By ~ 400

Author(s):

Y Hirata ◽

T Emori ◽

S Eguchi ◽

K Kanno ◽

T Imai ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Receptor Subtype ◽

Endothelin Receptor ◽

Subtype B ◽

Bovine Endothelial Cells

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Synthesis and Structure−Activity Relationships of 2-Substitutedd-Tryptophan-Containing Peptidic Endothelin Receptor Antagonists: Importance of the C-2 Substituent of thed-Tryptophan Residue for Endothelin A and B Receptor Subtype Selectivity

Journal of Medicinal Chemistry ◽

10.1021/jm9600914 ◽

1996 ◽

Vol 39 (12) ◽

pp. 2313-2330 ◽

Cited By ~ 14

Author(s):

Takehiro Fukami ◽

Takeru Yamakawa ◽

Kenji Niiyama ◽

Hisaki Kojima ◽

Yuuka Amano ◽

...

Keyword(s):

Tryptophan Residue ◽

Receptor Subtype ◽

Endothelin Receptor Antagonists ◽

Endothelin Receptor ◽

Receptor Antagonists ◽

Structure Activity Relationships ◽

Subtype Selectivity ◽

Structure Activity ◽

Endothelin A

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Sitaxentan for the Oral Treatment of Pulmonary Arterial Hypertension: Benefits from Endothelin Receptor Subtype Selectivity?

Clinical Medicine Therapeutics ◽

10.4137/cmt.s2344 ◽

2009 ◽

Vol 1 ◽

pp. CMT.S2344

Author(s):

Hermann A.M. Mucke

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Oral Treatment ◽

Right Heart Failure ◽

Oral Drug ◽

Receptor Subtype ◽

Endothelin Receptor ◽

Good Tolerability ◽

Subtype Selectivity ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly and underdiagnosed disease which causes right heart failure secondary to pressure overload resulting from the thickening of the pulmonary artery endothelium, associated with elevated levels of circulating endothelin-1. Sitaxentan was the first endothelin antagonist with high selectivity for receptor subtype A (over subtype ET-B) to gain regulatory approval for the treatment of PAH in major pharmaceutical markets. This review traces the development history of sitaxentan, summarizes the designs and results from its clinical studies, and relates the drug's profile to that of the two other broadly available endothelin receptor antagonists, bosentan and ambrisentan. All three drugs have comparable therapeutic efficacy in the 6-minute walk test–-a frequently employed standard–-during the first 3-4 months of therapy. Their performance might differ slightly in other clinically relevant outcome measures, especially in longer-term treatment where fully comparable data have not yet been reported. In clinical trials of up to one year duration the propensity of sitaxentan to induce elevation of liver transaminases and hepatic failure was significantly lower than that of bosentan. As a once-daily oral drug with good tolerability sitaxentan has become a crucial element in the treatment of PAH.

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