Selective Blockade of Endothelin Receptor Subtypes on Systemic and Renal Vascular Responses to Endothelin-1 and IRL1620, a Selective Endothelin ETB-Receptor Agonist, in Anesthetized Rats

The authors recently reported that infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes profound renal vasoconstriction and sodium retention. The relative roles of the ETA- and ETB-receptor subtypes in these effects in humans is unknown. Such information is essential in view of the recent introduction of endothelin-receptor blockers in clinical medicine. The study presented here was designed to define the role of the ETA- and ETB-receptor subtypes in the renal actions of endothelin-1 in humans. Systemic infusion of endothelin-1, a nonselective receptor agonist, was compared with infusion of equimolar dosages of the ETB-selective agonist endothelin-3 in healthy volunteers. Endothelin-1 infusion was associated with an approximate 2.5-fold increase in plasma levels of endothelin-1. This was accompanied by an increase in blood pressure by approximately 6 mm Hg (P < 0.05). During endothelin-1 infusion, RPF decreased from 642 +/- 42 to 480 +/- 36 mL/min (P < 0.05) and GFR from 121 +/- 4 to 109 +/- 7 mL/min (P < 0.05). Sodium excretion rate decreased during endothelin-1 infusion, from a baseline value of 182 +/- 33 to 84 +/- 28 mumol/min at the end of the endothelin-1 infusion. Endothelin-3 infusion also resulted in a approximate 2.5-fold increase of plasma levels of endothelin-3. However, in contrast to the endothelin-1 infusion, endothelin-3 had no effect on blood pressure, renal hemodynamics, and electrolyte excretion. These results suggest that the systemic and renal vasoconstrictor effects of endothelin-1 in humans are predominantly mediated by the ETA receptors.

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Expression and Cellular Localisation of Renal Endothelin-1 and Endothelin Receptor Subtypes in Autosomal-Dominant Polycystic Kidney Disease

Nephron Experimental Nephrology ◽

10.1159/000068518 ◽

2004 ◽

Vol 93 (2) ◽

pp. e80-e86 ◽

Cited By ~ 20

Author(s):

Albert C.M. Ong ◽

Linda J. Newby ◽

Michael R. Dashwood

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Receptor Subtypes ◽

Endothelin Receptor ◽

Polycystic Kidney ◽

Endothelin 1 ◽

Cellular Localisation ◽

Autosomal Dominant Polycystic Kidney

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Necessity of dual blockade of endothelin ETA and ETB receptor subtypes for antagonism of endothelin-1-induced contraction in human bronchi

British Journal of Pharmacology ◽

10.1111/j.1476-5381.1996.tb16688.x ◽

1996 ◽

Vol 117 (6) ◽

pp. 995-999 ◽

Cited By ~ 64

Author(s):

Takahiro Fukuroda ◽

Satoshi Ozaki ◽

Masaki Ihara ◽

Kiyofumi Ishikawa ◽

Mitsuo Yano ◽

...

Keyword(s):

Receptor Subtypes ◽

Endothelin 1 ◽

Etb Receptor ◽

Dual Blockade ◽

Human Bronchi

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1H NMR Studies of Sarafotoxin SRTb, a Nonselective Endothelin Receptor Agonist, and IRL 1620, an ETB Receptor-Specific Agonist

Biochemistry ◽

10.1021/bi00006a024 ◽

1995 ◽

Vol 34 (6) ◽

pp. 2026-2033 ◽

Cited By ~ 21

Author(s):

Annette R. Atkins ◽

Rodney C. Martin ◽

Ross Smith

Keyword(s):

1H Nmr ◽

Receptor Agonist ◽

Endothelin Receptor ◽

Nmr Studies ◽

Etb Receptor

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Analysis of vasocontractile responses to endothelin-1 in rabbit retinal vessels using an ETA receptor antagonist and an ETB receptor agonist

Life Sciences ◽

10.1016/0024-3205(93)90707-a ◽

1993 ◽

Vol 53 (6) ◽

pp. PL111-PL115 ◽

Cited By ~ 10

Author(s):

Kazuo Takei ◽

Tsuyoshi Sato ◽

Tomohito Nonoyama ◽

Takashi Miyauchi ◽

Katsutoshi Goto

Keyword(s):

Receptor Antagonist ◽

Receptor Agonist ◽

Retinal Vessels ◽

Endothelin 1 ◽

Eta Receptor ◽

Etb Receptor ◽

Eta Receptor Antagonist

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Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops

Blood ◽

10.1182/blood-2003-10-3559 ◽

2004 ◽

Vol 104 (7) ◽

pp. 2107-2115 ◽

Cited By ~ 43

Author(s):

Georgi Guruli ◽

Beth R. Pflug ◽

Stefana Pecher ◽

Valeria Makarenkova ◽

Michael R. Shurin ◽

...

Keyword(s):

Dendritic Cells ◽

Endothelin Receptors ◽

Interleukin 12 ◽

Endothelin 1 ◽

Selective Blockade ◽

Biologic Effects ◽

Eta Receptor ◽

Etb Receptor ◽

Major Antigen ◽

And Function

Abstract The biologic effects of endothelin-1 (ET-1) are not limited to its potent vasoconstricting activity. The endothelin receptors, ETA and ETB, have differential tissue and functional distributions. Here we showed that dendritic cells (DCs), the major antigen-presenting cells in the adaptive limb of the immune system, produce large amounts of ET-1 and significantly increase the expression of endothelin receptors upon maturation. Selective blockade of the ETA receptor significantly reduced expression of the mature DC marker CD83, decreased the production of the immunostimulatory cytokine interleukin-12, down-regulated DC ability to stimulate T cells, and promoted DC apoptosis. Selective ETB receptor blockade, on the other hand, resulted in increased expression of CD83 and improved DC survival. Therefore, ET-1/ETA/ETB autocrine/paracrine loops on DCs appear to be essential for the normal maturation and function of human DCs, presenting a unique target for immunomodulatory therapies. (Blood. 2004;104:2107-2115)

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