The Selective Endothelin-A-Receptor Antagonist LU 135.252 Inhibits the Direct Arrhythmogenic Action of Endothelin-1

2000 ◽  
Vol 36 ◽  
pp. S314-S316 ◽  
Author(s):  
Béla Merkely ◽  
Tamás Szabó ◽  
László Gellér ◽  
Orsolya Kiss ◽  
Ferenc Horkay ◽  
...  
2007 ◽  
Vol 292 (4) ◽  
pp. H1961-H1966 ◽  
Author(s):  
M. Tosun ◽  
Y. Erac ◽  
C. Selli ◽  
N. Karakaya

This study tested whether sarcoplasmic-endoplasmic reticulum Ca2+-ATPase regulates the ability of endothelin receptor antagonist to inhibit the endothelin-1 constriction. The endothelin A receptor antagonist BQ-123 (1 μM) completely relaxed constriction to 10 nM endothelin-1 in endothelium-denuded rat aorta. Challenge with cyclopiazonic acid (10 μM), a sarcoplasmic-endoplasmic reticulum Ca2+-ATPase inhibitor, during the plateau of endothelin-1 constriction enhanced the constriction by ∼30%. BQ-123 relaxed the endothelin-1 plus cyclopiazonic acid constriction by only ∼10%. In contrast, prazosin (1 μM), an α-adrenergic receptor antagonist, still completely relaxed the 0.3 μM phenylephrine constriction in the presence of cyclopiazonic acid. Verapamil relaxed the endothelin-1 plus cyclopiazonic acid constriction by ∼30%, whereas Ni2+ and 2-aminoethoxydiphenyl borate, nonselective cation channel and store-operated channel blockers, respectively, completely relaxed the constriction. These results suggest that lowered sarcoplasmic-endoplasmic reticulum Ca2+-ATPase activity selectively decreases the ability of endothelin receptor antagonist to inhibit the endothelin A receptor. The decreased antagonism may be related to the opening of store-operated channels and subsequent greater internalization of endothelin A receptor.


2000 ◽  
Vol 36 (Supplement 1) ◽  
pp. S314-S316 ◽  
Author(s):  
Béla Merkely ◽  
Tamás Szab ◽  
Lászl Gellér ◽  
Orsolya Kiss ◽  
Ferenc Horkay ◽  
...  

1996 ◽  
Vol 24 (12) ◽  
pp. 2007-2013 ◽  
Author(s):  
Nicholas P. Curzen ◽  
Jane A. Mitchell ◽  
Karen B. Jourdan ◽  
Mark J. D. Griffiths ◽  
Timothy W. Evans

Circulation ◽  
1995 ◽  
Vol 92 (9) ◽  
pp. 400-404 ◽  
Author(s):  
Takeshi Hiramatsu ◽  
Joseph Forbess ◽  
Takuya Miura ◽  
Stephen J. Roth ◽  
Mark A. Cioffi MAT ◽  
...  

1997 ◽  
Vol 158 (1) ◽  
pp. 253-257 ◽  
Author(s):  
Chieko Imajo ◽  
Paul D. Walden ◽  
Ellen Shapiro ◽  
Annette M. Doherty ◽  
Herbert Lepor

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2526-2534 ◽  
Author(s):  
Sebastian J. Buss ◽  
Johannes Backs ◽  
Michael M. Kreusser ◽  
Stefan E. Hardt ◽  
Christiane Maser-Gluth ◽  
...  

An impairment of cardiac norepinephrine (NE) reuptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS) fed a high-salt diet developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE reuptake and NET-binding sites, as assessed by clearance of bolus-injected [3H]NE in isolated perfused rat hearts and [3H]mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE reuptake, and myocardial NET density. Moreover, the ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The α1-inhibitor prazosin decreased blood pressure in DS similar to spironolactone treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE reuptake, or ventricular function. In a heart failure-independent model, Wistar rats that were infused with aldosterone and fed a high-salt diet developed impaired cardiac NE reuptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE reuptake. In conclusion, spironolactone preserves NET-dependent cardiac NE reuptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.


2000 ◽  
Vol 36 (Supplement 1) ◽  
pp. S317-S319 ◽  
Author(s):  
Orsolya Kiss ◽  
Lászl Gellér ◽  
Béla Merkely ◽  
Tamás Szabó ◽  
Manfred Raschack ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document