Beta-blockers reduce the release and synthesis of endothelin-1 in human endothelial cells.
BACKGROUND
Endothelins play an important role in cardiovascular diseases, and clinical trials have shown a reduction in endothelin levels after long-term treatment of chronic heart failure with beta-adrenergic antagonists. It is not known, however, whether this effect is caused by haemodynamic changes associated with the use of beta-adrenergic antagonists or by direct interaction of beta-blockers with human endothelial cells. The aim of this study was to determine whether beta-adrenergic antagonists have an influence on endothelin-1 (ET-1) synthesis and release in human endothelial cells.


METHODS
Pretreatment of cultured endothelial cells from human umbilical veins (HUVECs) with different concentrations of the non-selective beta-blocker propranolol, the beta 1-blocker metoprolol and the beta 1-blocker and beta 2-agonist celiprolol (all 10(-7)-10(-4) mol L-1) was found to reduce ET-1 production. This ET-1-reducing effect was even more pronounced in thrombin-stimulated cells (10(-5) mol L-1 of propranolol, metoprolol and celiprolol: 19% +/- 5.8%, 25% +/- 4% and 37% +/- 5.2% respectively).


RESULTS
Quantitative reverse transcriptase polymerase chain reaction and Northern blotting confirmed an inhibitory effect of the beta-blocker on biosynthesis. Furthermore, the ET-1-reducing effect of propranolol, metoprolol and celiprolol was not due to a compensatory increase in prostacyclin and was not reversible by N-nitro-L-arginine.


CONCLUSIONS
The effect of beta-adrenergic antagonists on ET-1 production of the endothelium may at least partially explain the efficacy of beta-blockers in the treatment of diseases such as advanced heart failure, essential hypertension as well as acute coronary syndromes.
Garlichs
C D
CD
Medical Clinic II, Friedrich-Alexander-University Erlangen-Nürnberg, Germany. Christoph.Garlichs@rzmail.uni-erlangen.de
Zhang
H
H
Mügge
A
A
Daniel
W G
WG
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D017272:Celiprolol / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism*; D016232:Endothelins / Q000032:analysis / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D008790:Metoprolol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013917:Thrombin / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D017077:Culture Media, Conditioned; D019332:Endothelin-1; D016232:Endothelins; D011412:Propanolamines; D011498:Protein Precursors; D012333:RNA, Messenger; D015121:6-Ketoprostaglandin F1 alpha; D011433:Propranolol; D017272:Celiprolol; D013917:Thrombin; D008790:Metoprolol