Beta-blockers reduce the release and synthesis of endothelin-1 in human endothelial cells

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.

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).

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.

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.