β-Blockers of the Third Generation Inhibit Endothelin-1 Liberation, mRNA Production and Proliferation of Human Coronary Smooth Muscle and Endothelial Cells

Abstract

Endothelin-1 (ET-1) plays an important role in atherogenesis. The aim of the study reported here was to investigate the effects of the third generation beta-blockers nebivolol and carvedilol on ET-1 liberation, preproendothelin-1 production and on proliferation of human coronary cells. Human coronary endothelial (HEC) and smooth muscle cells (HCSMC) were grown with carvedilol or nebivolol (10(-7)-10(-5) mol/l). Incubation for 1, 2 or 7 days resulted in an 80% concentration- and time-dependent reduction in HCSMC proliferation. beta-blockers such as propranolol or metoprolol did not influence cell proliferation. Nebivolol (10(-7) mol/l) inhibited accelerated HCSMC proliferation in the presence of growth factors such as transforming growth factor-beta1 or platelet-derived growth factor BB. During incubation with nebivolol or carvedilol ET-1 secretion decreased. For nebivolol this is a result of a reduction in preproendothelin-1 mRNA levels. beta-blockers of the third generation that reduce the cell proliferation and ET-1 secretion may represent strategies with great promise for antiproliferative therapy of coronary heart disease.

Plasma ET-1 Concentrations are Elevated in Patients with Hypertension – Meta-Analysis of Clinical Studies

“…RAAS blocking agents thus might influence ET-1 plasma concentrations independent of the actual blood pressure. It was likewise shown that also beta blockers [29, 30] and calcium channel blockers [31-32] alter the paracrine ET-1 system. The majority of the remaining studies reported plasma ET-1 concentrations in treatment naive hypertensive patients, see table 1.…”

Evidence for an estradiol-agonistic action of nebivolol in spontaneously hypertensive rats

“…Thus, prostacyclin production has been proposed as an additional vasodilator mechanism of NEB action [16]. Moreover the vasoconstriction factor endothelin-1 has been demonstrated to be suppressed by NEB [35]. Both substances are also regulated by estrogens (for review see [36]) contributing to gender-related differences in vascular tone and therefore being candidates for NEB action.…”

Effect of nebivolol treatment during pregnancy on the genital circulation, fetal growth and postnatal development in the Wistar rat

“…The pharmacological effects of nebivolol have been studied in vitro on segments of the thoracic aorta in mice (Broeders et al, 2000;Altwegg et al, 2000); coronary and carotid artery in canide (Ritter, 2001); aorta and small mesenteric arteries in rat and bovine (Cosentino et al, 2002;De Groot et al, 2003;Parenti et al, 2000); human aortic smooth muscle cells (André et al, 2000), coronary endothelium and smooth muscle cells (Brehm et al, 2000(Brehm et al, , 2001. In the current study, we investigated in vivo the potential pharmacological effects of nebivolol (vs. bisoprolol) on the body weight gain of moms during pregnancy, on the arterial pressure, heart rate and blood flow of reproductive tract but also on the vascularization of the uterus of rats.…”