Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis

Abstract

Objective. Increased endothelin activity may play a role in the pathogenesis of vascular injury, a primary feature of systemic sclerosis (SSc; scleroderma). Our goal was to test the hypothesis that treatment with the oral endothelin receptor antagonist bosentan might improve vascular endothelial function in SSc patients.Methods. A 4-week, prospective, parallel-group study compared 12 SSc patients who did not receive bosentan treatment with 12 patients who did receive treatment (125 mg/day) for pulmonary hypertension and/or digital ulcers. There were no differences in demographic and clinical characteristics or medications between the 2 groups. Baseline endothelial dysfunction was documented by decreased brachial artery ultrasound-derived flow-mediated dilation (FMD%; <5.5). Pulse wave analysis, venous occlusion plethysmography, and measurement of serum vascular markers were performed in parallel.Results. FMD%, the main end point, increased significantly from a mean ؎ SD of 3.1 ؎ 1.3% to 8.4 ؎ 2.6% after 4 weeks of bosentan treatment (P < 0.001, compared with a change from 2.4 ؎ 1.6% to 2.4 ؎ 2.2% in control patients). Arterial blood pressure, endothelium-independent vascular function, augmentation index, peripheral flow reserve, as well as circulating intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and endothelin 1 were not significantly affected by bosentan treatment. In patients continuously treated for 4 months, during which the dosage of bosentan remained at 125 mg/day (n ‫؍‬ 5) or increased to 250 mg/day (n ‫؍‬ 5), the 4-week results remained unchanged.Conclusion. Small doses of bosentan improve endothelial function without affecting hemodynamic parameters or endothelial activation-related processes, thus supporting a direct, reversible effect of endothelin in SSc-associated vascular injury. A long-term, controlled trial to examine the potentially global clinical benefit of endothelin receptor blockade in patients with early SSc may be warranted.

Evaluation of the Effect of Bosentan Treatment on Proinflammatory Cytokine Serum Levels in Patients Affected by Systemic Sclerosis

“…As already described, in our study ETl levels did not show significant variation after Bosentan treatment (8). Our results show that Bosentan significantly reduces IL-2, IL-6, IL-8 and IFN-y levels in SSc patients .…”

Bosentan Ameliorated Exercise-Induced Pulmonary Arterial Hypertension Complicated with Systemic Sclerosis

“…Increased production of ET-1 and decreased expression of ETB receptor in endothelial cells associated with increased expression of ETA receptor in vascular smooth muscle cells stimulates vascular contraction and proliferation of vascular smooth muscle and fibroblast cells (8,9). This suggests that bosentan therapy from an early stage in patients with SSc leads to prevention of peripheral and pulmonary arterial contraction and remodeling (9,10).…”

Acute Effect of Sildenafil Is Maintained in Pulmonary Arterial Hypertension Patients Chronically Treated With Bosentan

“…[18][19][20][21][22][23][24][25][26] This has also been reported in patients with PAH due to collagen diseases. 27,28) The vasodilating effect of sildenafil definitely requires cGMP-production and is also thought to be synergistically exerted in well-ventilated lung areas possessing an intact NO-cGMP system where NO is more abundant than in lung areas with ventilation disorders and/or an impaired NO-cGMP system. 29,30) Thus, the improvement of NO-production/bioavailability by the endothelin antagonism of bosentan might lead to the augmentation/improvement of c-GMP production, which finally results in enhancement of the vasodilating effect via PDE-V inhibition.…”