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

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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%; 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.