Improvement of plasma endothelin-1 and nitric oxide in patients with systemic sclerosis by bosentan therapy

Abstract

The aim of this study was to evaluate the effects of bosentan on plasma endothelin-1 (ET-1) and nitric oxide (NO) as pulmonary hypertension (PH)-associated biochemical markers in patients with systemic sclerosis (SSc). Twenty-four SSc patients receiving bosentan for 24 weeks were registered in this prospective observational study. Ten patients were complicated with clinically suspected PH. Plasma levels of ET-1 and NO were assessed at baseline and after 24 weeks of treatment in SSc patients and in 15 healthy controls. Plasma levels of ET-1 and NO at baseline were significantly higher in SSc patients than in healthy controls (p < 0.000), and they were also significantly higher in SSc patients with PH than in those without PH (p < 0.01). Plasma ET-1 levels were significantly decreased after 24 weeks of bosentan therapy (p < 0.0001), and ET-1 levels of SSc patients with PH decreased to a level comparable to that in patients without PH. In the 10 SSc patients with PH, changes in plasma ET-1 levels during the 24 weeks of the study were significantly larger in the 5 patients whose functional class (FC) improved than in the 5 patients whose FC was unchanged (p < 0.05). Plasma NO levels were also slightly decreased in SSc patients after 24 weeks of bosentan therapy. Plasma ET-1 levels could reflect the presence and severity of PH in SSc patients. Additionally, changes in plasma ET-1 levels may indicate the response to bosentan therapy in SSc patients with PH.

Exhaled Nitric Oxide in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

“…Immune activation leads to increased expression of inducible NO synthase (iNOS) in a variety of cell types, 23,24 and circulating NO metabolites are consistently elevated in SSc, 25,26 even among subjects with pulmonary hypertension. 27,28 Thus, inflammatory mechanisms may overshadow reduced NO production by the constitutive endothelial and neuronal NOS isoforms. 24,29 Our finding of a modestly lower J′aw NO in patients with SSc without pulmonary involvement relative to healthy controls mirrors earlier results of a study involving subjects with SSc-ILD.…”

The association between vibration and vascular injury in rheumatic diseases: A review of the literature

“…The endothelium also produces endothelin-1 (ET1), one of the most potent endogenous vasoconstrictors with effects on vascular remodeling [17,18], which can promote the proliferation of vascular smooth muscle and has multiple influences directed towards increasing microvascular tone [19][20][21]. It seems likely that ET1 is implicated in SSc, VRP and hand-arm vibration syndrome (HAVS), despite the change of ET1 levels is ambivalent in some studies [22][23][24][25][26]. A host of other changes, such as cytokine and growth factor expression, pericyte activation, increased circulating levels of angiotensin II, decreased plasma thiol concentration and increased plasma levels of malondialdehyde, are believed to contribute to the pathogenesis of vascular abnormalities [12,13,27,28].…”

Proteinase activated receptor‐2 counterbalances the vascular effects of endothelin‐1 in fibrotic tight‐skin mice

“…ET‐1 also triggers vascular cell proliferation, smooth muscle hypertrophy and irreversible vascular remodelling (Wort et al, ; Lambers et al, ; Maier et al, ; Kim et al, ). The relevance of ET‐1 to systemic sclerosis (SSc) is demonstrated by the elevated ET‐1 circulating levels (Morelli et al, ) and by the finding that the ET receptor pan‐antagonist, bosentan, is used in patients with arterial pulmonary hypertension, secondary to SSc (Heresi and Minai, ; Guiducci et al, ; Kawashiri et al, ).…”