The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial

Abstract

Aims/hypothesis Endothelial dysfunction is important in the development of vascular complications in diabetes. Patients with type 2 diabetes have increased production of the vasoconstrictor and pro-inflammatory peptide, endothelin-1. Short-term intra-arterial administration of endothelin antagonists improves endothelium-dependent vasodilatation in patients with type 2 diabetes. We tested the hypothesis that oral administration of the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. Methods This placebo-controlled and double-blind study was performed on 46 patients with type 2 diabetes and microalbuminuria (urine albumin/creatinine ratio >3 mg/mmol) at a medical university department. Patients were randomised to bosentan, 125 mg two times per day (n028), or placebo (n028) for 4 weeks. The computer-generated randomisation code was kept in sealed envelopes. Patients and people doing examinations or assessing outcomes were blinded. The primary endpoint was change in microvascular endothelium-dependent vasodilatation, based on change in digital reactive hyperaemia index. The secondary endpoint was change in brachial artery flow-mediated vasodilatation. Results Reactive hyperaemia index increased from 1.73± 0.43 (mean±SD) at baseline to 2.08±0.59 at follow-up (p< 0.05) in the bosentan group (n022), but did not change in the placebo group (1.84±0.49 to 1.87±0.47; n024). The change in reactive hyperaemia index from baseline was greater in the bosentan group than in the placebo group (p<0.05). Nitroglycerine-induced digital hyperaemia was not affected. Brachial artery flow-mediated vasodilatation and blood pressure did not change during treatment. Conclusions/interpretation Oral treatment of 4 weeks duration with the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria.

New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus

“…Oral avosentan for 4 months Reduction in albuminuria, but induction of fluid overload Kohan et al (2011) Type 2 diabetes and nephropathy, n = 89 Oral atrasentan for 8 weeks Reduction in albuminuria Rafnsson et al (2012) Type 2 diabetes and microalbuminuria, n = 46 Oral bosentan for 4 weeks Improved peripheral endothelial function translocation of GLUT4 transporters and stimulation of glucose uptake (Huang et al, 2005). Phosphorylation of Akt will also directly activate eNOS leading to enhanced production of NO (Dimmeler et al, 1999;Fulton et al, 1999), to maintain normal endothelial function.…”

“…Besides the aforementioned beneficial effects of ET receptor blockade following short-term intra-arterial infusions, a recent placebocontrolled double-blind study demonstrated that the dual ET A /ET B receptor antagonist bosentan improved peripheral endothelial function in patients with type-2 diabetes and microangiopathy (Rafnsson et al, 2012). The putative beneficial effect of long-term efficacy of ET receptor blockade on macro-and microvascular function in patients with type-2 diabetes mellitus is of considerable interest and should be further evaluated in additional randomized trials.…”

Diabetes Mellitus and Ischemic Diseases

“…88,89 Interestingly, oral treatment of 4-week duration with the dual endothelin receptor antagonist, Bosentan, improves peripheral endothelial function in patients with type 2 diabetes mellitus. 90 Finally, alteration in the mechanical properties of large compliance arteries may also fuel the pathogenesis of vascular dysfunction in diabetes mellitus. Hence, large arterial elasticity and fluid filtration across the arterial wall are impaired leading to decreased left ventriculararterial coupling in diabetes mellitus.…”

Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice

“…The study found that diabetic myocardial fibrosis was partly consequences of an activated ET system, which could lead to myocardial and vascular dysfunction (21). Unfortunately, few studies attempt to clarify the potent protective effect of bosentan, a non-selective ETa and ETb receptor antagonist, on diabetic cardiovascular complications (22).…”