The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial.
OBJECTIVE
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 (n = 28), or placebo (n = 28) 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 (n = 22), but did not change in the placebo group (1.84 ± 0.49 to 1.87 ± 0.47; n = 24). 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
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.
Karolinska Institutet, Department of Medicine, Cardiology Unit, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden. arnar.rafnsson@karolinska.se
A
A
Rafnsson
F
F
Böhm
M
M
Settergren
A
A
Gonon
K
K
Brismar
J
J
Pernow
D000368:Aged; D000419:Albuminuria / Q000150:complications* / Q000503:physiopathology; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000503:physiopathology / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000150:complications / Q000503:physiopathology; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000503:physiopathology / Q000517:prevention & control; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan