Endothelin (ET)-1 is a potent vasoconstrictor peptide originally isolated from endothelial cells. Its production is stimulated in a variety of different cell types under the influence of risk factors for cardiovascular disease and during the development of cardiovascular disease. Based on these observations and the biological effects induced by ET-1, including profound vasoconstriction, pro-inflammatory actions, mitogenic and proliferative effects, stimulation of free radical formation and platelet activation, ET-1 has been implicated as an important factor in the development of vascular dysfunction and cardiovascular disease. In the following the pathogenic role of ET-1, the mechanisms underlying the involvement of ET-1 for the development of vascular dysfunction and the potentially beneficial therapeutic effects of selective ET A and dual ET A /ET B receptor antagonists will be discussed. In particular the changes of pathophysiological importance mediated by ET-1 in clinical studies are reviewed. These changes may be of significance for the development of various cardiovascular diseases beyond pulmonary arterial hypertension which is the currently approved indication for ET receptor antagonists.

Background— Endothelial dysfunction plays an important role in the early development of atherosclerosis and vascular complications in type 2 diabetes mellitus. Increased expression and activity of arginase, metabolizing the nitric oxide substrate l -arginine, may result in reduced production of nitric oxide and thereby endothelial dysfunction. We hypothesized that inhibition of arginase activity improves endothelial function in patients with coronary artery disease (CAD) and type 2 diabetes mellitus. Methods and Results— Three groups of subjects were included: 16 patients with CAD, 16 patients with CAD and type 2 diabetes mellitus (CAD+Diabetes), and 16 age-matched healthy control subjects. Forearm endothelium-dependent and endothelium-independent vasodilatation were assessed with venous occlusion plethysmography before and during intra-arterial infusion of the arginase inhibitor N ω -hydroxy-nor- l -arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also coinfused with the nitric oxide synthase inhibitor ( N G -monomethyl L-arginine). The expression of arginase was determined in the internal mammary artery of patients undergoing bypass surgery. Nor-NOHA markedly increased endothelium-dependent vasodilatation (up to 2-fold) in patients with CAD+Diabetes and CAD ( P <0.001) but not in the control group. N G -monomethyl L-arginine completely inhibited the increase in endothelium-dependent vasodilatation induced by nor-NOHA. Endothelium-independent vasodilatation was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes mellitus. Conclusions— Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes mellitus suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction.

This prospective, randomised trial suggests that postconditioning does not reduce infarct size in patients with STEMI in the overall study group. The data indicate that postconditioning may be of value in patients with large areas at risk. Clinical trial registration information Karolinska Clinical Trial Registration (http://www.kctr.se). Unique identifier: CT20080014.

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The peptide urotensin II (U II) evokes potent vasoconstriction in non-human primates. In human blood vessels studied in vitro variable eects of U II are reported; vasoconstriction, vasodilatation or no response. It is therefore of importance to determine the vascular eect of U II in humans in vivo. U II (0.1 ± 300 pmol min 71 ) was infused into the brachial artery of nine healthy volunteers. Changes in forearm blood¯ow (FBF) were determined by venous occlusion plethysmography. U II induced dose-dependent reduction in FBF. A threshold response was obtained by 1 pmol min 71, and the highest dose of U II (300 pmol min 71 ) reduced FBF by 31+4% (P50.01). FBF returned to baseline values within 30 min. This study demonstrates that U II produces potent vasoconstriction in humans in vivo.

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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.

Lipid lowering is more important than pleiotropic effects of statins for improvement in endothelial function and inflammatory markers in patients with dysglycaemia and CAD.