Both selective and dual receptor blockade also

Both selective and dual receptor blockade also increased endothelium-independent vasodilatation induced by SNP. Previous studies using ET receptor blockade and other interventions aiming at increasing nitric oxide bioavailability have demonstrated that not only endothelium-dependent but also endothelium-independent vasodilatation was increased in patients with type 2 diabetes but not in patients without diabetes (Shemyakin et al., 2006, Shemyakin et al., 2012, Shemyakin et al., 2011). These observations suggest an effect on vascular smooth muscle cells or increased bioavailability also of exogenously administered NO among this patient group. Interestingly, selective ETA blockade increased cutaneous blood flow as measured by laser Doppler fluxmetry. This is a measure of total blood flow in the different vessels in the skin including venules, Topiroxostat as well as arterioles. This finding is in accordance with the previous demonstration that selective ETA inhibition improves nutritive cutaneous capillary flow in patients with type 2 diabetes and albuminuria (Settergren et al., 2008b). Although not significant, there was a trend towards increased laser Doppler flow also with dual receptor blockade and clinical studies have shown increased skin perfusion in patients with systemic sclerosis treated with the dual receptor antagonist bosentan (Rosato et al., 2010). The present study in addition demonstrates that dual receptor blockade significantly increased tcpO2 suggesting improved skin oxygenation. A similar trend is seen with selective ETA blockade although not significant. Further studies are warranted to evaluate the efficacy of ET receptor blockade on skin microvascular function in patients with type 2 diabetes and cutaneous microvascular complications. There are some limitations related to the study. First, the number of study subjects is arguably small but there is no indication that the results would have been any different with a larger study group. The effect of dual receptor blockade on endothelium-dependent vasodilatation was of the magnitude estimated the power estimation. Second, the method chosen for the primary endpoint measures changes in endothelial function as a reaction to the infused substances and therefore reflect short time changes in the vascular bed. There is a possibility that longer time treatment with oral substances might elicit changes different from those obtained in the present study. In support of our data is the observation that 4week oral administration of the dual antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes (Rafnsson et al., 2012). Third, the secondary endpoint of change in blood flow of the skin measured by laser Doppler is dependent on probe placement on different study occasions. Although care was taken to ensure correct placement this is a limitation in the study design.
Conclusion Both selective ETA and dual ETA/ETB receptor blockade increase endothelium-dependent vasodilatation in patients with type 2 diabetes and coronary artery disease. ETB blockade increases basal blood flow but does not additionally improve endothelium-dependent vasodilation beyond that induced by selective ETA blockade. Importantly, however, it does not attenuate the beneficial effect of ETA receptor blockade on endothelium-dependent vasodilatation in this patient group. This observation is of importance for future drug therapy aiming at improving vascular function in patients with type 2 diabetes.