Interestingly selective ETA blockade increased cutaneous
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, fura 2 am 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.
Conflict of interest statement
Acknowledgements We would like to thank Ann Lindström and Marita Wallin (Karolinska Institute, Department of Medicine, Cardiology Unit) for their invaluable work and skillful technical assistance. The study was supported by grants from the Swedish Research Council (10857), the Swedish Heart and Lung Foundation (20130240), the Stockholm County Council (ALF) (20130045), Karolinska Institutet/Stockholm County Council Strategic Cardiovascular Programme, King Gustav V and Queen Victoria Foundation, and Novo Nordisk Foundation.
Introduction Endothelial cells in general perform their functions through the expression and release of various cardioactive factors such as endothelin-1 (ET-1), angiotensin II (Ang-II), nitric oxide (NO), prostanoids and neuropeptide Y (NPY) (Bkaily et al., 2012, Bkaily et al., 2014, Cines et al., 1998, Jacques et al., 2003a, Jacques et al., 2003b, Shah et al., 1996). Both vascular endothelial as well as endocardial endothelial cells have been reported to release these factors (Bkaily et al., 2012, Bkaily et al., 2014, Brutsaert, 2003, Jacques et al., 2003a, Jacques et al., 2003b, Kuruvilla and Kartha, 2003). Complex interactions have been reported to exist between ET-1 and the other regulators of cardiovascular function, in particular NO and Ang II (Brunner et al., 2006).