Impact of endothelin blockade on acute exercise‐induced changes in blood flow and endothelial function in type 2 diabetes mellitus

Abstract

New FindingsPositive vascular effects of exercise training are mediated by acute increases in blood flow. Type 2 diabetes patients show attenuated exercise-induced increases in blood flow, possibly mediated by the endothelin pathway, preventing an optimal stimulus for vascular adaptation. We examined the impact of endothelin receptor blockade (bosentan) on exercise-induced blood flow in the brachial artery and on pre-and postexercise endothelial function in type 2 diabetes patients (n = 9, 60 ± 7 years old) and control subjects (n = 10, 60 ± 5 years old). Subjects reported twice to the laboratory to perform hand-grip exercise in the presence of endothelin receptor blockade or placebo. We examined brachial artery endothelial function (via flow-mediated dilatation) before and after exercise, as well as blood flow during exercise. Endothelin receptor blockade resulted in a larger increase in blood flow during exercise in type 2 diabetes patients (P = 0.046), but not in control subjects (P = 0.309). Exercise increased shear rate across the exercise protocol, unaffected by endothelin receptor blockade. Exercise did not alter brachial artery diameter in either group, but endothelin receptor blockade resulted in a larger brachial artery diameter in type 2 diabetes patients (P = 0.033). Exercise significantly increased brachial artery flow-mediated dilatation in both groups, unaffected by endothelin receptor blockade. Endothelin receptor blockade increased exercise-induced brachial artery blood flow in type 2 diabetes patients, but not in control subjects. Despite this effect of endothelin receptor blockade on blood flow, we found no impact on baseline or post-exercise endothelial function in type 2 diabetes patients or control subjects, possibly related to normalization of the shear stimulus during exercise. The successful increase in blood flow during exercise in type 2 diabetes patients through endothelin receptor blockade may have beneficial effects in repeated exercise training.

Randomized controlled trial using bosentan to enhance the impact of exercise training in subjects with type 2 diabetes mellitus

“…As a logical follow‐up to a recent study where we found ET blockade to enhance exercise‐induced blood flow in type 2 diabetes (Schreuder et al . ), the purpose of this study was to perform a randomized controlled trial to assess the effect of an 8 week exercise training programme combined with ET blockade. First, we confirmed the potent effect of exercise training, given the significantly improved peak oxygen uptake ( P = 0.006) and peak workload ( P = 0.001).…”

“…Even though, in a previous study, we have successfully increased exercise‐induced blood flow during a single bout of exercise using a dual ET‐1 blocker (Schreuder et al . ), larger effects may be achieved with selective ET A receptor blockade (Sachidanandam et al . ; Settergren et al .…”

“…Previous studies have demonstrated that type 2 diabetes is specifically associated with an upregulation of the ET A but not the ET B receptors. Even though, in a previous study, we have successfully increased exercise-induced blood flow during a single bout of exercise using a dual ET-1 blocker (Schreuder et al 2014), larger effects may be achieved with selective ET A receptor blockade (Sachidanandam et al 2008;Settergren et al 2008). A second limitation is that our main comparison was between subjects as opposed to within subjects.…”

“…We recently demonstrated that systemic endothelin-1 receptor (ET-1) blockade leads to an increase in the exercise-induced blood flow response during hand-grip exercise in type 2 diabetes patients, but not in healthy control subjects (Schreuder et al 2014). Accordingly, exercise training combined with an endothelin (ET) receptor antagonist in type 2 diabetes patients may enhance the blood flow response and thereby the impact of exercise training on the vasculature and physical fitness.…”

Adrenergic and non-adrenergic control of active skeletal muscle blood flow: Implications for blood pressure regulation during exercise

“…Considering the significant contribution of the ET-1 pathway to restraint of blood flow in active skeletal muscle and maintenance of arterial blood pressure, it becomes important to further understand its role during exercise in patient populations associated with high circulating concentrations of ET-1 (Ferri et al, 1995;Saito et al, 1990). Indeed, ET receptor blockade has been shown to markedly enhance the vasodilator response to moderate intensity handgrip exercise in both hypertensive and type 2 diabetic patients (McEniery et al, 2002;Schreuder et al, 2014). However, extrapolating limb specific effects to whole body dynamic exercise remains problematic, thus additional investigations in both healthy and disease populations during large muscle mass exercise are requisite to further elucidate the role of ET-1 receptor-mediated vasoconstriction.…”