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Emerging evidence suggests that type 2 diabetes (T2D) may impair the ability to properly adjust the circulation during exercise with augmented blood pressure (BP) and an attenuated contracting skeletal muscle blood flow (BF) response being reported. This review provides a brief overview of the current understanding of these altered exercise responses in T2D and the potential underlying mechanisms, with an emphasis on the sympathetic nervous system and its regulation during exercise. The research presented support augmented sympathetic activation, heightened BP, reduced skeletal muscle BF, and impairment in the ability to attenuate sympathetically mediated vasoconstriction (i.e., functional sympatholysis) as potential drivers of neurovascular dysregulation during exercise in T2D. Furthermore, emerging evidence supporting a contribution of the exercise pressor reflex and central command is discussed along with proposed future directions for studies in this important area of research.

Sympathetic vasoconstriction is blunted in exercising muscle (functional sympatholysis) but becomes attenuated with age. We tested the hypothesis that functional sympatholysis is further impaired in chronic obstructive pulmonary disease (COPD) patients. We determined leg blood flow and calculated leg vascular conductance (LVC) during 1) femoral-arterial Tyramine infusion (evokes endogenous norepinephrine release, 1 µmol·min−1·kg leg mass−1), 2) one-legged knee extensor exercise with and without Tyramine infusion [10 W and 20% of maximal workload (WLmax)], 3) ATP (0.05 µmol·min−1·kg leg mass−1) and Tyramine infusion, and 4) incremental ATP infusions (0.05, 0.3, and 3.0 µmol·min−1·kg leg mass−1). We included 10 patients with moderate to severe COPD and 8 age-matched healthy control subjects. Overall, leg blood flow and LVC were lower in COPD patients during exercise ( P < 0.05). Tyramine reduced LVC in both groups at 10-W exercise (COPD: −3 ± 1 ml·min−1·mmHg−1and controls: −3 ± 1 ml·min−1·mmHg−1, P < 0.05) and 20% WLmax(COPD: −4 ± 1 ml·min−1·mmHg−1and controls: −3 ± 1 ml·min−1·mmHg−1, P < 0.05) with no difference between groups. Incremental ATP infusions induced dose-dependent vasodilation with no difference between groups, and, in addition, the vasoconstrictor response to Tyramine infused together with ATP was not different between groups (COPD: −0.03 ± 0.01 l·min−1·kg leg mass−1vs. controls: −0.04 ± 0.01 l·min−1·kg leg mass−1, P > 0.05). Compared with age-matched healthy control subjects, the vasodilatory response to ATP is intact in COPD patients and their ability to blunt sympathetic vasoconstriction (functional sympatholysis) as evaluated by intra-arterial Tyramine during exercise or ATP infusion is maintained.NEW & NOTEWORTHY The ability to blunt sympathetic vasoconstriction in exercising muscle and ATP-induced dilation in chronic obstructive pulmonary disease patients remains unexplored. Chronic obstructive pulmonary disease patients demonstrated similar sympathetic vasoconstriction in response to intra-arterial Tyramine during exercise and ATP-induced vasodilation compared with age-matched healthy control subjects.

Sympathetic vasoconstriction is attenuated in exercising muscles to assist in matching of blood flow with metabolic demand. This “functional sympatholysis” may be impaired in young obese individuals due to greater sympathetic activation and/or reduced local vasodilatory capacity of both small and large arteries, but this remains poorly understood. We tested the hypothesis that functional sympatholysis is impaired in obese individuals compared with normal‐weight counterparts. In 36 obese and normal‐weight young healthy adults (n = 18/group), we measured forearm blood flow and calculated forearm vascular conductance (FVC) responses to reflex increases in sympathetic nerve activity induced by lower body negative pressure (LBNP) at rest and during rhythmic handgrip exercise at 15% and 30% of the maximal voluntary contraction (MVC). FVC was normalized to lean forearm mass. In normal‐weight individuals, LBNP evoked a decrease in FVC (−16.1 ± 5.7%) in the resting forearm, and the reduction in FVC (15%MVC: −8.1 ± 3.3%; 30%MVC: −1.0 ± 4.0%) was blunted during exercise in an intensity‐dependent manner (P 0.05) and was intensity‐dependent (P

Increasing the relaxation phase of the contraction–relaxation cycle will increase active skeletal muscle blood flow (Q˙m). However, it remains unknown if this increase in Q˙m alters the vasoconstriction responses in active skeletal muscle. This investigation determined if decreasing mechanical impedance would impact vasoconstriction of the active skeletal muscle. Eight healthy men performed rhythmic handgrip exercise under three different conditions; “low” duty cycle at 20% maximal voluntary contraction (MVC), “low” duty cycle at 15% MVC, and “high” duty cycle at 20% MVC. Relaxation time between low and high duty cycles were 2.4 sec versus 1.5 sec, respectively. During steady‐state exercise lower body negative pressure (LBNP) was used to evoke vasoconstriction. Finger photoplethysmography and Doppler ultrasound derived diameters and velocities were used to measure blood pressure, forearm blood flow (FBF: mL min−1) and forearm vascular conductance (FVC: mL min−1 mmHg) throughout testing. The low duty cycle increased FBF and FVC versus the high duty cycle under steady‐state conditions at 20% MVC (P

The purpose of this study is to investigate that dipeptidyl peptidase IV (DPP‐IV) released from skeletal and vascular smooth muscle can increase arteriolar diameter in a skeletal muscle vascular bed by reducing neuropeptide Y (NPY)‐mediated vasoconstriction. We hypothesized that the effect of myokine DPP‐IV would be greatest in the smallest and least in the largest arterioles. Eight male Sprague Dawley rats (age 7–9 weeks; mass, mean ± SD: 258 ± 41 g) were anesthetized and the gluteus maximus dissected in situ for intravital microscopy analysis of arteriolar diameter of the vascular network. Computational modeling was performed on the diameter measurements to evaluate the overall impact of diameter changes on network resistance and flow distribution. In the first set of experiments, whey protein isolate powder was added to physiological saline solution, put in a heated reservoir, and applied to the preparation to induce release of DPP‐IV from the muscle. This resulted in an order‐dependent increase in arteriolar diameter, with the largest change in the 6A arterioles (63% more reactive than 1A arterioles; P

Blunting of sympathetic vasoconstriction in exercising muscle is well established. Whether it persists during the early post-exercise period is unknown. This study tested the hypothesis that it persists in human skeletal muscle during the first 10 minutes of recovery from exercise. Eight healthy young males (21.4 ±0.8 yrs, SE) performed 7 minutes of forearm rhythmic isometric handgrip exercise at 15% below forearm critical power. In separate trials, a cold pressor test (CPT) of 2 min duration was used to evoke forearm sympathetic vasoconstriction in each of Rest (R), Steady State Exercise (Ex), 2-4 min Post Exercise (PEearly), and 8-10 min Post Exercise (PElate). A 7 min control exercise trial with no CPT was also performed. Exercising forearm brachial artery blood flow, arterial blood pressure, cardiac output, heart rate, forearm deep venous catecholamine concentration and arterialized venous catecholamine concentration were obtained immediately prior to and following the CPT in each trial. CPT resulted in a significant increase in forearm venous plasma norepinephrine concentration in all trials (P=0.007), but no change in arterialized plasma norepinephrine (P=0.32). CPT did not change forearm venous plasma epinephrine (P=0.596) or arterialized plasma epinephrine concentration (P=0.15). As assessed by the %reduction in forearm vascular conductance (FVC) the CPT evoked a robust vasoconstriction at rest that was severely blunted in exercise (R -39.9 ±4.6% vs. Ex 5.5 ±7.4%, P

Duchenne and Becker muscular dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSµ) which binds spectrin-like repeats within dystrophin’s rod domain and the adaptor protein α-syntrophin. Dystrophin deficiency causes loss of sarcolemmal nNOSµ and reduces paracrine signaling of muscle-derived nitric oxide (NO) to the microvasculature, which renders the diseased muscle fibers susceptible to functional muscle ischemia during exercise. Repeated bouts of functional ischemia superimposed on muscle fibers already weakened by dystrophin deficiency result in use-dependent focal muscle injury. Genetic and pharmacologic strategies to boost nNOSµ-NO signaling in dystrophic muscle alleviate functional muscle ischemia and show promise as novel therapeutic interventions for the treatment of DMD/BMD.

These results demonstrate that a1- and a2- adrenergic receptor responsiveness to infusion of selective a1- and a2- adrenergic receptor agonists and endogenous norepinephrine release (tyramine) does not decline during prolonged mild-intensity exercise. Thus a decrease in a-adrenergic receptor responsiveness over time does not appear to be responsible for the decrease in sympathetic restraint of muscle blood flow during prolonged exercise.