Potentiation of cGMP signaling increases oxygen delivery and oxidative metabolism in contracting skeletal muscle of older but not young humans

Aging is associated with progressive loss of cardiovascular and skeletal muscle function. The impairment in physical capacity with advancing age could be related to an insufficient peripheral O(2) delivery to the exercising muscles. Furthermore, the mechanisms underlying an impaired blood flow regulation remain unresolved. Cyclic guanosine monophosphate (cGMP) is one of the main second messengers that mediate smooth muscle vasodilation and alterations in cGMP signaling could, therefore, be one mechanism by which skeletal muscle perfusion is impaired with advancing age. The current study aimed to evaluate the effect of inhibiting the main enzyme involved in cGMP degradation, phosphodiesterase 5 (PDE5), on blood flow and O(2) delivery in contracting skeletal muscle of young and older humans. A group of young (23 ± 1 years) and a group of older (72 ± 2 years) male human subjects performed submaximal knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. Sildenafil increased leg O(2) delivery (6–9%) and leg O(2) uptake (10–12%) at all three exercise intensities in older but not young subjects. The increase in leg O(2) delivery with sildenafil in the older subjects correlated with the increase in leg O(2) uptake (r(2) = 0.843). These findings suggest an insufficient O(2) delivery to the contracting skeletal muscle of aged individuals and that reduced cGMP availability is a novel mechanism underlying impaired skeletal muscle perfusion with advancing age

The effect of tyramine infusion and exercise on blood flow, coagulation and clot microstructure in healthy individuals

BackgroundThe long term benefits of exercise on the cardiovascular status of a patient have been proven, however, their benefit/risk relationship with exercise intensity is unclear. Furthermore, many thromboembolic diseases such as myocardial infarction and ischaemic stroke are associated with profound catecholamine release. In this study we explore the relationship between catecholamine release and hemodynamic changes and their effect on coagulation.Materials and methodsTwelve healthy recreationally active males were recruited. Local anesthesia was given and catheters were placed under aseptic conditions, in the femoral artery and vein of the experimental leg. The first experiment involved tyramine infusion into the femoral artery at a dose of 1.0 μmol·min−1·L leg volume−1. The second experiment involved single leg knee-extensor exercise performed at 30 W for 15 min. Venous blood was collected at each time point to assess clot microstructure using the df biomarker.Results and conclusionsTyramine infusion causes a local noradrenaline release in the leg. The increase in noradrenaline was associated with a significant increase in clot microstructure formation (df increased from 1.692 ± 0.029 to 1.722 ± 0.047, p = 0.016). Additionally moderate intensity single leg knee extensor exercise, which minimally alters sympathetic activity, also induced an increases in df (from 1.688 ± 0.025 to 1.723 ± 0.023, p = 0.001). This suggests that exercise can alter clot microstructure formation both via an increase in catecholeamine levels and by factors related to muscle activity per se, such as increased blood flow and consequent shear. These findings have implications for recommendations of exercise in patients at risk of cardiovascular events

Reduced blood flow to contracting skeletal muscle in ageing humans:Is it all an effect of sand through the hourglass?

The ability to sustain a given absolute submaximal workload declines with advancing age, likely to be due to a lower level of blood flow and O(2) delivery to the exercising muscles. Given that physical inactivity mimics many of the physiological changes associated with ageing, separating the physiological consequences of ageing and physical inactivity can be challenging; yet, observations from cross‐sectional and longitudinal studies on the effects of physical activity have provided some insight. Physical activity has the potential to offset the age‐related decline in blood flow to contracting skeletal muscle during exercise where systemic blood flow is not limited by cardiac output, thereby improving O(2) delivery and allowing for an enhanced energy production from oxidative metabolism. The mechanisms underlying the increase in blood flow with regular physical activity include improved endothelial function and the ability for functional sympatholysis – an attenuation of the vasoconstrictor effect of sympathetic nervous activity. These vascular adaptations with physical activity are likely to be an effect of improved nitric oxide and ATP signalling. Collectively, precise matching of blood flow and O(2) delivery to meet the O(2) demand of the active skeletal muscle of aged individuals during conditions where systemic blood flow is not limited by cardiac output seems to a large extent to be related to the level of physical activity

Contribution of intravascular versus interstitial purines and nitric oxide in the regulation of exercise hyperaemia in humans

The regulation of blood flow to skeletal muscle involves a complex interaction between several locally formed vasodilators that are produced both in the skeletal muscle interstitium and intravascularly. The gas nitric oxide (NO) and the purines ATP and adenosine, are potent vasodilators that are formed by multiple cell types and released into the skeletal muscle interstitium and in plasma in response to muscle contraction. Cellular sources of ATP and NO in plasma are erythrocytes and endothelial cells, whereas interstitial sources are skeletal muscle cells and endothelial cells. Adenosine originates primarily from extracellular degradation of ATP. During exercise the concentrations of ATP and adenosine increase markedly in the interstitium with smaller increases occurring in plasma, and thus the interstitial concentration during exercise is severalfold higher than in plasma. The concentration of NO metabolites (NOx) in interstitium and plasma does not change during exercise and is similar in the two compartments. Adenosine and NO have been shown to contribute to exercise hyperaemia whereas the role of ATP remains unclear due to lack of specific purinergic receptor blockers. The relative role of intravascular versus interstitial vasodilators is not known but evidence suggests that both compartments are important. In cardiovascular disease, a reduced capacity to form adenosine in the muscle interstitium may be a contributing factor in increased peripheral vascular resistance