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

Abstract

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 O2 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 O2 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 O2 delivery (6–9%) and leg O2 uptake (10–12%) at all three exercise intensities in older but not young subjects. The increase in leg O2 delivery with sildenafil in the older subjects correlated with the increase in leg O2 uptake (r2 = 0.843). These findings suggest an insufficient O2 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.

Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans

“…In a recent study, the current group of older subjects were reported to have a reduced vasodilator response to ACh compared with that of young (26), which is in line with previous observations (20,40). Through inhibition of enzymatic NO formation this reduced vascular response has been shown to be an effect of a lower NO bioavailability (40).…”

“…Written informed consent was obtained from all subjects before enrollment into the study. Baseline characteristics and measurements obtained during control exercise without and with sildenafil on experimental day 1 for 9 young and 8 older subjects have been published previously (26).…”

“…This increase in blood flow to the exercising muscle is the result of a local attenuation of the vasoconstrictor effect of sympathetic nervous activity, termed functional sympatholysis, and vasodilation induced by local vasoactive mechanisms (6,15). Since the first report on the hemodynamic response to exercise in older individuals in 1974 (42), evidence has accumulated for an insufficient blood flow to contracting skeletal muscle in aging (3,5,17,18,23,26,28,30,31). This altered regulation with aging could be related to a diminished ability for functional sympatholysis (10,20,36) and/or reduced efficacy of local vasodilator pathways (20,38,40).…”

“…In humans with type 2 diabetes, a condition in which ATP release from erythrocytes is impaired, inhibition of cGMP-binding phosphodiesterase 5 (PDE5) effectively rescues low O 2 -induced ATP release in isolated erythrocytes (32). Hence, systemic inhibition of PDE5 in older humans could poten-tially lead to an increase in plasma [ATP] in conditions of low PO 2 such as during skeletal muscle contractions which could explain the increased exercise hyperemia in older subjects following PDE5 inhibition (26). Importantly, when infused into the arterial vasculature supplying skeletal muscle, ATP can significantly blunt ␣-adrenergic vasoconstriction in both young (34) and older (16,20) subjects.…”

“…Consequently, the increase in exercise hyperemia with PDE5 inhibition in older subjects (26) could also reflect that a lower cGMP level during exercise was, at least in part, related to a diminished NO bioavailability. As opposed to the reports on the vascular effects of ATP, consistent evidence has been provided to support that NO is neither sufficient nor essential for functional sympatholysis in humans (9,31,33,41).…”