Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans

Abstract

Purpose Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA). Methods FBF (Doppler ultrasound) was assessed at rest and during 5 minutes of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: 1) oral SDF (n=10), 2) intra-arterial L-NMMA (n=20), 3) SDF and L-NMMA (n=10). FBF responses to intra-arterial sodium nitroprusside (NTP, NO donor) were also assessed. Results FBF increased with exercise (p<0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17±1 to 15±1 mL/dL/min, p<0.01). Although the hyperemic response to NTP was augmented by SDF (Area under the curve: 41±7 vs 61±11 AU, p<0.01), there was no effect of SDF on exercise hyperemia (p=0.33). Conclusions Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans.

Exercise training improves blood flow to contracting skeletal muscle of older men via enhanced cGMP signaling

“…The nucleotide cyclic guanosine monophosphate (cGMP) is a second messenger for several vasodilator compounds including NO, and potentiation of cGMP signaling can, therefore, potentially compensate for impaired NO formation (16). Recently, potentiation of cGMP signaling was shown to increase blood flow, O 2 delivery, and oxidative metabolism in the exercising limb of older but not young subjects (15,22). Hence one mechanism underlying an improved matching of skeletal muscle blood flow and metabolic demand with exercise training in aging humans may be enhanced cGMP signaling.…”

Acute exercise inhibits gastric emptying of liquids in rats: influence of the NO-cGMP pathway

“…Acute exercise promotes the release of several vasodilator agents such as nitric oxide, prostaglandins, and the endothelial-derived hyperpolarizing factor (32,33). Recently, physical activity was shown to elicit hyperemia in skeletal musculature via recruitment of a NO-cGMP pathway (34) in healthy subjects (35). Herein, the 15-min acute exercise against 5% of body weight increased the circulating levels of NO in rats, as reported in previous studies (36).…”

Dynamics of skeletal muscle blood flow and vasodilation with age

“…al. (160) demonstrated that in the forearm of young healthy adults, potentiation of NO bioavailability via phosphodiesterase-5 (PDE-5) inhibition did not have any effect on forearm blood flow and vasodilation in response to exercise. Conversely, Nyberg (209,210) showed that PDE-5 inhibition augmented O 2 delivery, which was related to elevations in O 2 uptake selectively in the leg of older, but not young adults.…”

“…NO-mediated vasodilation within the skeletal muscle vasculature declines with age (283), and it is unclear whether this is due to reductions in bioavailable NO or alterations in NO signaling (187,210,283). Previous evidence within the forearm demonstrate that local inhibition of endothelial NO synthase (eNOS) reduces the hyperemic and vasodilator responses both at the onset of skeletal muscle contractions, as well as the transition period(kinetics) preceding steady-state exercise (41,43,135,160). Importantly, previous evidence indicates this NO-mediated reduction in O 2 delivery is apparent during the initial phase of exercise (~180 seconds), but compensated with a marked elevation in O 2 extraction (via higher arterio-venous O 2 difference) (48).…”

“…In an effort to potentiate NO signaling, Limberg et. al (160). demonstrated that in the forearm of young healthy adults, phosphodiesterase-5 (PDE-5) inhibition had no effect on blood flow and vasodilation in response to handgrip exercise.…”