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-N^G-monomethyl arginine (L-NMMA).

Methods: FBF (Doppler ultrasound) was assessed at rest and during 5 min 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.

Keywords: Blood flow; Cyclic GMP; Exercise; Nitric oxide; Regional; Sildenafil.

Fig. 1. Hyperemic response to dynamic handgrip exercise and role of the NO-cGMP pathway

Forearm blood flow increased with exercise (Main effect of exercise, p<0.01). Blood flow was not altered by sildenafil citrate (Main effect of SDF, p=0.81). L-NMMA resulted in a reduction in blood flow alone (Main effect of L-NMMA, p<0.01) and when combined with sildenafil citrate (Main effect of SDF+L-NMMA, p=0.04). ^*p<0.05 vs Rest, ^†p<0.05 vs Control.

Fig. 2. Vasodilatory responses to intra-arterial infusion of sodium nitroprusside

The rise in forearm vascular conductance in response to intra-arterial sodium nitroprusside infusion was calculated (FVC_infusion – FVC_baseline). Sodium nitroprusside-mediated vasodilation was increased in oral SDF (A: Main effect of drug versus control, p<0.01) and remained high when sildenafil citrate was combined with L-NMMA (B: Main effect of drug versus control, p=0.049). ^†p<0.05 vs Control.