Individual and Combined Effects of Phosphodiesterase‐5 and Nitric Oxide Synthase Inhibition to Vasodilation During Moderate Exercise
Authors: Kellawan Jeremy Mikhail , Limberg Jacqueline K , Scruggs Zachariah M , Nicholson Wayne T , Schrage William G , Joyner Michael J , Curry Timothy B 
Published: November 2023

Background

Nitric oxide (NO) contributes ~30% to the rate of vasodilation during dynamic exercise in healthy humans. This NO‐mediated dilation occurs via increases in cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase‐5 (PDE‐5). Therefore, we sought to determine the nature of NO‐cGMP signalling to the exercise vasodilator response in healthy humans. We hypothesized the time‐course of exercise vasodilation would be: 1) accelerated by sildenafil citrate (SDF, PDE‐5 inhibitor) 2) slowed by the NO synthase inhibitor L‐NG‐monomethyl arginine (L‐NMMA) 3) similarly slowed by the combination of SDF+L‐NMMA.

Methods

Data from 29 healthy individuals were included in the present study. All subjects completed 5‐min of dynamic forearm exercise at 15% of maximal voluntary contraction under control conditions (CON, arterial saline infusion), followed by an identical exercise protocol during: 1) PDE‐5 inhibition via SDF (100mg oral dose, n = 8), 2) NOS inhibition via intra‐arterial infusion of L‐NMMA (50 mg loading dose and 1 mg/min maintenance dose, n = 15), or

3) combined SDF+L‐NMMA (n = 6). Forearm blood flow (FBF; Doppler ultrasound) and mean brachial artery blood pressure (MAP, transducer) were measured continuously. To determine time to steady‐state vasodilation, forearm vascular conductance (FVC = FBF/100mmHg/dL FAV) data were curve fit with a monoexponential model and mean response time (MRT, time to achieve 63% of steady state response) was calculated. In addition, the increase in relative forearm vascular conductance from rest to steady state exercise (average of the last 30s of exercise, ΔFVC = FVCexercise − FVCrest) was used to assess the total vasodilatory response.

Results

Data are reported as mean ± SE (FVC = mL/dL/100mmHg/min, MRT = s). In contrast to our hypothesis, SDF alone had no effect on exercise vasodilation (Δ FVC CON = 20±3 vs. SDF = 21±3, p = 0.50) or time to steady‐state vasodilation (MRT: CON = 32± 7 vs SDF= 33±4, p = 0.90) in young healthy adults. NOS inhibition with L‐NMMA reduced ΔFVC (CON = 16±2 vs. L‐NNMA = 14±1, p = 0.049) and increased the time to reach steady‐state vasodilation (MRT: CON = 22±5 vs. L‐NMMA = 40±6, p = 0.01). Surprisingly, when subjects were given L‐NMMA combined with SDF, reductions in Δ FVC or increases in MRT were no longer observed (Δ FVC: CON = 23±4 vs. SDF+L‐NMMA = 23±6, p = 0.90; MRT: CON = 45±8 vs. SDF+L‐NMMA = 49±11, p = 0.80).

Conclusion

These data indicate inhibiting PDE‐5 during moderate exercise does not improve the magnitude or time‐course of vasodilation. Whereas, NOS inhibition limits the magnitude and time‐course of the vasodilatory response to dynamic handgrip exercise in healthy adults, combined inhibition of PDE‐5 restores the response to control levels. These data suggest PDE‐5 inhibition does not potentiate the NO‐cGMP pathway during moderate exercise. However, PDE‐5 inhibition may have therapeutic use in pathologies where limited NO bioavailability may contribute to impaired blood flow responses to exercise.

Support or Funding Information

American Heart Association (15POST23100020) ‐ JMKNational Institutes of Health (HL46493)

‐ MJJ National Institutes of Health (HL078019) ‐ MJJ National Institutes of Health (HL105820)

‐ WGS National Institutes of Health (RR17520) ‐ N/A National Institutes of Health (UL1 TR000135) ‐ N/A