PDE-5 inhibition mitigates mental stress-induced endothelial dysfunction in resistant hypertension

Resistant hypertension (RH) is associated with an increased risk of adverse cardiovascular events, and mental stress (MS) is one of the major risk factors. We aimed to test the hypothesis that a phosphodiesterase 5 inhibitor (iPDE5) would minimize the deleterious effects of MS on the endothelial function of those patients. In two experimental days, patients with RH (63 ± 5 yr; 30.2 ± 3.1 kg/m²) received iPDE5 (sildenafil citrate; 50 mg) or a placebo (PL) pill, in a randomized, crossover, double-blind, and placebo-controlled clinical trial. After 30 min, subjects underwent a 5-min MS task (modified Stroop Color-Word Test). Flow-mediated dilatation (FMD) and blood flow (BF) measurements (vascular ultrasound), pulse wave analysis (applanation tonometry), and blood sampling (for vasoactive substances and cGMP measurements) were performed at baseline, during or immediately after MS, and 30 min after MS (MS30). Blood pressure, heart rate, and BF increased during the MS task in both conditions (<i>P</i> ≤ 0.02 vs. rest). FMD decreased immediately after MS (<i>P</i> < 0.01 vs. baseline) and MS30 (<i>P</i> < 0.01 vs. baseline) in the PL condition, whereas it was higher in MS (<i>P</i> = 0.03 vs. PL) and MS30 (<i>P</i> < 0.01 vs. baseline; <i>P</i> = 0.04 vs. MS; <i>P</i> < 0.01 vs. PL) in the iPDE5 condition. Peripheral and central systolic blood pressures were lower while plasma nitrate and cGMP were higher in the iPDE5 condition throughout the protocol (<i>P</i> ≤ 0.04 vs. rest). Present data suggest that iPDE5 prevents MS-induced endothelial dysfunction and improves cardiovascular hemodynamics in RH.<b>NEW & NOTEWORTHY</b> Considering that mental stress (MS)-induced endothelial dysfunction causes major cardiovascular events, the present study explored the involvement of NO-cGMP pathway in resistant hypertension (RH) pathophysiology. Our results suggest that phosphodiesterase 5 inhibition prevents endothelial dysfunction and improves cardiovascular hemodynamics of patients with resistant hypertension faced with stressful circumstances.