Effects of Local Alpha-adrenergic Blockade and Phosphodiesterase Inhibition on Mental Stress-Induced Vasodilation in Forearm Microvasculature

Introduction. The forearm blood flow (FBF) response to mental stress is mediated through neuronal nitric oxide synthase (nNOS) but may be blunted by sympathetic activity, including that elicited by the orally administered phosphodiesterase 5 (PDE5) inhibitorsildenafil1. We therefore examined the effect of local α-adrenergic blockade and PDE5 inhibition on the FBF response to mental stress.

Methods. Thirty-three normotensive participants (19 men, age 29.8±2.2 years) underwent left brachial artery cannulation and strain gauge plethysmography to measure FBF during infusion of saline vehicle, mental stress (elicited by the Stroop test), vasoactive drug and combination of mental stress and vasoactive drug. On preliminary testing, those participants with an impaired FBF to stress (n=10) were assigned to receive phentolamine (20µg/min) and verapamil (5μg/min, as a control vasodilator) on two separate occasions. The remaining participants (n=23) received sildenafil (40μg/min). Non-specific effects of phentolamine on FBF during mental stress were corrected using the response to verapamil. The effect of sildenafil on stress-induced FBF was corrected for the effect of sildenafil on resting FBF.

Results. Data are shown as the percentage change from the preceding baseline (mean ± SEM). The FBF was 39.1±7.5%during stress vs. 66.7±13% during stress and phentolamine (p=0.016), 33.8±8.7%during stress vs. 37.7±15% during stress and verapamil (p=0.80), and 61.7±13% during stress vs. 41.6±11% during stress and sildenafil (p=0.02, see figure).

Conclusions. The improvement in mental stress-induced FBF with phentolamine suggests that individuals with an impaired mental stress response have increased local α-adrenergic activity, which functionally antagonises nNOS-mediated vasodilation. These data are consistent with the observation that individuals with essential hypertension – a condition of increased sympathetic tone - have impaired stress-induced blood flow2. The mechanism of attenuation of stress-induced FBF by sildenafil requires further investigation.

1 Phillips et al, Circulation, 2000. 102(25): p. 3068-73.

2 Khan et al, Hypertension, 2015. 65: p903-9.