Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment.
OBJECTIVE
This study was designed to investigate the role of cortisol in stress-induced endothelial dysfunction and impaired baroreflex sensitivity (BRS) by blocking cortisol production with metyrapone before subjecting healthy volunteers to mental stress.


BACKGROUND
Mental stress raises cortisol levels and is associated with increased coronary heart disease (CHD) morbidity and mortality, especially from sudden cardiac death. It also causes endothelial dysfunction and impaired BRS.


METHODS
We measured brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and BRS in 36 subjects without CHD risk factors who were then randomized in a double-blind fashion to oral metyrapone 750 mg x 2 or placebo. Five hours later we subjected subjects to mental stress and then remeasured endothelial function and BRS.


RESULTS
Prestress cortisol levels were significantly higher in the placebo group at 270.5 (30.9) nmol/l versus 89.1 (11.8) nmol/l (p = 0.01), and the increase with stress was higher at 57.9 (17.9) nmol/l versus 11.2 (2.2) nmol/l (p < 0.001). In the placebo group, compared to baseline, FMD and BRS fell significantly from 4.5% (0.7%) to 1.4% (1.1%) (p = 0.02) and 21.4 (2.3) ms/mmHg to 16.3 (1.5) ms/mmHg (p = 0.04), respectively. In the metyrapone group, FMD and BRS were unchanged from baseline: 4.3% (0.9%) versus 5.1% (0.8%) (p = 0.48) and 26.4 (2.9) ms/mmHg versus 24.9 (2.6) ms/mmHg (p = 0.62), respectively. Analysis of covariation showed a significant effect of metyrapone on change in both FMD (p = 0.009) and BRS (p = 0.024).


CONCLUSIONS
Stress-related endothelial dysfunction and BRS impairment can be prevented by blocking cortisol production with metyrapone, demonstrating a direct or facilitative role for cortisol in these phenomena and suggesting mechanisms by which stress contributes to CHD and sudden cardiac death.
Broadley
Andrew J M
AJ
Heart and Lung Unit, Torbay Hospital, Torquay, United Kingdom.
Korszun
Ania
A
Abdelaal
Eltigani
E
Moskvina
Valentina
V
Jones
Christopher J H
CJ
Nash
Gerard B
GB
Ray
Clare
C
Deanfield
John
J
Frenneaux
Michael P
MP
D000328:Adult; D017704:Baroreflex / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D001916:Brachial Artery / Q000000981:diagnostic imaging; D003327:Coronary Disease / Q000503:physiopathology; D004311:Double-Blind Method; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008297:Male; D008797:Metyrapone; D008991:Monitoring, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D013315:Stress, Psychological / Q000503:physiopathology*; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D006854:Hydrocortisone; D008797:Metyrapone