Uric Acid Effects on Endothelium and Oxydative Stress
Status:
Completed
Trial end date:
2020-02-27
Target enrollment:
Participant gender:
Summary
Cardiovascular disease is the leading cause of mortality worldwide. Endothelial dysfunction
(ED) is the main mechanism which leads to atherosclerosis, where the balance between pro and
antioxidant factors results in a decreased nitric oxide (NO) bioavailability. Xanthine
OxidoReductase (XOR) is one of the main generators of reactive oxygen species (ROS). Uric
acid (UA), a major antioxidant in human plasma and end product of purine metabolism, is
associated with cardiovascular diseases since many years; however the precise mechanisms
which relate UA to ED are still not well understood.
The purpose of this study is to unravel the XOR and UA pathways involved in ED. Three groups
of participants (young (< 40 y) male healthy participants [1] ; male and female helthy
participants (40 to 65 y) [2] and patients with primary hypertension [3]) will be exposed to
febuxostat (a strong and selective XOR inhibitor), or recombinant uricase (which oxidizes UA
into allantoin) to vary UA levels and concomitantly control for confounding changes in XOR
activity. Oxidative stress will be estimated by several markers. Endothelial function will be
assessed by a laser Doppler imager in the presence of hyperthermia and endothelium
stimulators. This study is specifically designed to untie the respective effects of UA and
XOR pathways on oxidative stress and endothelial function in humans.
The investigators will test the following hypothesis:
1. An extremely low level of uric acid after uricase administration induces endothelial
dysfunction and oxydative stress,
2. A specific XO inhibitor limits unfavourable effects of the serum UA reduction elicited
by uricase administration,
3. Endothelial function and oxydative stress are further improved with febuxostat as
compared to placebo,
4. All these observations are more marked in hypertensives then in older participants than
in young healthy subjects.
Phase:
N/A
Details
Lead Sponsor:
Erasme University Hospital
Collaborators:
Fonds Erasme Fonds National de la Recherche Scientifique