Systemic effects of mild renal insufficiency: the relation between forearm blood flow and ADMA.

According to different studies in patients with mild renal insufficiency the
cardiovascular risk is elevated more than can be explained on the basis of
traditional risk factors. At the same time the concentration of ADMA
(asymmetric dymethylarginine) in the blood is elevated in patients with mild
renal insufficiency. ADMA is an endogenous inhibitor of nitric oxide (NO) and
elevated concentrations of this substance lead to diminished
endothelium-dependent vasodilatation. The increased ADMA levels may originate
either from the kidney or from the systemic vasculature. Nevertheless,
abnormalities of the endothelium-dependent vasodilatation lay the foundation
for the development of atherosclerosis. It is likely that the ADMA-induced
endothelial dysfunction is a causal factor in the progression of systemic
atherosclerosis found in patients with mild renal insufficiency.
In this study the relationship between the systemic NO-mediated
endothelium-dependant vasodilatation, measured as forearm blood flow and venous
ADMA-level is studied, in hypertensive as well as healthy subjects. In the
hypertensive subjects it also will be examined to what extend the forearm blood
flow (FBF) can be influenced by treatment with an angiotensin-II-
receptorblocker (olmesartan) and/or a statin (rosuvastatin).
It has been documented that ADMA levels in hypertensive subjects are higher
than in healthy subjects. The ADMA-level in hypertensive subjects will be
reversely related to the basal blood flow and the endothelial NO-availability
in the forearm. Pre-treatment with an angiotensin-II- receptorblocker and/or a
statin will decrease the ADMA-levels via increased clearance of ADMA and,
consequently, will *normalise* the forearm blood flow and NO-availability.

The results of this study will give better insights in the role of ADMA in the
development of systemic endothelial dysfunction.

The study is an intervention study. A control group (n=15) will undergo a FBF
measurement once and 4 patients groups (n=60) will undergo FBF measurement
twice. After a baseline FBF measurement without medication the patients will be
treated with placebo, olmesartan and/or rosuvastatin during a three-weeks
interval. Next, FBF will be assessed again after sampling for ADMA and DDAH
activity (ADMA degrading enzyme).

The intervention will consist of a three-week treatmentperiod with placebo,
eprosartan 600mg and/or rosuvastatin 20 mg.

The patients will visit the hospital twice for FBF-measurements with an
interval of 3 weeks. During this interval medication will be used and home
blood pressure measurements will be performed. For the FBF-measurements 80 and
85 ml of blood will be drawn. The control group will undergo one screening
visit (7 ml blood will be drawn) and one FBF-measurements (60 ml blood will be
drawn) 7-10 days later. The control group has to collect urine for 24 hours.
The week before the FBF-measurements a low-salt diet will be followed by all
participants.
The risks associated with participation include mainly small inconveniences
(tingling feeling in the arm during the FBF, small haematoma at the site of
the puncture of the brachial artery and veins, and sometimes muscle aches as a
side-effect of the statin use. The solutions used to determine the FBF are
safe. The hypertensive subjects will be deprived of antihypertensive medication
3 weeks longer than usual.