Insulin-induced microvascular activity in patients with essential hypertension: possible interactions with angiotensin II - Amendement 24-09-2007

There is an relation between hypertension and insulin resistance, both
associated with increased cardiovascular risk. Hypertension and insulin
resistance are characterized by dysfunctions in microcirculation, however it is
unclear if microcirculation is the link between these two abnormalities. In
addition to its actions in mediating glucose uptake, insulin knows several
vascular effects. Insulin induces a vasodilatory response by resistance vessels
and preterminal arterioles leading to an overall increase in blood flow
(glucose) to the muscles.
The local activity of the vasoconstrictor angiotensin II is elevated in
patients with hypertension. Previous studies show a possible role for
angiotensin II in the hypertensive, insulin resis-tant phenotype, however a
mechanism remains unexplained. In this study we hypothesize that angiotensin II
impairs the microvascular actions of insulin (as mentioned above), resulting in
a decreased level of glucose uptake and as a consequence hyperinsulinaemia and
insulin resis-tance.

The goal of this study is examining the acute effects of insulin on
microcirculation in hypertensive insulinresistant subjects and investigate if
angiotensine II influences these effects.

Amendement: The goal of the amendement is to exame the bloodpressure response
to angiotensinII and phenylephrine, without concomittant insulin infusion.

Amendement: All subjects will bring 2 visits to the AZM after a ten hour fast.
The bloodpressure response to infusion of angiotenisinII and phenylephrine will
be measured during these visits (automatic blood pressure device, Accutorr).
During each visit 2 catheters will be inserted in the antecubital vein of both
arms. Angiotensin II (day1) of Phenylephrine (day2) (randomized) will be
infused through the cathether in the non-dominant arm (dosage and time (120
min) of this infusion will be exactly the same as applied in MEC 06-2-074).
Blood pressure will be measured before, after 30 minutes infusion and after 110
minutes infusion of angiotensinII of phenylefrin. At these three timepoints 2
venous bloodsamples of 5 ml will also be taken from the catheter in the
dominant-arm for determination of plasma angiotensinII levels (equals 30 ml of
blood in total for 1 studyday). A study day will take 3 hours. At least 24 hrs
will be scheduled between each visit.

If the difference in bloodpressure respons to AngiotensinII and phenylephrine
still exists without the co-infusion of insulin, we will ask the subjects to
come for a third study day. The bloodpressure respons to a lower dosage (1
ng/kg/min) of angiotensin II will be measured during this visit. It is
estimated that this lowered dosage will give an equal rise in blood pressure as
can be seen with phenylephrine. If so, this lower dosage of ang II will be
applied in MEC 06-2-074. The subjects will be imformed about the possibility of
this third study day in advance.

The subjects in MEC 06-2-074 were measured during a high sodium diet. As salt
intake can influence the blood pressure response we will ask the participents
of this study to start with the high sodium diet again 7 days prior to the
first visit. The subjects will be asked to collect there urine for 24 hours, on
the day before visit 1.

Amendement:
Angiotensin II and phenylephrine will be infused intravenously.
During the visit 6x5 ml venous blood samples will be taken, blood pressure and
heart rate will be monitored.

Amendement:
Inserting the catheters can be a little bit painful and after removal sometimes
bruises can appear. There are no risks involved in the infusion of angiotensin
II and phenylephrine. There will be taken 30 ml of blood during one study day.
No burden or risk is involved with this amount. De subject will be sober during
the whole study day. Previous studies showed that this isn't a big burden for a
subject.