HerzSupplement - Pentalong von Actavis

oxidativen Spektrums nicht nur ausschließlich
zur Behandlung von symptomatischen
Erkrankungen der Koronararterien einsetzen
lässt, sondern auch in Form einer zusätzlichen
Medikation als Prävention gegen
Arteriosklerose verwendet werden könnte.
Des Weiteren zeigt die Normalisierung aller
gemessenen Parameter im Tiermodell des
STZ-induzierten Diabetes mellitus Typ 1
mittels Insulin, dass eine STZ-bedingte vaskuläre
Dysfunktion abhängig von der Insulinproduktion
ist und nicht über unspezifisch
toxische Nebenwirkungen des Präparates
ausgelöst wird, womit letztendlich
auch die klinische Relevanz dieses Tiermodells
hervorgehoben werden konnte. n
Summary
In contrast to other organic nitrates pentaerithrityl
tetranitrate (PETN)-treatment in
Wistar rats induces neither nitrate tolerance
nor cross-tolerance, what can be explained
by induction of antioxidant mechanisms
like heme oxygenase-1 (HO-1) and
ferritin. With the present studies we tested
in an animal model of angiotensin-II (AT-
II) induced hypertension, whether chronic
treatment with PETN will preserve it’s beneficial
effects compared to effects of chronic
treatment with isosorbide-5-mononitrate
(ISMN). Additionally we tested in a
rat model of streptozotocin (STZ) induced
diabetes mellitus, whether chronic treatment
with PETN, isosorbide dinitrate
(ISDN) or ISMN improves diabetesassociated
vascular oxidative stress and
dysfunction. Therefore male Wistar rats
(230–250 g) were treated with AT-II (1 mg/
kg/d) alone or together with PETN (15 mg/
kg/d) or ISMN (75 mg/kg/d) via subcutaneous
osmotic minipumps for 7 days. Control
pumps were applied with the solving
reagent, respectively. Diabetes was induced
by a single i.v. injection of STZ (60 mg/kg)
in male wistar rats (220–250 g). PETN,
ISMN and ISDN therapy started 7 d after
STZ-Injection (dose: 15 mg/kg/d, 75 mg/kg/
d and 10 mg/kg/d, respectively). The rats
were sacrificed after 8 weeks. A small collective
of STZ-rats was treated with insulin
(2.5 U/d) for the 2 weeks before sacrifice.
Reactive oxygen species (ROS) were
detected by chemiluminescence, HPLC or
fluorescent microtopography, protein expression
was measured by Western blotting
Herz 35 · 2010 · Supplement II © Urban & Vogel
and vascular function was assessed by isometric
tension studies. Additionally the antioxidative
capacity of blood serum was
measured photometrically by reduction of
the DPP-radical. Ang-II infusion caused
endothelial dysfunction and reduced endothelial
independent relaxation, indicated by
a decreased vasodilator potency of acetylcholine
and nitroglycerin in isolated aortic
rings, an increase of reactive superoxide
species (ROS) in aortic vessels and in
NADPH oxidase activity in heart membrane
fractions, as detected by lucigenin (5µM)
derived chemiluminescence (LDCL). Staining
of aortic sections and HPLC-derived
measurements with the fluorescent dye dihydroethidine
showed O2-formation
throughout the vessel wall. In addition, expression
of HO-1 was increased in aorta. In
contrast to ISMN, co-treatment with PETN
normalized in part vascular function and
ROS-formation. Furthermore, HO-1 expression
was further enhanced by PETN,
not by ISMN. STZ-treated rats showed a
dramatically increase in blood glucose levels,
decrease in weight gain, increased vascular
and cardiac ROS production (mitochondria,
NADPH oxidase activity), decreased
antioxidative capacity of serum and
impaired endothelial and smooth muscle
function. PETN therapy improved almost
all parameters more efficiently than ISDN,
except endothelial and smooth muscle function,
where both nitrates showed identical
beneficial effects. ISMN, which was used to
examine differences to its dinitrate derivative
ISDN, had no protective effects. Insulin
normalized all parameters completely.
Thus, the beneficial effects of PETN on
AT-II induced hypertension may be also
explained by induction of antioxidant mechanisms
and thereby it’s preserved nitrovasodilatory
action. The study shows for the
first time that chronic treatment with an organic
nitrate can improve endothelial dysfunction
and oxidative stress in different
diseased animal models. Insulin completely
normalized all tested parameters in STZinduced
diabetes and thereby identified the
underlying mechanism of cardiovascular
dysfunction to strictly depend on insulin levels
highlighting the clinical importance of
this experimental animal model. In summary,
these so far completely positive animal
experimental data point towards potential
beneficial effects for patients as well. Patients
with coronary artery disease could take
Organische Nitrate
43