The effect of cilostazol on glucose tolerance and insulin resistance in
a rat
model of non-insulin dependent diabetes mellitus.
Reference: Korean J Intern Med 2001;16(2):87-92.
BACKGROUND: It has been reported that many peripheral vasodilating drugs
might improve
insulin resistance. Cilostazol, a antithrombotic agent, increases peripheral
blood flow in
non-insulin dependent diabetic patients. The effect of cilostazol treatment
on insulin resistance in
streptozotocin (STZ)-induced non-insulin dependent diabetic Wistar rats
was examined.
METHODS: About a half of two-day old neonate siblings were injected intraperitoneally
with
STZ and maintained for six months, at which time they were compared with
age-matched control
rats for intraperitoneal glucose tolerance test (IPGTT) and for glucose
infusion rate (GINF) in a
euglycemic hyperinsulinemic glucose-clamp study. After that, these studies
were also performed
after feeding rat chow containing cilostazol (100 mg/kg/day) to rats with
STZ-induced non-insulin
dependent diabetes mellitus for four-weeks and compared with those of age-matched
control
rats. RESULTS: In the intraperitoneal glucose tolerance test studies, plasma
glucose levels of
STZ-induced non-insulin dependent diabetic rats were significantly higher
and plasma insulin
levels significantly lower than those of age-matched control rats in the
age of six months. Glucose
infusion rate was lower in STZ-induced non-insulin dependent diabetic rats
than those of
age-matched control rats. However, after a four-week cilostazol treatment,
glucose infusion rate
of STZ-induced non-insulin dependent diabetic rats was not significantly
different from that of
control rats. CONCLUSION: These findings suggested that cilostazol may
improve insulin
resistance in STZ-induced non-insulin dependent diabetic rats.
Systemic atherosclerosis risk and the mandate for intervention in
atherosclerotic peripheral arterial disease.
Reference: Am J Cardiol 2001;88(7S2):43-7.
Peripheral arterial disease (PAD), characterized by obstruction of the
arteries in the lower limbs,
is an important manifestation of atherosclerosis. There are >10 million
individuals with PAD in the
United States alone, and as the overall population in developed countries
ages, PAD will become
increasingly prevalent. Many individuals with PAD are asymptomatic and
therefore remain
undiagnosed and untreated. Most patients with PAD are at high risk for
having a serious
coronary or cerebrovascular event. Even for patients in whom symptoms,
such as leg pain, are
clearly evident, current treatment strategies tend to ignore the systemic
nature of the disease and
do not reduce overall atherosclerotic risk. Proven medical treatment options
for patients with
intermittent claudication include smoking cessation, exercise, and cilostazol.
Pentoxifylline
appears marginally effective. Several novel therapies for PAD are currently
under investigation.
Of particular interest are the observations from some studies that show
that lipid-lowering therapy
might be of benefit to PAD patients. The results of 2 ongoing prospective
trials of dyslipidemic
therapy in claudicants should further clarify the benefits of reducing
serum lipid levels in patients
with established PAD.
Interplay Between Inhibition of Adenosine Uptake and Phosphodiesterase
Type 3 on Cardiac Function by Cilostazol, an Agent to Treat Intermittent
Claudication.
Reference: J Cardiovasc Pharmacol 2001;38(5):775-83.
SUMMARY: The authors have recently shown that cilostazol, a type 3 cyclic
nucleotide
phosphodiesterase (PDE3) inhibitor, has a much weaker positive inotropic
effect than milrinone,
a PDE3 inhibitor of similar potency. They have also shown that cilostazol
inhibits adenosine
uptake, whereas milrinone has no such effect. This study investigated the
possible cardiac
functional significance of cilostazol on adenosine uptake inhibition. In
isolated rabbit hearts, 10
}mgr; M of cilostazol elevated adenosine concentration in interstitial
dialysate (0.16 +/- 0.01
&mgr; M, or approximately 0.81 &mgr; M in the interstitial space
when adjusted for recovery
rate of microdialysis) and coronary effluent (0.69 +/- 0.03 &mgr; M
). The values are
significantly higher than those for 10 &mgr; M of milrinone (0.11 +/-
0.1 &mgr; M in interstitial
dialysate and 0.2 +/- 0.04 &mgr; M in coronary effluent). Although
cilostazol increased
contractility, heart rate, and coronary flow in isolated rabbit hearts,
the effect on contractility and
heart rate was significantly augmented in the presence of an adenosine
A 1 receptor antagonist.
Conversely, an adenosine A 1 receptor agonist or an adenosine uptake inhibitor
attenuated the
positive inotropic effect of milrinone. These results indicate that adenosine
uptake inhibition by
cilostazol increases interstitial and circulatory adenosine concentration,
and antagonizes PDE3
inhibition-induced contractility and heart rate increases through an adenosine
A 1
receptor-mediated mechanism.
Endothelium-dependent relaxation by cilostazol, a phosphodiesteras III
inhibitor, on rat thoracic aorta.
Reference: Life Sci 2001;69(15):1709-15.
The relaxation effect of cilostazol, a phosphodiesterase III inhibitor,
on the thoracic aorta was
investigated. Cilostazol induced the relaxation of the thoracic aorta precontracted
by
phenylephrine in a concentration-dependent manner. The concentration-dependent
relaxation
was shifted to the right in the endothelium denuded aorta compared with
that of intact
endothelium, suggesting that this relaxation was partly dependent on endothelium.
Cilostazol-induced relaxation of thoracic aorta tone was reversed by treatment
with N(G)-nitro
L-arginine (L-NNA), a competitive inhibitor of nitric oxide (NO) synthase.
Cilostazol also
significantly increased the NO level in the porcine thoracic aorta. In
rats treated with cilostazol,
the urinary excretion of nitrites, a stable metabolite of NO, and basal
production of NO of the
aortic ring were significantly greater than in those without treatment.
These findings indicate that
cilostazol-induced vasodilation of the rat thoracic aorta was dependent
on the endothelium, which
released NO from aortic endothelial cells.
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Volume
4, Number 11: November 2001
