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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016
AFRICA
167
The endothelium is involved in the beneficial vascular action
of the glitazones.
21
Various authors have shown that pioglitazone
directly dilates blood vessels by blocking the calcium channels.
11,22
It has been reported that a decrease in blood pressure due to
pioglitazone is due to direct dilation of the vascular smooth
muscles by blocking the calcium channels or reducing total
peripheral resistance.
11,22,23
In vivo
PPAR-alpha and -gamma agonists have been shown
to reduce superoxide generation, restore endothelial dysfunction
and improve vasorelaxation to acetyl choline in the aorta of
diabetic rats.
10,24
Majithiya and colleagues reported that treatment
with pioglitazone reduced blood pressure, reduced oxidative
stress and restored endothelial function in STZ-induced diabetic
rats. The fact that pioglitazone reduced oxidative stress may have
been a cause of the reduction in blood pressure.
The protective effect of pioglitazone against oxidative stress
may prevent the breakdown of NO, which may improve vascular
function. Similar observations were made by Bagi and co-workers
that pioglitazone increased NO bio-availability and reduced
oxidative stress in coronary arterioles of mice with type 2 diabetes.
25
Matsumoto and colleagues reported that chronic treatment with
pioglitazone restored impaired NO-mediated, endothelium-
dependent relaxation in diabetic rat aortae.
26
It has been shown that
reduction in blood pressure in the case of STZ-induced diabetic rats
was NO mediated.
4
Calnek and co-workers reported that PPAR-
gamma agonists increased NO bioavailability in cultured cells.
27
Pioglitazone was shown to directly induce a relaxation
of rat aortae pre-contracted with phenylephrine, which was
inhibited by L-NAME.
10
Similarly, indomethacin-treated vessels
incubated with pioglitazone markedly reduced the phenylephrine
contractions.
3
Although most researchers agree that the
sensitivity to phenylephrine was unchanged during the early
stage of diabetes (up to 12 weeks in STZ-induced diabetic rats),
they disagree on the response to phenylephrine. Agrawal and
McNeill reported an increase in contractility in response to
phenylephrine,
28
Pfaffman and co-workers reported a decrease,
29
and Scarborough and Carrier and White and Carrier reported
no change.
30,31
In contrast, studies that extended the diabetic
duration up to 43–52 weeks have demonstrated a consistent
increase in sensitivity to noradrenaline in rat aortae
32
and
mesenteric arteries
33
from STZ-induced diabetic rats.
-log M Clonidine
9
8
7
6
5
4
Contraction (mg)
400
300
200
100
0
–100
Cont
Pio
Los
Pio + Los
**
*
Fig. 6.
Effects of pioglitazone and losartan on the response of
aortic segments to increasing concentrations of cloni-
dine in the HT group. Cont: control, Pio: pioglitazone,
Los: losartan, Pio
+
Los: pioglitazone
+
losartan. Values
are expressed as mean
±
SEM (
n
=
5). *Cont vs Pio
(
p
=
0.004); *Cont Clo vs Los (
p
=
0.014); *Cont Clo vs
Pio
+
Los (
p
=
0.001).
-log M Clonidine
9
8
7
6
5
4
Contraction (mg)
400
300
200
100
0
–100
–200
–300
–400
Cont
Pio
Los
Pio + Los
#
*
*
Fig. 5.
Effects of pioglitazone and losartan on the response of
aortic segments to increasing concentrations of cloni-
dine in the control group. Cont: control, Pio: pioglita-
zone, Los: losartan, Pio
+
Los: pioglitazone
+
losartan.
Values are expressed as mean
±
SEM (
n
=
14). *Cont
vs Pio (
p
=
0.001); *Cont vs Los (
p
=
0.011);
#
Cont vs
Pio
+
Los (
p
<
0.001).
*
-log M Clonidine
9
8
7
6
5
4
Contraction (mg)
400
300
200
100
0
Cont
Pio
Los
Pio + Los
Fig. 7.
Effects of pioglitazone and losartan on the response of
aortic segments to increasing concentrations of cloni-
dine in DM group. Cont: control, Pio: pioglitazone, Los:
losartan, Pio
+
Los: pioglitazone
+
losartan. Values are
expressed as mean
±
SEM (
n
=
16). *Cont vs Pio
+
Los
(
p
=
0.005).
-log M Clonidine
9
8
7
6
5
4
Contraction (mg)
400
300
200
100
0
–100
Cont
Pio
Los
Pio + Los
Fig. 8.
Effects of pioglitazone and losartan on the response of
aortic segments to increasing concentrations of cloni-
dine in the HT
+
DM group. Cont: control, Pio: pioglita-
zone, Los: losartan, Pio
+
Los: pioglitazone
+
losartan.
Values are expressed as mean
±
SEM (
n
=
13).