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RESEARCH ARTICLE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
24
VOLUME 14 NUMBER 1 • JULY 2017
Effects of a PPAR-gamma receptor agonist and an
angiotensin receptor antagonist on aortic contractile
responses to alpha receptor agonists in diabetic and/or
hypertensive rats
Ibrahim Tugrul, Turhan Dost, Omer Demir, Filiz Gokalp, Ozlem Oz, Necip Girit,
Mustafa Birincioglu
Correspondence to: Ibrahim Tugrul
Turhan Dost, Omer Demir, Filiz Gokalp, Ozlem Oz, Necip Girit, Mustafa
Birincioglu
Department of Medical Pharmacology, Faculty of Medicine,
Adnan Menderes University, Aydin, Turkey
Previously published in
Cardiovasc J Afr
2016;
27
: 164–169
S Afr J Diabetes Vasc Dis
2017;
14
: 24–28
Abstract
Aim:
The aim of this study was to investigate the effects
of pioglitazone and losartan pre-treatment on the aortic
contractile response to the alpha-1 agonist, phenylephrine,
and the alpha-2 agonist, clonidine, in L-NAME-induced
hypertensive, STZ-induced diabetic, and hypertensive
diabetic rats.
Methods:
Male Wistar rats were randomly allocated to four
groups: control, diabetic (DM), hypertensive (HT) and
hypertensive diabetic (HT + DM) groups. Three weeks
after drug application,
in vitro
dose–response curves to
phenylephrine (Phe) (10-9–10-5 M) and clonidine (Clo) (10-9–
10-5 M) were recorded in aortic rings in the absence (control)
and presence of pioglitazone (10 µM) and/or losartan
(10 µM).
Results:
Pioglitazone and losartan caused a shift to the
right in contractile response to phenylephrine in all groups.
The sensitivity of the aortic rings to phenylephrine was
decreased in the presence of pioglitazone and/or losartan in
all groups. The contractile response of clonidine decreased in
the presence of pioglitazone and/or losartan in the control,
HT and DM groups.
Conclusion:
The sensitivity of aortic rings to alpha-1 and
alpha-2 adrenoceptors was decreased in the presence of
pioglitazone and/or losartan in diabetic and hypertensive
rats. Concomitant use of PPAR-gamma agonists, thiazolidine-
diones, and angiotensin receptor blockers may be effective
treatment for diabetes and hypertension.
Keywords:
diabetes, hypertension, pioglitazone, losartan, alpha
adrenoceptors
Hypertension and diabetes mellitus are both common diseases
worldwide and they co-exist frequently, resulting in significant rates
of morbidity and mortality. Diabetes mellitus and hypertension
have been identified as risk factors for cardiovascular disease and
cause altered vascular responsiveness to several vasoconstrictors
and vasodilators.
1-3
Endothelium-dependent vasodilation is reduced
in diabetes, largely due to excessive oxidative stress and the
bio-availability of nitric oxide. Endothelium-derived nitric oxide
(NO) is a potent endogenous nitrovasodilator and plays a major
role in modulation of vascular tone.
4
NG-nitro-L-arginine methyl
ester (L-NAME)- induced hypertension has been one of the most
frequently used models of experimental hypertension since 1990.
5
Thiazolidinediones (TZDs) such as pioglitazone are a class of
oral antidiabetic agent that act primarily by decreasing insulin
resistance. Drugs in this class act as potent and highly selective
agonists for peroxisome proliferator-activated receptor gamma
(PPARg).
6
Pioglitazone repairs blunted endothelium-dependent
vasodilatation, protects against oxidative stress and lowers blood
pressure.
7-11
The vascular endothelium mediates relaxant responses
to a wide range of vasodilators and modulates the constrictor
responses to alpha agonists such as phenylephrine and clonidine.
The streptozotocin (STZ)-induced diabetic rat model has been
widely used to study changes in vascular reactivity to alpha
adrenoceptor agonists.
12
Hyperglycaemia is likely to modulate
physiological responses to angiotensin II and may contribute to
the pathogenesis of vascular dysfunction in diabetes.
13
Angiotensin
type 1 receptor (AT1R) blockers (ARBs) such as losartan are widely
used in the treatment of hypertension.
14,15
It is not clear how concomitant use of medication in the
treatment of hypertension and diabetes has effects on vascular
contractility. Hence the aim of this study was to investigate the
effect of pioglitazone and losartan pre-treatment on the aortic
contractile response to the alpha-1 agonist, phenylephrine (Phe),
and the alpha-2 agonist, clonidine (Clo), in L-NAME-induced
hypertensive, STZ-induced diabetic, and hypertensive diabetic rats.
Methods
Male Wistar rats (250–300 g) were obtained from the experimental
animal centre of Adnan Menderes University and all experiments
were performed according to the principles and guidelines of the
Adnan Menderes University animal ethics committee. Male Wistar
rats were randomly allocated to four groups: a control group (Cont)
(
n
= 15), a diabetic group (DM) (
n
= 20), a hypertensive group (HT)
(
n
= 20), and a hypertensive diabetic group (HT + DM) (
n
= 20).
All rats were housed at 22–24°C on a 12-hour dark–light cycle
and received food and water (or L-NAME solution in drinking water
in the hypertensive groups) ad libitum. Diabetes was induced by a