Cardiovascular Journal of Africa: Vol 27 No 3 (May/June 2016)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016 164 AFRICA
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
Abstract
Aim: The aim of this study was to investigate the effects of
pioglitazone and losartan pre-treatment on the aortic contrac-
tile 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 hyper-
tensive 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
Submitted 27/3/15, accepted 4/10/15
Published online 4/5/16
Cardiovasc J Afr 2016; 27: 164–169
DOI: 10.5830/CVJA-2015-080
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
Department of Medical Pharmacology, Faculty of Medicine,
Adnan Menderes University, Aydin, Turkey
Ibrahim Tugrul, MD,
Turhan Dost, MD
Omer Demir, MD
Filiz Gokalp, MD
Ozlem Oz, MD
Necip Girit, MD
Mustafa Birincioglu, MD