AJH
2006; 19:646 – 653
REVIEW
Actions of Peroxisome Proliferator–Activated
Receptors–␥ Agonists Explaining a Possible
Blood Pressure–Lowering Effect
Panteleimon A. Sarafidis and Anastasios N. Lasaridis
The metabolic syndrome is a cluster of disturbances such
as type 2 diabetes mellitus, hypertension, central obesity,
dyslipidemia, and others for which insulin resistance and
compensatory hyperinsulinemia have been proposed to be
the underlying disorders. Several possible mechanisms linking insulin resistance and compensatory hyperinsulinemia
with hypertension have been described, such as renal sodium
reabsorption enhancement, sympathetic nervous system activation, and blunted insulin-mediated vasodilation caused by
endothelial dysfunction. Peroxisome proliferator–activated
receptors–␥ agonists or thiazolidinediones (TZD) are a class
of agents for the treatment of type 2 diabetes mellitus that act
through improvement of insulin sensitivity. In parallel to their
antihyperglycemic action, these drugs were found to exert
beneficial effects on other components of the metabolic syndrome. For example all TZD have been shown to reduce
blood pressure (BP) levels in both animal and human studies.
In addition a considerable number of in vitro and in vivo
studies report actions of TZD on the cardiovascular system
that could explain this blood pressure–lowering effect of
TZD, such as restoration of blunted endothelium-mediated
vasodilation, attenuation of sympathetic overactivity, inhibition of intracellular Ca2⫹ increase, and proliferation of vascular smooth muscle cells and others. This review summarizes the current evidence about these actions of TZD
that could positively influence BP, representing possible
mechanisms of BP amelioration. Am J Hypertens 2006;
19:646 – 653 © 2006 American Journal of Hypertension,
Ltd.
he term “metabolic syndrome” or “insulin resistance syndrome” refers to a cluster of disorders,
such as type 2 diabetes mellitus (DM), hypertension, central obesity, and dyslipidemia, that are major risk
factors for cardiovascular disease (CVD).1 Insulin resistance (IR) was originally proposed to be the underlying
disorder of the syndrome, causally related to the other
components through various mechanisms.2 An independent association between IR and high blood pressure (BP)
was previously documented,3 but the pathophysiologic
pathways connecting those disorders were not originally
clear. However during the past 15 years several mechanisms potentially linking IR and compensatory hyperinsulinemia with BP elevation were described. For example
the physiologic property of insulin to enhance renal sodium reabsorption was found to be sensitive in insulinresistant states,4 and this was the case for the enhancement
of sympathetic activity from insulin.5 In contrast the ability of insulin to cause endothelium-dependent vasodilation
in normal subjects is blunted in individuals with IR,6 and
T
therefore in insulin-resistant states vasodilation cannot
compensate for the former pressor effects (Fig. 1). Moreover hyperinsulinemia in insulin-resistant states could elevate BP through other actions such as modulation of
transmembrane cation transport and intracellular ion content, ending in increase in intracellular calcium and vasoconstriction7 or promotion of growth of vascular smooth
muscle cells (VSMC).8
Peroxisome proliferator–activated receptors–␥ (PPAR␥)
are nuclear receptors present in various cells such as
adipose tissue cells, VSMC, macrophages, vascular endothelial cells, and others.9 Through transcriptional regulation of various genes, these receptors play an important
role in adipocyte differentiation and lipid and carbohydrate
metabolism.10 The PPAR␥ agonists or thiazolidinediones
(TZD) (troglitazone, pioglitazone, and rosiglitazone) are
oral agents for the treatment of type 2 DM acting through
improvement of insulin sensitivity.9 Accumulating data
suggest that, in addition to their antihyperglycemic properties, TZD present beneficial effects for other metabolic
Received September 5, 2005. First decision December 12, 2005. Accepted December 15, 2005.
From the 1st Department of Medicine, AHEPA University Hospital,
Aristotle University, Thessaloniki, Greece.
Address correspondence and reprint requests to Dr. Panteleimon A.
Sarafidis, 1st Department of Medicine, AHEPA University Hospital,
54006, St. Kiriakidi 1, Thessaloniki, Greece; e-mail: psarafidis11@
yahoo.gr
0895-7061/06/$32.00
doi:10.1016/j.amjhyper.2005.12.017
Key Words: PPAR␥ agonists, troglitazone, pioglitazone, rosiglitazone, blood pressure.
© 2006 by the American Journal of Hypertension, Ltd.
Published by Elsevier Inc.
BLOOD PRESSURE–LOWERING ACTIONS OF PPAR␥ Agonists
AJH–June 2006 –VOL. 19, NO. 6
resistance in insulinstimulated glucose uptake
maintenance of
glucose homeostasis
hyperinsulinemia
actions of insulin on tissues with
preserved insulin sensitivity
kidney
enhanced sodium
reabsorption
CNS
increased
sympathetic
activity
actions of insulin on tissues
with insulin resistance
VSMC
growth
promotion
blood vessels
blunted endotheliumdependent vasodilatation
BP INCREASE
FIG. 1. Possible mechanisms connecting insulin resistance and
compensatory hyperinsulinemia with increase in blood pressure
(BP). CNS ⫽ central nervous system; VSMC ⫽ vascular smooth
muscle cells.
syndrome components such as triglyceride reduction,
HDL-cholesterol elevation, redistribution of body fat away
from the central compartment, and decrease in C-reactive
protein, among others.9
With regard to BP, during the past years several studies
in animal models of IR or hypertension or both have
shown that all TZD can reduce BP or protect against the
development of hypertension.11–20 In patients with various
components of the metabolic syndrome, TZD were also
associated with significant reductions of BP levels.21–28
The clinical magnitude of this BP reduction seems to be
about 4 to 5 mm Hg for systolic BP (SBP) and 2 to
4 mm Hg for diastolic BP (DBP), as indicated from
studies that used ambulatory BP measurements.21,25,27
These findings are supported from the results of the PROspective pioglitAzone Clinical Trial In macroVascular
Events (PROactive), the first prospective outcome trial
with a TZD, in which pioglitazone was associated with a
median change of ⫺3/⫺2 mm Hg (P ⫽ .03 for SBP and
P ⫽ .13 for DBP versus placebo respectively), although
the study was not designed to assess differences in BP.29
This possible effect of TZD on BP cannot be overlooked in
view of the evidence connecting BP levels to cardiovascular mortality, according to which a decrease of 10 mm
Hg in SBP or 5 mm Hg in DBP would be associated in the
long term with about 40% and 30% lower risk of death
from stroke and ischemic heart disease (IHD) respectively,
and even a 2– mm Hg lower SBP would involve about
10% and 7% lower stroke and IHD mortality, respectively,
throughout middle age.30
In parallel to BP decrease, in many of the abovementioned animal studies12,13,14,18,20 and human studies,21,23,24,26 –28 reductions in plasma insulin or improvement of insulin sensitivity were observed. These
findings support a connection of IR and hyperinsulinemia
647
reversion with BP amelioration, which is in agreement
with the “prohypertensive” effects of hyperinsulinemia in
insulin-resistant states.4 – 8 However animal studies indicate that the effect of PPAR␥-agonism on BP could also be
independent of IR changes. For example it was noted that
a specific negative PPAR␥ mutation in mice is phenotypically associated with hypertension but not IR,31 and that
treatment of mice with PPAR␥ disruption in endothelial
cells with a TZD cannot prevent high-fat diet–induced BP
increase but can lower serum insulin levels.32 In addition
the particular effect of troglitazone on BP could be in part
related not to PPAR␥ activation but to the vitamin-E
moiety of this compound, inasmuch as animal data indicate that dietary vitamin-E supplementation attenuates
BP increase.33 However this hypothesis is not particularly
strong, as human studies of vitamin E and BP are restricted
and give conflicting results,34,35 and the above-mentioned
data21–28 do not support a more pronounced effect of
troglitazone on BP in comparison to the other TZD. It
seems that no firm conclusions can be drawn on this; a
comparison of the BP effect of all TZD in human subjects
is unlikely because troglitazone was associated with severe hepatotoxicity and cases of liver failure and was
withdrawn from clinical use in 2000.9
Overall the determination of pathways through which
attenuation of IR and hyperinsulinemia contribute to BP
reduction or even possible direct TZD actions that have a
beneficial impact on BP seems very interesting. This review summarizes evidence from in vitro, animal, and
human studies on actions of TZD that could represent
possible mechanisms of BP amelioration and could explain, at least in part, the positive effect of these drugs.
Data From In Vitro
and Animal Studies
Studies on Intracellular Cation Changes,
Vascular Tone and Endothelial Function
Troglitazone was previously shown to inhibit L-type
Ca2⫹ currents in rat aortic VSMC36 and to decrease
Ca2⫹ influx and cytosolic Ca2⫹ concentration in VSMC,
thereby causing relaxation in strips of porcine coronary
artery.37 In animal studies, troglitazone reduced intracellular Ca2⫹ concentration in fructose-fed borderline hypertensive rats,13 attenuated the impaired insulin-mediated
skeletal muscle vasodilation noted in sucrose-fed rats38
and increased endothelium-dependent aortic relaxation in
Otsuka Long-Evans Tokushima Fatty rats.39
Pioglitazone was also shown to reduce the voltagegated (L-type) Ca2⫹ currents in cultured and freshly dissociated rat artery VSMC.40 Buchanan et al14 observed
that pioglitazone blunted the contractile responses of aortic rings to norepinephrine, arginine-vasopressin, and potassium chloride, and that the blunting of the responses to
norepinephrine was maintained after removal of the endothelium. To examine this further the investigators measured
648
BLOOD PRESSURE–LOWERING ACTIONS OF PPAR␥ Agonists
contractile responses to norepinephrine in the absence and
after acute restoration of calcium. Pioglitazone had no
effect on the contractile response in the absence of calcium
but blunted by 42% the response that occurred when the
extracellular calcium supply was restored. These findings
suggest that pioglitazone action was at least partly mediated by blockade of calcium VSMC uptake, which was
supported by the dose-dependent blocking with pioglitazone of the intracellular Ca2⫹ increase in response to
arginine-vasopressine.14 In another study pioglitazone was
found to attenuate the force of contractions produced by
either potassium (through membrane depolarization) or
norepinephrine in intact rat-tail arterial tissue rings, in
contrast to glyburide.41
Kotchen et al16 reported that vasodilation in response to
graded dose of acetylcholine was reduced in strips of the
aorta of fructose-fed Sprague-Dawley rats compared
with controls but was normal in fructose-fed rats receiving pioglitazone, a finding suggesting that BP attenuation in the latter could be associated with normalization
of endothelium-dependent vasodilation. Verma et al42
showed that pioglitazone markedly inhibited argininevasopressin and norepinephrine responses in aortae and
mesenteric arteries from spontaneously hypertensive rats
(SHR) without affecting responses to potassium chloride,
concluding that the antihypertensive action of pioglitazone
may be mediated by a direct vasodepressor effect. In rats
receiving angiotensin II, both pioglitazone and rosiglitazone normalized, increased media/lumen ratio, and impaired acetylcholine-induced vasorelaxation of mesenteric
arteries, an action probably contributing to the attenuation
of hypertension development.43
Finally rosiglitazone was found to reduce the voltagegated Ca2⫹ currents in rat aorta cells, although less
potently than troglitazone.36 Walker et al18 noted that
maximal acetylcholine-induced relaxation of norepinephrine-induced constriction of mesenteric arteries was impaired in untreated fatty Zucker rats versus controls, but
this defect was partially prevented in rosiglitazone-treated
rats. Insulin-induced attenuation of the contractile response to norepinephrine was also blunted in fatty Zucker
rats and also restored by rosiglitazone treatment. In a
recent study, Ryan et al used a transgenic hypertensive
murine model expressing both human renin and angiotensinogen transgenes, that is, R(⫹)A(⫹), and observed
that relaxation of carotid arteries to acetylcholine and
nitric oxide (NO) was impaired in untreated R(⫹)A(⫹)
when compared with littermate controls, that is, RA(⫺);
but it was significantly improved in rosiglitazone-treated
R(⫹)A(⫹) mice.19 Moreover the investigators showed
that carotid arteries from R(⫹)A(⫹) and RA(⫺) mice
relaxed in a concentration-dependent manner to rosiglitazone and this response was not inhibited from a NO
synthase inhibitor or a PPAR␥ antagonist, findings suggesting that rosiglitazone could exert direct endotheliumand PPAR␥-independent effect in blood vessels, which
may contribute to improved BP and vessel function.19
AJH–June 2006 –VOL. 19, NO. 6
Another interesting study aimed to evaluate the effect
of rosiglitazone treatment on the reduced muscle vasopermeability of the fructose-fed rat, according to the hypothesis that obliteration of muscle regional microcirculation
might lead to restricting access of nutrients and hormones
to their target cells, and therefore in IR, and hypertension.20 Apart from BP lowering, rosiglitazone produced a
significant increase of 30% to 50% in muscle vasopermeability, regardless of the skeletal muscle group studied,
and significant increases in NO synthase (NOS) activity
and endothelial NOS immunoreactive mass compared
with values in controls. These findings indicate that endothelium-dependent improvement in muscle microcirculation could be an additional mechanism of IR and BP
improvement.
Studies on Cell Growth
In all major cells of the vasculature including VSMC,
PPAR␥ receptors have been found44,45; and all TZD have
been shown to inhibit VSMC proliferation in vitro at drug
levels that are achieved when patients take the usual
hypoglycemic doses of these drugs. In particular, troglitazone was found to inhibit VSMC proliferation induced by
various substances such as PDGF, basic fibroblast growth
factor (bFGF), insulin and angiotensin II,45– 48 and rosiglitazone to inhibit VSMC proliferation induced by bFGF.45
In addition TZD were shown to inhibit the proliferation of
other cell types. For example, de Tios et al reported that
troglitazone inhibited the proliferation of cultured bovine
aortic endothelial cells, whereas rosiglitazone did not.49
Moreover troglitazone and rosiglitazone inhibited PDGFinduced DNA synthesis in cultured primary rat mesangial
cells,50 and troglitazone also decreased glomerular cell
proliferation in a rat model of nondiabetic glomerulosclerosis.51
In an earlier study pioglitazone was shown to inhibit
proliferation of cultured preglomerular renal rat VSMC
induced by insulin, epidermal growth factor, or fetal calf
serum.52 Yoshimoto et al observed that pioglitazone prevented renal arteriolosclerosis and aortic medial wall
thickening in genetically obese diabetic Wistar fatty rats.15
In another study from the same investigative group pioglitazone decreased carotid neointimal thickening after
endothelial injury in Wistar rats and the medial wall thickness of the mesenteric artery in stroke-prone SHR, findings supporting an in vivo vasculoprotective effect of the
drug both in acute vascular injury and in chronic hypertensive vascular hypertrophy through inhibition of VSMC
proliferation.53
In rats receiving angiotensin II both pioglitazone and
rosiglitazone were found to normalize cell growth and to
prevent upregulation of cell cycle proteins and proinflammatory mediators induced by angiotensin II.43 Moreover,
Iglarz et al reported that rosiglitazone abrogated the increase in endogenous production of endothelin-1 in the
mesenteric vasculature of hypertensive DOCA-salt rats,
AJH–June 2006 –VOL. 19, NO. 6
BLOOD PRESSURE–LOWERING ACTIONS OF PPAR␥ Agonists
which overexpress endothelin-1, and prevented hypertrophic vascular remodeling, increase in vascular superoxide
anion production, and progression of hypertension.54
It is worth noting that an intracellular mechanism
through which PPAR␥ activation inhibits VSMC proliferation has been also described. The TZD block events that
are critical for the re-entry of quiescent VSMC into the
cell cycle, that is, formation and activation of cyclin and
cyclin-dependent kinase (CDK) complexes. This is not a
result of intervention with cyclin or CDK levels, as troglitazone and rosiglitazone have not been found to affect
them, but rather of attenuation of the mitogen-induced
degradation of a CDK inhibitor, p27Kip1, which negatively
regulates growth in a variety of cell types including
VSMC.44,55
Studies on Renal Functions and
Membrane Ion Transport Changes
Troglitazone was reported to increase sodium excretion,
sodium/potassium ratio, and creatinine clearance in obese
Zucker rats.11 Fujiwara et al12 observed that the pressure–
natriuresis curve was shifted to higher renal perfusion
pressure and the basal renal nitrate/nitrite levels were
reduced in obese Zucker rats compared with lean Zucker
rats, disturbances that were both improved by troglitazone
treatment. An increase in renal nitrate/nitrite excretion,
along with increased expression of renal endothelial and
neuronal NO synthase, was recently documented with
pioglitazone treatment in obese hypertensive SpragueDawley rats. In that study pioglitazone also decreased urinary isoprostanes and renal lipid peroxides, and the authors
concluded that the drug prevented hypertension and renal
oxidative stress both by increasing NO availability and by
reducing free-radical production.17
Another interesting pathway connecting hyperinsulinemia with BP elevation was described by Umrani et al.56
This group tested the hypothesis that a defective dopamine
D1–like receptor function, accompanied by reduction in
D1 receptor numbers and inability of dopamine to inhibit
Na⫹-K⫹-ATPase and Na⫹/H⫹-exchanger in the proximal
tubules of obese Zucker rats, was a result of hyperinsulinemia, by treating such animals with rosiglitazone. At study
end, rosiglitazone treatment caused significant decreases
in plasma insulin and BP and a significant increase in renal
sodium excretion compared with values in untreated rats.
In parallel rosiglitazone restored both the number of D1
receptor and the inhibitory effect of dopamine on Na⫹K⫹-ATPase in the isolated proximal tubular membranes of
treated rats. In another set of experiments, treatment of
primary proximal tubule epithelial cells in culture with
insulin caused a decrease in D1 receptor abundance, suggesting a direct role of insulin on D1 receptor regulation
and allowing the investigators to conclude that hyperinsulinemia causes downregulation of D1 receptor function,
blunted dopamine-mediated Na⫹-K⫹-ATPase and Na⫹/
H⫹-exchanger inhibition and therefore sodium retention,
649
whereas lowering of insulin levels leads to restoration of
this impairment.56 Blunted coupling of D1A receptors to
G proteins and impaired dopamine-induced recruitment of
D1A receptors to the plasma membrane of obese Zucker
rats were shown to be responsible for this defective dopamine D1-like receptor function. Rosiglitazone treatment
both reversed these disturbances and restored the natriuretic and diuretic response to a D1A receptor agonist,
which was diminished in untreated obese Zucker rats.57
In addition, in the study of de Tios et al,49 troglitazone
was associated with a significant inhibition of Na⫹/H⫹
exchanger activity in cultured endothelial cells, whereas
rosiglitazone had no significant effect. In borderline hypertensive rats troglitazone was shown to reduce platelet
Na⫹/H⫹ exchanger activity that was elevated with a fructose-rich diet, along with induction of hyperinsulinemia
and BP increase. This change in Na⫹/H⫹ exchanger activity was positively correlated with the change in plasma
insulin levels.13
Studies on Additional Mechanisms
In sucrose-fed SHR, pioglitazone attenuated the development of hypertension and also significantly reduced
the urinary excretion of catecholamines and plasma
renin activity, findings suggesting that a reduction in
sympathetic nervous system or renin-angiotensin system activity could also participate in TZD-associated
lowering of BP.58 Aubert et al studied the effect of insulin
on the secretion of angiotensinogen from the adipose
tissue, which is an important source of body angiotensinogen.59 Within a physiologic range of concentrations, insulin exerted a negative effect on angiotensinogen gene
expression and secretion from cultured adipocytes,
whereas attenuation of IR with rosiglitazone led respectively to an increase in the potency of insulin to downregulate angiotensinogen gene expression by about 60%,
introducing a new mechanism linking IR improvement to
lowering of BP. In addition troglitazone has been found to
downregulate the expression of angiotensin II type 1
(AT1) receptor mRNA and to reduce the expression of
AT1 receptor protein in VSMC.60 These findings could
explain the above-mentioned inhibition of angiotensin II–
induced VSMC proliferation with troglitazone.48 Furthermore this reduction of AT1 receptor expression in the
surface of VSMC could blunt an even more important
mechanism for BP increase, the direct vasoconstrictive
effect of angiotensin II. Findings from the study of Takeda
et al60 support this possibility too, inasmuch as, apart from
AT1 receptor reduction, troglitazone also inhibited the
intracellular calcium response of VSMC to angiotensin II.
Taken together the above data from in vitro and
animal studies strongly indicate that TZD have vasodilating properties, as they have been found to produce
direct attenuation of vasoconstriction through inhibition
of intracellular Ca2⫹ increase in VSMC and to restore
blunted endothelium-mediated vasodilation in insulin-
650
BLOOD PRESSURE–LOWERING ACTIONS OF PPAR␥ Agonists
resistant animals. In addition, stimulation of PPAR␥ with
TZD inhibited proliferation of VSMC or other cell types
induced by insulin or various growth factors, an action that
could protect against the atherosclerotic processes that
contribute in the development of hypertension. The TZD
could also protect from BP elevation through other possible
mechanisms such as attenuation of the sodium-retaining
property of insulin and interference with the sympathetic
nervous system or the renin-angiotensin system; but these
actions need to be further investigated.
Data From Human Studies
Studies of Vascular Tone
and Endothelial Function
In human studies the most extensively studied actions of
TZD among those that possibly lower BP are these related
to the vascular function. In the first study evaluating the
effect of a TZD in vasodilation in human beings in vivo,
Fujishima et al examined 11 lean healthy male volunteers
after a single oral dose of 200 mg of troglitazone.61 Forearm blood flow (FBF) showed significant reduction and
forearm vascular resistance a respective decrease with
troglitazone, whereas both of these parameters did not
change during the control recordings obtained without the
drug. Glucose and insulin levels did not change but serum
concentrations of nitrate ions decreased significantly after
troglitazone administration, findings suggesting that troglitazone increases muscular vasodilation by a mechanism
other than the hyperinsulinemia correction or NO increase.
In a cardiac safety study in patients with type 2 DM, Ghazi
et al reported together with a decrease in office DBP a
significant decrease in peripheral vascular resistance that
was possibly responsible for the increases of stroke volume and cardiac output.22 Sung et al23 also noted a significant reduction in peripheral vascular resistance with
troglitazone; but heart rate, stroke volume, and cardiac
output were not affected in their study.
Pioglitazone reduced pulse wave velocity (PWV) in
patients with type 2 DM up to after 12 months of treatment,62 findings consistent with an increase in the elastic
properties of the aorta. Rosiglitazone was associated with
significant decrease in systemic vascular resistance and
significant increase in small artery elasticity, along with an
insignificant increase in large artery elasticity in patients
with type 2 DM.26 In postmenopausal women with type 2
DM, however, rosiglitazone was shown to produce a significant increase in compliance in large proximal arteries,
as measured by the distensibility index.63 In a long-term
study, Stakos et al made different observations, as lowdose troglitazone treatment led to an increase in PWV.64
However this finding must be interpreted carefully because the study population consisted of offspring of patients with type 2 DM who normal glucose tolerance and
who probably had much less IR and arteriosclerotic vascular damage than did patients with type 2 DM.
As far as endothelial function is concerned, in patients
AJH–June 2006 –VOL. 19, NO. 6
with peripheral vascular disease and occult DM blunted
brachial artery vasoactivity, an in vivo index of arterial
endothelial function, was normalized after 4 months of
treatment with troglitazone.65 Troglitazone was also found
to improve the impaired flow-mediated dilation of the
brachial artery in subjects with hyperinsulinemic response
to oral glucose load, an improvement that was inversely
correlated with the change in the area under the curve for
insulin.66 Moreover Paradisi et al showed that troglitazone
improved impaired endothelial function in women with
polycystic ovary syndrome to near normal levels, as after
3 months of troglitazone treatment the maximal leg blood
flow increments after administration of metacholine hydrochloride were significantly improved and were very
close to those achieved from control obese women.67
In another study in patients with type 2 DM, Natali et al
noted a significant improvement in the slope of the FBF
response to intra-arterial acetylcholine infusion with rosiglitazone, along with a reduction in ambulatory DBP after
16 weeks of treatment, whereas no change in those parameters was observed with either metformin or placebo.
However FBF response to blockade of NO synthase were
not affected by either treatment.27 Vinik et al68 investigated the effect of rosiglitazone on in vivo NO production
from the skin microvascular bed in patients with type 2
DM. Nitric oxide production was significantly elevated by
rosiglitazone and this increase was almost significantly
correlated with the change in fasting serum C-peptide
levels (r ⫽ ⫺0.65, P ⫽ .08), data supporting a restoration
of blunted endothelial function with TZD treatment. In a
cross-over trial rosiglitazone and nateglinide were administered in patients with recently diagnosed type 2 DM.69
Although the two drugs produced comparable improvements in glycemic control, rosiglitazone produced a 60%
greater decrease in IR compared with nateglinide, along
with a higher increase in FBF in response to acetylcholine
infusion with or without co-infusion of exogenous insulin.
This increased vasodilation with rosiglitazone was largely
prevented by N-monomethyl-L-arginine-acetate, an antagonist of NO synthase regardless of the presence or absence
of insulin.
Studies on Sympathetic
Nervous System Activity
In addition to the above, a few human studies have evaluated the effect of TZD on sympathetic activity. Yosefy
et al randomized 48 subjects with type 2 DM, hypertension, and hyperlipidemi treated for 4 weeks with cilazapril
and simvastatin to additional treatment with rosiglitazone
or glibenclamide for 8 weeks.28 Rosiglitazone produced
reductions of plasma insulin, SBP, and DBP, which were
accompanied from a decline in sympathetic skin activity,
measured as sympathetic skin potentials with a computerized electromyographic device, whereas in the glibenclamide group plasma insulin, SBP, and skin sympathetic
activity were increased. Finally Watanabe et al70 showed
AJH–June 2006 –VOL. 19, NO. 6
BLOOD PRESSURE–LOWERING ACTIONS OF PPAR␥ Agonists
that the addition of troglitazone on the antihypertensive
treatment of patients with mild hypertension for 6 months
was associated with clinic BP reduction and improvement
of cardiac sympathetic nervous dysfunction (evaluated
using the heart-to-mediastinum ratio and mean washout
rate measured by 123I-meta-iodobenzylguanidine cardiac
imaging), changes that were significantly correlated with
the change in IR.
Conclusions
Hypertension is established as one of the basic components of the metabolic syndrome, as several mechanisms
connecting IR and compensatory hyperinsulinemia to BP
elevation have been elucidated over the last few years. The
introduction of TZD has provided new perspectives for the
integrated treatment of patients with the metabolic syndrome, as IR amelioration with these drugs could be
shown to be beneficial for disorders of the syndrome other
than type 2 DM. Data from animal and human studies
have persistently shown that all TZD can slightly lower
BP or protect against the development of hypertension.
In support of these findings, a considerable number of
studies provide evidence for actions of TZD that can
attenuate some of the mechanisms linking IR with BP
elevation or that have a direct decremental effect on BP. In
vitro data strongly indicate that TZD attenuate intracellular Ca2⫹ increase in VSMC, inhibit the proliferation of
various vascular cell types, and reduce the expression of
AT1 receptor protein in VSMC. Ex vivo and in vivo
studies suggest that these compounds restore blunted endothelial function and thus promote vasodilation and attenuate sympathetic overactivity of insulin-resistant states.
All of these data represent important mechanistic explanations of a possible beneficial action of TZD on BP.
However further research is undoubtedly needed in regard
to the mechanisms responsible for this BP amelioration, in
parallel to clinical trials and sufficient to provide definite
answers for the magnitude of the effect of TZD on BP. In
view of the importance of the metabolic syndrome components for cardiovascular morbidity and mortality and the
great benefit that patients can derive from even small
decreases in BP,30 this clarification of the properties of
TZD properties seems of particular interest. If the beneficial effect of TZD on BP is confirmed, these agents could
be a valuable therapeutic tool for the patients at high-risk
within the frame of a multifactorial intervention.
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