Clinical and Experimental Pharmacology and Physiology (2006) 33, 407414

BRIEF REVIEW

Obesity
DW
Stepp
andPublishing
insulin resistance
on blood flow
Blackwell
Ltd

IMPACT OF OBESITY AND INSULIN RESISTANCE ON VASOMOTOR

TONE: NITRIC OXIDE AND BEYOND
David W Stepp
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, USA

SUMMARY
1. Obesity is rapidly increasing in Western populations,
driving a parallel increase in hypertension, diabetes and vascular
disease. Prior to the development of overt diabetes or hypertension, obese patients spend years in a state of progressive insulin
resistance and metabolic disease. Mounting evidence suggests
that this insulin-resistant state has deleterious effects on the
control of blood flow, thus placing organ systems at a higher risk
for end-organ damage and increasing cardiovascular mortality.
2. The purpose of the present review is to examine the current
literature on the effects of obesity and insulin resistance on the
acute control of vascular tone. Effects on nitric oxide (NO)mediated control of vascular tone are particularly examined
with regard to proximal causes and distal mechanisms of the
impaired NO-mediation of vasodilation.
3. Finally, novel pathways of impaired control of perfusion
are summarized from the recent literature to identify new
avenues of exploring impaired vascular function in patients with
metabolic disease.
Key words: adrenergic, angiotensin II, endothelin, endothelium, insulin resistance, sympathetic.

INTRODUCTION
Obesity is a rapidly expanding epidemic in Western cultures, with
rates of over 30% in the US and across Europe.14 The obese population is one of the most at-risk populations for cardiovascular
mortality and morbidity, but the links between the comorbidities
of obesity and the cardiovascular outcomes remain unclear. Obese
individuals spend their lives in a slow progression towards type II
diabetes, a state of insulin resistance (IR) characterized by impaired
glycaemic control, dyslipidaemia and high plasma insulin levels.5
This progression has led to the realization that IR is itself a risk factor
for cardiovascular (CV) dysfunction, but the underlying effects of
IR on vascular function are yet to be fully determined.6,7

Correspondence: Dr David W Stepp, Vascular Biology Center, Medical

College of Georgia, 1459 Laney Walker Blvd, Augusta, GA 30912-2500,
USA. Email: dstepp@mail.mcg.edu
Received 13 May 2005; revision 12 December 2005; accepted 22
December 2005.
2006 The Author
Journal compilation 2006 Blackwell Publishing Asia Pty Ltd

Prominent among the effects of obesity and IR on CV health are

an increased incidence of atherosclerosis and hypertension.810
Although large vessel and renal disease have been studied intensively, more recent evidence suggests that alterations in peripheral
microvascular function and the control of vascular tone may also
represent a site of pathology in obese and IR patients. Microvascular
alterations relative to organ perfusion can be divided into two basic
types: (i) alterations in chronic perfusion; and (ii) alterations in acute
adjustments in vascular resistance. Changes in chronic perfusion
often reflect changes in the structure and/or number of capillaries
or small arteries in a given tissue. The skeletal muscle circulation of
obese Zucker rats shows rarefaction11,12 and structural remodelling,13
although these phenomena remain largely unexplored in most vascular beds. Also of interest are observations in insulin-mediated control of tissue perfusion. Because insulin is both a vasodilator and an
anabolic hormone, it has been suggested that the two functions act
in concert to link perfusion and glucose uptake.14,15 Such a relationship would likely be corrupted in IR and, indeed, obese Zucker
rats show impaired insulin-induced dilation16,17 and glucose uptake,16
with no impairment in glucose uptake or capillary recruitment
secondary to simulated exercise.18 This relationship has been reviewed
previously1921 and, thus, the present review will focus on the second
category, namely acute control of vascular resistance.
In addition to the aforementioned CV complications, obesity and
the metabolic syndrome are a major risk factor for acute coronary
events such as myocardial infarction (MI) and stroke.22,23 Data from
the National Health and Nutrition Examination Survey (NHANES)
III trial indicate that obesity and the metabolic syndrome are greater
risk factors for coronary disease than type II diabetes alone and that
the combination of type II diabetes and the metabolic syndrome were
essentially additive.23 The severity of an acute event is significantly
influenced by the control of vascular tone. Vascular tone is controlled
by endogenous dilators (i.e. nitric oxide (NO), adenosine) or constrictors (i.e. endothelin, noradrenaline) that cause acute adjustments
in resistance, thus matching perfusion to functional demand. Superimposed on these adjustments are hormonal (i.e. angiotensin) and
neural (i.e. sympathetic) factors that fine-tune resistance to preserve
whole-body haemodynamics. Inadequate control of vascular tone
may limit perfusion and exacerbate ischaemia or fail to limit perfusion and result in over-pressurization, the net result of either condition worsening end-organ damage. The focus of the present review
will be the acute control of vascular resistance in response to major
vasodilator and constrictor stimuli. The aims are twofold: (i) to
examine the evidence presented to date that obesity impairs

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DW Stepp

NO-mediated vasodilation; and (ii) to review novel mechanisms of

impaired control of organ blood flow in obesity and IR.

IMPACT OF OBESITY ON NO SIGNALLING

Seminal work from late 1970s and early 1980s revolutionized our
understanding of the role of the endothelium in controlling vascular
tone.24,25 A key endothelial dilator was later identified as NO by
Ignarro et al.26 and, to date, a significant body of literature has
emerged examining the loss of NO as a cardinal mechanism of
cardiovascular dysfunction.
Understanding the impact of obesity on NO-mediated vasodilation in humans has been confounded by the common copresentation
of other comorbid conditions (hypertension, type II diabetes), which
were previously known to impair NO-dependent function as assessed
by measurements of forearm blood flow or plasma NO metabolites.
In 1996, Steinberg et al.27 demonstrated that endothelium-dependent
vasodilation of the leg circulation was impaired in obese patients
with metabolic dysfunction, but not in patients with only clinical
hypertension or frank type II diabetes. Similar results were later
reported in the forearm circulation2831 and the coronary circulation.32
Thus, it now seems likely that obesity and its concomitant metabolic
conditions can impair NO-mediated dilation in human patients prior
to and independent of hypertension and the onset of type II diabetes.

IMPAIRED RELAXATION TO NO IN OBESITY:

IS INSULIN RESISTANCE THE CAUSE?
The consensus that impaired NO-mediated dilation may be an early
cardiovascular dysfunction in obese, prediabetic patients has led to
a vigorous examination of potential mechanisms. Animal studies
afford the ability to perform high-resolution mechanistic studies, but
the literature is often clouded by confusion over whether animal
models best represent the prediabetic, IR state or more overt type
II diabetes. Figure 1 illustrates the progressive nature of IR and
subsequent diabetes with animal model labels at key points. A key
difference among different animal strains that distinguishes IR
models versus frank type II diabetic models regards the severity of
the intervention and the fragility of the pancreas. For example,
mutant db/db mice are found in two commercially available strains,
namely C57BL6 and C57BLKS. The C57BLKS strain demonstrates
early and severe depletion of pancreatic b-cells, resulting in uncontrolled hyperglycaemia and early mortality.33 The C57BL6 strain
demonstrates a more stable pancreas with limited hyperglycaemia
until much later in life, despite similar levels of obesity. Thus, the
former strain can be considered a better model of frank type II
diabetes and the latter a better model of prediabetic IR. A similar
paradigm exists for the fa/fa obese Zucker rat (OZR) and the Zucker
diabetic fatty (ZDF), in which the latter is characterized by early
pancreatic dysfunction.34,35 For the purpose of the present review, the
focus will be on data from prediabetic obese and IR animal models.
The two models that have provided most of the known mechanistic
information are the OZR and the fructose-fed rat. The OZR provides
a solid model of obesity induced insulin resistance,36 whereas the
non-obese fructose-fed model provides a moderate form of insulin
resistance more similar to early stages of metabolic dysfunction.37
Nitric oxide-mediated dilation has been examined in several vascular
beds in the OZR. Studies from aortic preparations have yielded
conflicting results, in which some have documented no difference

Fig. 1 A schematic depicting the progression of insulin resistance through

type II diabetes in terms of plasma glucose (
) and insulin (-----)
concentrations. Arrows indicate animal models that best mimic the denoted
degree of progression. OZR, obese Zucker rat; FF-R, fructose-fed rat; ZDF,
Zucker diabetic fatty. Lower case italicized letters refer to strain designation.

or even a hyperreactivity of endothelium-dependent vasodilation,3840

whereas others have reported impairment.41 Subsequent studies in
the microcirculation have largely yielded more consistent results.
Impaired NO-mediated dilation has been documented in the cerebral,4244 coronary,17 mesenteric,45,46 renal4749 and skeletal muscle50
circulations. Mesenteric microvessels from the ob/ob mouse strain
have also been found to show impaired NO-dependent vasodilation,
providing parallel results in leptin-deficient, as opposed to leptin
receptor-deficient, animals.51 The ubiquity of this finding across
several circulatory beds suggests that the root cause of impaired NOmediated vasodilation may lie in the plasma, the one component of
the body that touches all circulations. Several candidate factors have
been suggested, including glucose,52,53 free fatty acids,54,55 leptin56
and adiponectin.57,58 The identity of this casual factor, should such
be the case, remains to be elucidated. The difference between the
microvascular and conduit preparations is not clear, but may reflect
differential sensitivity of aortic versus microvascular endothelium
to changes in plasma chemistry caused by IR.
Studies in fructose-fed rats have also identified impairments in
NO-mediated vasodilation. In 1996, studies from Verma et al.59 documented impaired endothelium-dependent vasodilation in mesenteric
arteries from fructose-fed Sprague-Dawley rats. These findings were
extended to the aorta60 and renal61 circulation in subsequent years,
although some conflicting results have also been reported.62,63 There
are two key conclusions from these studies. First, as in the OZR,
the ubiquity of impaired endothelium-dependent dilation across the
circulation argues that the proximal mechanism lies in the plasma.
It seems likely the function of endothelial cells becomes altered in
response to some plasma element, the outcome of that alteration
being impaired NO-dependent vasodilation. Second, the fact that
fructose feeding induces a relatively moderately IR (modest
hypertriglyceridaemia, twofold hyperinsulinaemia) compared with
OZR (marked hypertriglyceridaemia, 10-fold hyperinsulinaemia)
suggests that the degree of IR required to produce impaired NOdependent vasodilation may be relatively moderate. Patients with IR
would experience the deleterious effects of inadequate NO long
before clinical symptoms of diabetes are manifested.

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Obesity and insulin resistance on blood flow

The potential link between IR and NO has led to the interest in
reversing IR as a mechanism of improving NO-mediated dilation.
Although some studies show positive results with insulin-sensitizing
peroxisome proliferator activated receptor (PPAR) agonists,49,64 the
mechanism is not clear. Additional studies have shown that PPAR
agonists improve NO-mediated dilation not only in models of IR,
but also hypertension65 and type I diabetes.66 Further evidence
suggests that PPAR agonists induce NO production from cultured
endothelial cells, potentially by mechanisms not involving PPAR.67,68
Thus, the efficaciousness of PPAR agonists in IR states cannot be
attributed purely to improved IR, but may reflect a direct effect of
PPAR on NO signalling.

IMPAIRED RELAXATION TO NO IN INSULIN

RESISTANCE: WHAT ARE THE MECHANISMS?
Although the effects of obesity and IR on NO-mediated dilation are
convincing, the mechanisms remain elusive. The most obvious
mechanism would simply be a reduction in the expression of
endothelial NO synthase (eNOS), the enzyme that generates NO
from arginine precursors. Indeed, Kuboki et al.69 demonstrated that
insulin increases eNOS expression in cultured endothelial cells and
described a reduction in eNOS in arterioles from fat pads in OZR.
Selective deletion of endothelial insulin receptors in the Vascular
ENdothelium Insulin Receptor Knock Out (VENIRKO) mouse also
results in reduced expression of eNOS.70 Therefore, it has been
tempting to speculate that the loss of insulin signalling in IR states
would reduce eNOS expression and corrupt NO-mediated vasodilation.
However, subsequent studies in other beds have failed to substantiate the results from adipose arterioles. Examination of eNOS
expression in the aorta71,72 or the coronary17 and cerebral43,44 circulations in OZR has found no differences or mild increases in eNOS
expression. Furthermore, the level of eNOS phosphorylation and
its conjugation to the molecular chaperone heat shock protein (HSP)
90 appear largely unaffected in different tissues of the OZR.72 One
explanation for the disparate results is that eNOS expression is
influenced by many factors, most notably blood flow and associated
shear stress.73 Blood flow to adipose tissues has been shown to be
reduced in OZR74 and, thus, the reduced eNOS expression reported
by Kuboki et al.69 may reflect not only an impaired response to
insulin, but also a reduced level of shear stress caused by low blood
flow.
Another potential mechanism of impaired NO-mediated vasodilation is interference with either NO production or NO action by
superoxide (SO) radicals. Generated by a number of redox enzymes75,76
and even eNOS itself,77 SO can degrade bioactive NO into the deleterious compound peroxynitrite.78 Furthermore, SO can degrade
tetrahydrobiopterin (BH4), a cofactor for eNOS, into biologically
inactive dihydrobiopterin, thus impeding eNOS action.79 Laight et al.80
identified elevated oxidant stress in OZR, as measured by elevated
plasma lipid peroxides, and found that impaired depressor responses
to nitrodilators were corrected in these animals with anti-oxidant
doses of vitamin E or the SO scavenger tiron. Examining skeletal
muscle arterioles in vivo, Frisbee and Stepp also reported impaired
NO-dependent dilation that correlated with SO generation as
assessed by dihyrdoethidine staining and found that cell-permeable
SO dismutase (SOD) improved vasodilator impairments.50 Similar
results were later obtained in the cerebral circulation of OZR.42 The
exact mechanism by which SO blocks the actions of NO are unclear,

409

but may include degradation of BH4 or other cofactors because NO

production has been found to be decreased (as assessed by plasma
or tissue nitrites) in OZR.47,72
The source of SO production in insulin-resistant states is unclear.
Sonta et al.,81 using whole-body electron spin resonance techniques
in OZR, found that elevated SO levels could be reduced by NADPH
oxidase antagonism with apocynin and improved with insulinsensitizing drugs. Katakam et al.17 also identified an apocynininduced improvement of NO-mediated dilation in coronary microvessels. Levels of expression of SOD were found to be comparable
to those found in lean rats. Shinozaki et al. identified increased
SO from NADPH oxidase in aorta from fructose-fed rats.60,82
Other potential pathways for SO generation, such as dysfunctional
eNOS or activation of xanthine oxidase pathways, remain largely
unexplored in models of obesity and IR.
A broader question is why does IR lead to free radical generation?
Although no clear consensus has emerged, several pathways have
been identified as potential links between the IR state and impaired
NO signalling. A schematic of these pathways is shown in Fig. 2.
Studies by Mather et al.83 found that endothelin receptor blockade
with endothelin receptor antagonist BQ-123 restored leg blood flow
responses to methacholine and that both the impairment in flow
and the improvement with BQ-123 were present in obese, prediabetic patients. Furthermore, constriction to inhibition of NO
production was augmented in obese, but not diabetic, patients when
endothelin receptors were blocked.84 This argues that the NO
production capacity is intact in obese individuals but limited in an
endothelin-dependent manner. Given that endothelin is documented
to increase SO generation in vivo,8587 it is tempting to speculate that
elevated endothelin or endothelin receptor activation in the IR state
provokes the generation of SO and limits NO-dependent dilation. In
further support of this thesis, Park et al.88 found that glucose induces
endothelin production via protein kinase C (PKC)-b-activated
mechanisms. Yokota et al.89 extended this observation to diabetic
rats, finding that endothelin expression was reduced in endothelial
cells by PKC-b antagonism as well as insulin. Data from Bohlen90
add a key piece to this puzzle, demonstrating that PKC-b antagonism
improves NO-mediated vasodilation in OZR. Although endothelin
and SO have not been linked directly in IR animal models, these data
offer compelling incentive to further examine this potential mechanism.

BEYOND NO: OBESITY AND NO-INDEPENDENT

VASODILATION
Increases in blood flow to any organ involve vasodilators other
than NO but, to date, examination of these pathways in the setting
of obesity and IR remains limited. The most studied of the NOindependent pathways of vasodilation involves products of arachidonic acid (AA) metabolism. Studies in the human forearm circulation
have identified a suppression of bradykinin-induced vasodilation in
viscerally obese patients that persisted after inhibition of NOS.91
Depolarization with oubain eliminated this dilation, suggesting that
a hyperpolarizing factor-dependent dilation was impaired in visceral
obesity. Although the chemical nature of endothelium-derived hyperpolarising factors (EDHF) remains controversial, considerable
evidence suggests that a product of cytochrome P450 (CYP) metabolism of AA is a major EDHF.92,93 Zhao et al.94 identified a decrease
in CYP2C11 and CYP2J in the mesenteric circulation in OZR. In
this bed, these enzymes are major sources of AA-derived EDHF.

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DW Stepp

Fig. 2 A schematic outlining potential mechanisms of impaired nitric oxide-dependent vasodilation in obesity and insulin resistance synthesised from the
existing literature. ACh, acetylcholine; eNOS, endothelial nitric oxide synthase; Arg, arginine; BH4, tetrahydrobiopterin; ET A, endothelin ETA receptor;
INS-R, insulin receptor; HSP90, heat shock protein 90; PKC-b, protein kinase C b; , negative action; ??, potential mechanistic links.

Furthermore, an increase in epoxide hydrolase, the EDHF degradative

pathway, was observed, suggesting a shift in the balance of EDHF
levels towards decreased production and increased metabolism.
This change in CYP profile accompanied a reduction in NOindependent endothelial vasodilation. Traupe et al.95 found that a highfat diet provoked an increased prostanoid-dependent contraction that
correlated with increased expression of thromboxane synthase. In the
fructose-fed rat model, decreased EDHF-dependent vasodilation has
been observed in the mesenteric,96 cerebral63 and coronary62 circulations.
In addition to reduced production of AA mediators, evidence of
corrupted signalling pathways of AA metabolites has been identified. Studies in the fructose-fed rat have found that potassium
channel signalling is impaired in the mesenteric97 and cerebral
circulations.63,98 Such dysfunction would limit the ability of putative
EDHF to act, even if production was normalized. Frisbee observed
that, in OZR, vasodilation to the prostacyclin analogue iloprost is
limited by the production of SO,99 indicating that oxidant stress
has broader deleterious effects than simply opposing NO. These
studies illustrate the importance of expanding our understanding of
vasodilator control beyond NO in obesity and IR.

BEYOND NO: SYMPATHETIC/ADRENERGIC

CONTROL
In addition to its effects on metabolic function, obesity produces
chronic elevations in the activity of the sympathetic nervous system
(SNS).100102 Whether this contributes to hypertension or IR in obese
individuals is beyond the scope of the present review. Of interest in

terms of vascular tone is whether increased sympathetic activation

affects baseline tone and whether acute vascular control is impacted
by increased sympathetic activation. Resting blood pressure has
been shown to be more sensitive to ganglionic blockade in animal
models103105 and to adrenergic blockade in humans.106 Basal levels
of muscle sympathetic nerve activity (SNA) are increased concomitant with increased vascular resistance in the forearm.107 Obesity
has been shown to impair stress-induced vasodilation to cold stress,
mental stress108 or handgrip.109 Agapitov et al. examined normotensive obese individuals and found impaired forearm dilation to mental
stress compared with controls.110 These studies indicate that, independent of hypertension, altered activity of or reactivity to SNA
impacts vascular resistance and acute control of blood pressure
in the setting of obesity.
Two basic mechanisms by which pressor responses to acute SNS
activation can be increased are evident: (i) increased activation of
the neural components of the SNS; or (ii) increased vascular sensitivity to sympathetic neurotransmitters. Evidence for each mechanism is found in both humans and animals. Mental stress provokes
increased SNA in obese humans108 and basal levels of SNA are
increased in rodent models of obesity.111 The effects of obesity on
adrenergic reactivity are less clear. Increased whole-body pressor
reactivity to phenylephrine has been reported,104 but this is likely
artefactual based on erroneous assumptions about plasma volume
in OZR.105 Different vascular beds display a wide array of responsiveness to adrenergic stimulation in obesity. The skeletal muscle
circulation appears more reactive,105,112,113 whereas the mesenteric
circulation appears less reactive.105,114 Reactivity in the renal

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Obesity and insulin resistance on blood flow

circulation is reduced115 or no different.105 Although the mechanism
of altered adrenergic reactivity is unknown, it seems clear from
the heterogeneous changes in reactivity across the circulatory system
that local factors must play a critical role in determining vascular
sensitivity to adrenergic stimulation in the setting of obesity and
IR. The relative contributions of SNA and vascular tone to the
heightened stress responses observed in obesity remain to be
fully determined.

The author gratefully acknowledges the insightful discussion and

collegial interaction of the following colleagues: Drs Jefferson Frisbee (Department of Physiology, West Virginia University, Morgantown,
WV, USA), Ann Schreihofer (Department of Physiology, Medical College
of Georgia), David Fulton, Mario Marrero, David Pollock and John
Imig (all from Vascular Biology Center, Medical College of Georgia).

BEYOND NO: PEPTIDE VASOCONSTRICTORS

REFERENCES

Organ perfusion is also heavily impacted by the actions of peptide

constrictors, notably angiotensin and endothelin. Because of their
central role in blood pressure regulation, the effects of these agents
have received particular attention in the control of vascular
resistance in obese patients.
Angiotensin (Ang) II is the constrictor product generated by the
reninangiotensin pathway. Data on the action of AngII in the vasculature of obese humans have been mixed. Nielsen et al. reported
increased vascular reactivity to AngII in the forearm circulation,116
whereas Goosens et al. have found no difference in reactivity in
either skeletal or adipose blood flow.117 Animal studies have also
failed to produce a consensus, with increases in pressor sensitivity118
or coronary vasoconstriction119 to AngII being reported along with
no difference in skeletal muscle reactivity.112 Reactivity to AngII is
mediated by a family of receptors with sometimes opposing effects
and the expression of these receptors is under a complex set of controls.120 Because of this complexity, more complete studies in which
factors such as salt load, renin activity and expression of receptor
subtypes are examined are needed before a clear understanding of
the efffect of obesity on AngII-mediated constriction can be obtained.
Increased vascular tone caused by endothelin has been implicated
in human studies,83,84,115,121 but mechanisms remain unclear. Increased
vascular reactivity to endothelin has generally not been found in
animal models112,115,122124 and Verma et al.125 have reported reduced
reactivity in fructose-fed rats. Alternatively, elevated effects of
endothelin on vascular tone in obese humans could be due to
elevated plasma concentrations of endothelin126128 or more complex
paracrine actions of endothelin on other cell signalling pathways.95,129

CONCLUSIONS
The rising tide of obesity is one of the greatest threats to cardiovascular health in the 21st century. Increasing evidence suggests that
the prediabetic IR state that precedes frank diabetes in obese patients
has deleterious effects on cardiovascular function, including impacting the acute control of organ perfusion. Impairment of NOmediated dilation is a prominent feature of vascular dysfunction in
obese individuals and this may be secondary to interference in NO
production and action by SO radicals. In addition to the effects of
NO, there are impairments in other vasodilator pathways, increased
activation and/or sensitivity to the SNS and elevated contributions
of peptide vasoconstrictors. These factors may limit physiological
control of organ perfusion, predisposing the obese and IR population
to elevated risk of ischaemia or over-pressurization injury. Identification of the mechanisms underlying these impairments may allow
the early diagnosis of vascular injury in the obese population and
lead to the development of protective interventions before the onset
of type II diabetes.

ACKNOWLEDGEMENTS

1.

2.
3.
4.

5.
6.

7.
8.

9.
10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

Mensah GA, Mokdad AH, Ford E et al. Obesity, metabolic syndrome,

and type 2 diabetes: Emerging epidemics and their cardiovascular
implications. Cardiol. Clin. 2004; 22: 485504.
Meigs JB. Epidemiology of the insulin resistance syndrome. Curr.
Diabet. Rep. 2003; 3: 739.
Seidell JC. Time trends in obesity: An epidemiological perspective.
Horm. Metab. Res. 1997; 29: 1558.
Wolf HK, Tuomilehto J, Kuulasmaa K et al. Blood pressure levels in
the 41 populations of the WHO MONICA Project. J. Hum. Hypertens.
1997; 11: 73342.
Goldstein BJ. Insulin resistance: From benign to type 2 diabetes
mellitus. Rev. Cardiovasc. Med. 2003; 4 (Suppl. 6): S310.
Busija DW, Miller AW, Katakam P, Simandle S, Erdos B. Mechanisms
of vascular dysfunctionin insulin resistance. Curr. Opin. Invest. Drugs
2004; 5: 92935.
Ferroni P, Basili S, Falco A, Davi G. Inflammation, insulin resistance,
and obesity. Curr. Atheroscler. Rep. 2004; 6: 42431.
Hall JE, Jones DW, Kuo JJ, da Silva A, Tallam LS, Liu J. Impact of
the obesity epidemic on hypertension and renal disease. Curr.
Hypertens. Rep. 2003; 5: 38692.
Hall JE, Brands MW, Henegar JR. Mechanisms of hypertension and
kidney disease in obesity. Ann. N.Y. Acad. Sci. 1999; 892: 91107.
Fruchart JC, Nierman MC, Stroes ES, Kastelein JJ, Duriez P. New risk
factors for atherosclerosis and patient risk assessment. Circulation
2004; 109 (Suppl. 1): III1519.
Frisbee JC. Hypertension-independent microvascular rarefaction in the
obese Zucker rat model of the metabolic syndrome. Microcirculation
2005; 12: 38392.
Frisbee JC. Reduced nitric oxide bioavailability contributes to skeletal
muscle microvessel rarefaction in the metabolic syndrome. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 2005; 289: R307R316.
Stepp DW, Pollock DM, Frisbee JC. Low-flow vascular remodeling in
the metabolic syndrome X. Am. J. Physiol. Heart Circ. Physiol. 2004;
286: H96470.
Vincent MA, Clerk LH, Lindner JR et al. Microvascular recruitment
is an early insulin effect that regulates skeletal muscle glucose uptake
in vivo. Diabetes 2004; 53: 141823.
Vincent MA, Barrett EJ, Lindner JR, Clark MG, Rattigan S. Inhibiting
NOS blocks microvascular recruitment and blunts muscle glucose
uptake in response to insulin. Am. J. Physiol. Endocrinol. Metab. 2003;
285: E1239.
Wallis MG, Wheatley CM, Rattigan S, Barrett EJ, Clark AD, Clark
MG. Insulin-mediated hemodynamic changes are impaired in muscle
of Zucker obese rats. Diabetes 2002; 51: 34928.
Katakam PV, Tulbert CD, Snipes JA, Erdos B, Miller AW, Busija DW.
Impaired insulin-induced vasodilation in small coronary arteries of
Zucker obese rats is mediated by reactive oxygen species. Am. J.
Physiol. Heart Circ. Physiol. 2005; 288: H85460.
Wheatley CM, Rattigan S, Richards SM, Barrett EJ, Clark MG.
Skeletal muscle contraction stimulates capillary recruitment and
glucose uptake in insulin-resistant obese Zucker rats. Am. J. Physiol.
Endocrinol. Metab. 2004; 287: E8049.
Vincent MA, Clerk LH, Rattigan S, Clark MG, Barrett EJ. Active role
for the vasculature in the delivery of insulin to skeletal muscle. Clin.
Exp. Pharmacol. Physiol. 2005; 32: 3027.

2006 The Author

Journal compilation 2006 Blackwell Publishing Asia Pty Ltd

412
20.
21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.
37.

38.
39.

40.

41.

DW Stepp
Baron AD, Clark MG. Role of blood flow in the regulation of muscle
glucose uptake. Annu. Rev. Nutr. 1997; 17: 48799.
Rattigan S, Wheatley C, Richards SM, Barrett EJ, Clark MG. Exercise
and insulin-mediated capillary recruitment in muscle. Exerc. Sport Sci.
Rev. 2005; 33: 438.
Ninomiya JK, LItalien G, Criqui MH, Whyte JL, Gamst A, Chen RS.
Association of the metabolic syndrome with history of myocardial
infarction and stroke in the third National Health and Nutrition
Examination Survey. Circulation 2004; 109: 426.
Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEPdefined metabolic syndrome, diabetes, and prevalence of coronary
heart disease among NHANES III participants age 50 years and older.
Diabetes 2003; 52: 1210 14.
Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated
from arteries transforms prostaglandin endoperoxides to an unstable
substance that inhibits platelet aggregation. Nature 1976; 263: 6635.
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells
in the relaxation of arterial smooth muscle by acetylcholine. Nature
1980; 288: 3736.
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and
vein is nitric oxide. Proc. Natl Acad. Sci. USA 1987; 84: 92659.
Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron
AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J. Clin.
Invest. 1996; 97: 260110.
Brook RD, Bard RL, Rubenfire M, Ridker PM, Rajagopalan S. Usefulness of visceral obesity (waist/hip ratio) in predicting vascular
endothelial function in healthy overweight adults. Am. J. Cardiol. 2001;
88: 12649.
Nestel PJ, Yamashita T, Sasahara T et al. Control of the forearm microcirculation: Interactions with measures of obesity and noradrenaline
kinetics. Clin. Sci. 1998; 95: 203 12.
Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Chayama K, Oshima T.
Effect of obesity on endothelium-dependent, nitric oxide-mediated
vasodilation in normotensive individuals and patients with essential
hypertension. Am. J. Hypertens. 2001; 14: 1038 45.
Perticone F, Ceravolo R, Candigliota M et al. Obesity and body fat
distribution induce endothelial dysfunction by oxidative stress: Protective effect of vitamin C. Diabetes 2001; 50: 159 65.
Sundell J, Laine H, Luotolahti M et al. Obesity affects myocardial vasoreactivity and coronary flow response to insulin. Obes. Res. 2002; 10:
61724.
Hummel KP, Coleman DL, Lane PW. The influence of genetic background on expression of mutations at the diabetes locus in the mouse.
I. C57BL-KsJ and C57BL-6J strains. Biochem. Genet. 1972; 7: 113.
Smith SA, Lister CA, Toseland CD, Buckingham RE. Rosiglitazone
prevents the onset of hyperglycaemia and proteinuria in the Zucker
diabetic fatty rat. Diabetes Obes. Metab. 2000; 2: 36372.
Zhou YP, Cockburn BN, Pugh W, Polonsky KS. Basal insulin hypersecretion in insulin-resistant Zucker diabetic and Zucker fatty rats: Role
of enhanced fuel metabolism. Metabolism 1999; 48: 85764.
Zucker LM, Antoniades HN. Insulin and obesity in the Zucker
genetically obese rat fatty. Endocrinology 1972; 90: 132030.
Zavaroni I, Sander S, Scott S, Reaven GM. Effect of fructose feeding
on insulin secretion and insulin action in the rat. Metabolism 1980; 29:
9703.
Cox RH, Kikta DC. Age-related changes in thoracic aorta of obese
Zucker rats. Am. J. Physiol. 1992; 262: H154856.
Laight DW, Anggard EE, Carrier MJ. Investigation of basal endothelial
function in the obese Zucker rat in vitro. Gen. Pharmacol. 2000; 35:
3039.
Auguet M, Delaflotte S, Braquet P. Increased influence of endothelium in obese Zucker rat aorta. J. Pharm. Pharmacol. 1989; 41:
8614.
Brooks-Asplund EM, Shoukas AA, Kim SY, Burke SA, Berkowitz DE.
Estrogen has opposing effects on vascular reactivity in obese, insulinresistant male Zucker rats. J. Appl. Physiol. 2002; 92: 203544.

42.

43.

44.

45.

46.

47.
48.

49.
50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

Phillips SA, Sylvester FA, Frisbee JC. Oxidant stress and constrictor
reactivity impair cerebral artery dilation in obese Zucker rats. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 2005; 288: R52230.
Karagiannis J, Reid JJ, Darby I, Roche P, Rand MJ, Li CG. Impaired
nitric oxide function in the basilar artery of the obese Zucker rat.
J. Cardiovasc. Pharmacol. 2003; 42: 497505.
Erdos B, Snipes JA, Miller AW, Busija DW. Cerebrovascular dysfunction in Zucker obese rats is mediated by oxidative stress and
protein kinase C. Diabetes 2004; 53: 13529.
Wu X, Makynen H, Kahonen M, Arvola P, Porsti I. Mesenteric arterial
function in vitro in three models of experimental hypertension.
J. Hypertens. 1996; 14: 36572.
Zanchi A, Delacretaz E, Taleb V et al. Endothelial function of the
mesenteric arteriole and mechanical behaviour of the carotid artery in
rats with insulin resistance and hypercholesterolaemia. J. Hypertens.
1995; 13: 146370.
Fujiwara K, Hayashi K, Matsuda H et al. Altered pressure-natriuresis
in obese Zucker rats. Hypertension 1999; 33: 14705.
Hayashi K, Matsuda H, Nagahama T et al. Impaired nitric oxideindependent dilation of renal afferent arterioles in spontaneously
hypertensive rats. Hypertens. Res. 1999; 22: 317.
Hayashi K, Kanda T, Homma K et al. Altered renal microvascular
response in Zucker obese rats. Metabolism 2002; 51: 1553 61.
Frisbee JC, Stepp DW. Impaired NO-dependent dilation of skeletal
muscle arterioles in hypertensive diabetic obese Zucker rats. Am. J.
Physiol. Heart Circ. Physiol. 2001; 281: H130411.
Winters B, Mo Z, Brooks-Asplund E et al. Reduction of obesity, as
induced by leptin, reverses endothelial dysfunction in obese (Lep(ob))
mice. J. Appl. Physiol. 2000; 89: 238290.
Gupta S, Sussman I, McArthur CS, Tornheim K, Cohen RA, Ruderman
NB. Endothelium-dependent inhibition of Na(+)-K+ ATPase activity
in rabbit aorta by hyperglycemia. Possible role of endothelium-derived
nitric oxide. J. Clin. Invest. 1992; 90: 72732.
Tesfamariam B, Palacino JJ, Weisbrod RM, Cohen RA. Aldose reductase inhibition restores endothelial cell function in diabetic rabbit aorta.
J. Cardiovasc. Pharmacol. 1993; 21: 20511.
Sainsbury CA, Sattar N, Connell JM, Hillier C, Petrie JR. Nonesterified fatty acids impair endothelium-dependent vasodilation in
rat mesenteric resistance vessels. Clin. Sci. 2004; 107: 6259.
Kim F, Tysseling KA, Rice J et al. Free fatty acid impairment of nitric
oxide production in endothelial cells is mediated by IKKbeta. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 98994.
Knudson JD, Dincer UD, Dick GM et al. Leptin resistance extends to
the coronary vasculature in prediabetic dogs and provides a protective
adaptation against endothelial dysfunction. Am. J. Physiol. Heart Circ.
Physiol. 2005; 289: H103846.
Tan KC, Xu A, Chow WS et al. Hypoadiponectinemia is associated
with impaired endothelium-dependent vasodilation. J. Clin. Endocrinol. Metab. 2004; 89: 7659.
Hattori S, Hattori Y, Kasai K. Hypoadiponectinemia is caused by
chronic blockade of nitric oxide synthesis in rats. Metabolism 2005;
54: 4827.
Verma S, Bhanot S, Yao L, McNeill JH. Defective endotheliumdependent relaxation in fructose-hypertensive rats. Am. J. Hypertens.
1996; 9: 3706.
Shinozaki K, Kashiwagi A, Nishio Y et al. Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation
through nitric oxide/O2- imbalance in insulin-resistant rat aorta.
Diabetes 1999; 48: 243745.
Kamata K, Yamashita K. Insulin resistance and impaired endotheliumdependent renal vasodilatation in fructose-fed hypertensive rats. Res.
Commun. Mol. Pathol. Pharmacol. 1999; 103: 195210.
Miller AW, Katakam PV, Ujhelyi MR. Impaired endotheliummediated relaxation in coronary arteries from insulin-resistant rats.
J. Vasc. Res. 1999; 36: 38592.
Erdos B, Miller AW, Busija DW. Impaired endothelium-mediated
relaxation in isolated cerebral arteries from insulin-resistant rats. Am.
J. Physiol. Heart Circ. Physiol. 2002; 282: H20605.

2006 The Author

Journal compilation 2006 Blackwell Publishing Asia Pty Ltd

Obesity and insulin resistance on blood flow

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.
76.

77.
78.
79.

80.

81.

82.

83.

84.

Natali A, Baldeweg S, Toschi E et al. Vascular effects of improving

metabolic control with metformin or rosiglitazone in type 2 diabetes.
Diabetes Care 2004; 27: 134957.
Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD.
PPAR(gamma) agonist rosiglitazone improves vascular function and
lowers blood pressure in hypertensive transgenic mice. Hypertension
2004; 43: 6616.
Majithiya JB, Paramar AN, Balaraman R. Pioglitazone, a PPARgamma
agonist, restores endothelial function in aorta of streptozotocin-induced
diabetic rats. Cardiovasc. Res. 2005; 66: 15061.
Cho DH, Choi YJ, Jo SA, Jo I. Nitric oxide production and regulation
of endothelial nitric-oxide synthase phosphorylation by prolonged
treatment with troglitazone: Evidence for involvement of peroxisome
proliferator-activated receptor (PPAR) gamma-dependent and
PPARgamma-independent signaling pathways. J. Biol. Chem. 2004;
279: 2499506.
Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome
proliferator-activated receptor gamma ligands increase release of nitric
oxide from endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2003;
23: 527.
Kuboki K, Jiang ZY, Takahara N et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in
vivo: A specific vascular action of insulin. Circulation 2000; 101: 67681.
Vicent D, Ilany J, Kondo T et al. The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J. Clin.
Invest. 2003; 111: 137380.
Lee DH, Lee JU, Kang DG, Paek YW, Chung DJ, Chung MY.
Increased vascular endothelin-1 gene expression with unaltered nitric
oxide synthase levels in fructose-induced hypertensive rats. Metabolism 2001; 50: 74 8.
Fulton D, Harris MB, Kemp BE, Venema RC, Marrero MB, Stepp DW.
Insulin resistance does not diminish eNOS expression, phosphorylation
or binding to hsp90. Am. J Physiol Heart Circ. Physiol 2004; 287:
H238493.
Gimbrone Jr MA, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G.
Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann.
N.Y. Acad. Sci. 2000; 902: 230 40.
West DB, Prinz WA, Francendese AA, Greenwood MR. Adipocyte
blood flow is decreased in obese Zucker rats. Am. J. Physiol. 1987;
253: R22833.
Brandes RP, Kreuzer J. Vascular NADPH oxidases: Molecular mechanisms of activation. Cardiovasc. Res. 2005; 65: 1627.
Touyz RM. Reactive oxygen species, vascular oxidative stress, and
redox signaling in hypertension: What is the clinical significance?
Hypertension 2004; 44: 24852.
Zou MH, Cohen R, Ullrich V. Peroxynitrite and vascular endothelial
dysfunction in diabetes mellitus. Endothelium 2004; 11: 8997.
Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology:
Implications in hypertension. Histochem. Cell Biol. 2004; 122: 33952.
Alp NJ, Channon KM. Regulation of endothelial nitric oxide synthase
by tetrahydrobiopterin in vascular disease. Arterioscler. Thromb. Vasc.
Biol. 2004; 24: 41320.
Laight DW, Kengatharan KM, Gopaul NK, Anggard EE, Carrier MJ.
Investigation of oxidant stress and vasodepression to glyceryl trinitrate
in the obese Zucker rat in vivo. Br. J. Pharmacol. 1998; 125: 895901.
Sonta T, Inoguchi T, Tsubouchi H et al. Evidence for contribution of
vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic. Biol. Med. 2004; 37: 11523.
Shinozaki K, Ayajiki K, Nishio Y, Sugaya T, Kashiwagi A, Okamura T.
Evidence for a causal role of the reninangiotensin system in
vascular dysfunction associated with insulin resistance. Hypertension
2004; 43: 25562.
Mather KJ, Mirzamohammadi B, Lteif A, Steinberg HO, Baron AD.
Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes. Diabetes 2002; 51: 351723.
Mather KJ, Lteif A, Steinberg HO, Baron AD. Interactions between
endothelin and nitric oxide in the regulation of vascular tone in obesity
and diabetes. Diabetes 2004; 53: 20606.

85.

86.

87.
88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.
101.
102.
103.

104.

105.

106.

107.

413

Elmarakby AA, Loomis ED, Pollock JS, Pollock DM. NADPH oxidase
inhibition attenuates oxidative stress but not hypertension produced by
chronic ET-1. Hypertension 2005; 45: 2837.
Sedeek MH, Llinas MT, Drummond H et al. Role of reactive oxygen
species in endothelin-induced hypertension. Hypertension 2003; 42:
80610.
Pollock DM. Endothelin, angiotensin, and oxidative stress in hypertension. Hypertension 2005; 45: 47780.
Park JY, Takahara N, Gabriele A et al. Induction of endothelin-1
expression by glucose: An effect of protein kinase C activation.
Diabetes 2000; 49: 123948.
Yokota T, Ma RC, Park JY et al. Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of
diabetic rats and cultured retinal capillary pericytes. Diabetes 2003; 52:
83845.
Bohlen HG. Protein kinase betaII in Zucker obese rats compromises
oxygen and flow-mediated regulation of nitric oxide formation. Am. J.
Physiol. Heart Circ. Physiol. 2004; 286: H4927.
Vigili de Kreutzenberg S, Kiwanuka E, Tiengo A, Avogaro A. Visceral
obesity is characterized by impaired nitric oxide-independent vasodilation. Eur. Heart J. 2003; 24: 121015.
Spector AA, Fang X, Snyder GD, Weintraub NL. Epoxyeicosatrienoic
acids (EETs): Metabolism and biochemical function. Prog. Lipid Res.
2004; 43: 5590.
Campbell WB, Gauthier KM. What is new in endothelium-derived
hyperpolarizing factors? Curr. Opin. Nephrol. Hypertens. 2002; 11:
17783.
Zhao X, Dey A, Romanko OP et al. Decreased epoxygenase and
increased epoxide hydrolase expression in the mesenteric artery of
obese Zucker rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005;
288: R18896.
Traupe T, Lang M, Goettsch W et al. Obesity increases prostanoidmediated vasoconstriction and vascular thromboxane receptor gene
expression. J. Hypertens. 2002; 20: 223945.
Katakam PV, Ujhelyi MR, Miller AW. EDHF-mediated relaxation is
impaired in fructose-fed rats. J. Cardiovasc. Pharmacol. 1999; 34:
4617.
Dimitropoulou C, Han G, Miller AW et al. Potassium (BK(Ca))
currents are reduced in microvascular smooth muscle cells from insulinresistant rats. Am. J. Physiol. Heart Circ. Physiol. 2002; 282: H90817.
Erdos B, Miller AW, Busija DW. Alterations in KATP and KCa channel
function in cerebral arteries of insulin-resistant rats. Am. J. Physiol.
Heart Circ. Physiol. 2002; 283: H24727.
Frisbee JC. Impaired dilation of skeletal muscle microvessels to
reduced oxygen tension in diabetic obese Zucker rats. Am. J. Physiol.
Heart Circ. Physiol. 2001; 281: H156874.
Abate NI, Mansour YH, Tuncel M et al. Overweight and sympathetic
overactivity in black Americans. Hypertension 2001; 38: 37983.
Alvarez GE, Beske SD, Ballard TP, Davy KP. Sympathetic neural activation in visceral obesity. Circulation 2002; 106: 25336.
Davy KP, Hall JE. Obesity and hypertension: Two epidemics or one?
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004; 286: R803 13.
Carlson SH, Shelton J, White CR, Wyss JM. Elevated sympathetic
activity contributes to hypertension and salt sensitivity in diabetic obese
Zucker rats. Hypertension 2000; 35: 4038.
Pamidimukkala J, Jandhyala BS. Evaluation of hemodynamics, vascular reactivity and baroreceptor compensation in the insulin resistant
Zucker obese rats. Clin. Exp. Hypertens. 1996; 18: 1089104.
Schreihofer AM, Hair CD, Stepp DW. Reduced plasma volume and
mesenteric vascular reactivity in obese Zucker rats. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 2005; 288: R25361.
Wofford MR, Anderson Jr DC, Brown CA, Jones DW, Miller ME,
Hall JE. Antihypertensive effect of alpha- and beta-adrenergic
blockade in obese and lean hypertensive subjects. Am. J. Hypertens.
2001; 14: 6948.
Ribeiro MM, Trombetta IC, Batalha LT et al. Muscle sympathetic
nerve activity and hemodynamic alterations in middle-aged obese
women. Braz. J. Med. Biol. Res. 2001; 34: 4758.

2006 The Author

Journal compilation 2006 Blackwell Publishing Asia Pty Ltd

414
108.

109.

110.

111.
112.

113.

114.

115.

116.

117.

118.

DW Stepp
Kuniyoshi FH, Trombetta IC, Batalha LT et al. Abnormal neurovascular control during sympathoexcitation in obesity. Obes. Res.
2003; 11: 141119.
Sung BH, Wilson MF, Izzo Jr JL, Ramirez L, Dandona P. Moderately
obese, insulin-resistant women exhibit abnormal vascular reactivity
to stress. Hypertension 1997; 30: 84853.
Agapitov AV, Correia ML, Sinkey CA, Dopp JM, Haynes WG.
Impaired skeletal muscle and skin microcirculatory function in human
obesity. J. Hypertens. 2002; 20: 14015.
Morgan DA, Anderson EA, Mark AL. Renal sympathetic nerve activity is increased in obese Zucker rats. Hypertension 1995; 25: 8348.
Stepp DW, Frisbee JC. Augmented adrenergic vasoconstriction in
hypertensive diabetic obese Zucker rats. Am. J. Physiol. Heart Circ.
Physiol. 2002; 282: H816 20.
Egan BM, Schork NJ, Weder AB. Regional hemodynamic abnormalities in overweight men. Focus on alpha-adrenergic vascular
responses. Am. J. Hypertens. 1989; 2: 42834.
He Y, MacLeod KM. Modulation of noradrenaline-induced vasoconstriction in isolated perfused mesenteric arterial beds from obese
Zucker rats in the presence and absence of insulin. Can. J. Physiol.
Pharmacol. 2002; 80: 1719.
Ratz PH, West DB, Granger JP. Decreased potency of contraction to
alpha-adrenoceptor stimulation in renal arteries from obese hypertensive dogs. Am. J. Physiol. 1993; 265: R798803.
Nielsen S, Halliwill JR, Joyner MJ, Jensen MD. Vascular response
to angiotensin II in upper body obesity. Hypertension 2004; 44: 435
41.
Goossens GH, Blaak EE, Saris WH, van Baak MA. Angiotensin
II-induced effects on adipose and skeletal muscle tissue blood flow
and lipolysis in normal-weight and obese subjects. J. Clin.
Endocrinol. Metab. 2004; 89: 26906.
Alonso-Galicia M, Brands MW, Zappe DH, Hall JE. Hypertension
in obese Zucker rats. Role of angiotensin II and adrenergic activity.
Hypertension 1996; 28: 104754.

119.

120.
121.

122.

123.

124.

125.

126.

127.

128.
129.

Zhang C, Knudson JD, Setty S et al. Coronary arteriolar vasoconstriction to angiotensin II is augmented in prediabetic metabolic
syndrome via activation of AT1 receptors. Am. J. Physiol. Heart
Circ. Physiol. 2005; 288: H215462.
Wang DH, Elijovich F. Modulation and function of extrarenal angiotensin receptors. Cell Biochem. Biophys. 1999; 31: 117.
Cardillo C, Campia U, Iantorno M, Panza JA. Enhanced vascular
activity of endogenous endothelin-1 in obese hypertensive patients.
Hypertension 2004; 43: 3640.
Erdos B, Snipes JA, Kis B, Miller AW, Busija DW. Vasoconstrictor
mechanisms in the cerebral circulation are unaffected by insulin resistance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004; 287:
R145661.
Subramanian R, MacLeod KM. Age-dependent changes in blood
pressure and arterial reactivity in obese Zucker rats. Eur. J. Pharmacol. 2003; 477: 14352.
Navarro-Cid J, Maeso R, Perez-Vizcaino F et al. Effects of losartan
on blood pressure, metabolic alterations, and vascular reactivity in the
fructose-induced hypertensive rat. Hypertension 1995; 26: 1074 8.
Verma S, Skarsgard P, Bhanot S, Yao L, Laher I, McNeill JH.
Reactivity of mesenteric arteries from fructose hypertensive rats to
endothelin-1. Am. J. Hypertens. 1997; 10: 101019.
Ferri C, Bellini C, Desideri G et al. Circulating endothelin-1 levels
in obese patients with the metabolic syndrome. Exp. Clin. Endocrinol.
Diabetes 1997; 105 (Suppl. 2): 3840.
Parrinello G, Scaglione R, Pinto A et al. Central obesity and hypertension: The role of plasma endothelin. Am. J. Hypertens. 1996; 9:
118691.
Ferri C, Bellini C, Desideri G et al. Plasma endothelin-1 levels in
obese hypertensive and normotensive men. Diabetes 1995; 44: 4316.
Wu SQ, Hopfner RL, McNeill JR, Wilson TW, Gopalakrishnan V.
Altered paracrine effect of endothelin in blood vessels of the hyperinsulinemic, insulin resistant obese Zucker rat. Cardiovasc. Res.
2000; 45: 9941000.

2006 The Author

Journal compilation 2006 Blackwell Publishing Asia Pty Ltd