(Hypertension. 1998;31:1266-1271.)
© 1998 American Heart Association, Inc.
Insulin-Mediated Venodilation Is Impaired in Patients With High Cholesterol
Bong Hee Sung;
Marilou Ching;
Joseph Izzo, Jr;
Paresh Dandona;
; Michael F. Wilson
From the Department of Medicine, State University of New York, and
Millard Fillmore Hospital, Buffalo, NY.
Correspondence to Bong Hee Sung, PhD, Department of Medicine, Millard Fillmore Hospital, 3 Gates Cir, Buffalo, NY 14209. E-mail bsung{at}MFHS.edu
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Abstract
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Abstract—Recently we have reported
that insulin attenuates norepinephrine (NE)-induced
vasoconstriction via a cyclic GMP–NO synthase pathway. Because
hypercholesterolemia has been associated with
abnormal endothelial function, we investigated whether
insulin-mediated vasodilation is impaired in
hypercholesterolemia. To assess vasoreactivity,
NE (12.5, 25, 50, and 100 ng/min), NE (100 ng/min) combined with
insulin (8, 16, 24, and 32 µU/min), and NE (100 ng/min) combined with
sodium nitroprusside (0.01, 0.1, 1, 10, and 100 ng/min) were infused
into dorsal hand veins. Changes in venous diameter were measured by
ultrasonography, using a 7.5-MHz transducer. Twenty-two healthy,
normotensive hypercholesterolemic subjects (HC; mean
total cholesterol 6.93 mmol/L, HDL 1.45 mmol/L,
LDL 4.81 mmol/L) and 18 age-matched normal control subjects (NC;
mean total cholesterol 4.81 mmol/L, HDL 1.16
mmol/L, LDL 3.18 mmol/L) were studied. All HC had normal glucose
tolerance test results. Baseline vein diameters were similar between
groups, and the vasoconstrictor response to NE was not significantly
different between HC and NC. Insulin significantly attenuated
NE-induced vasoconstriction in NC but not in HC
(P<0.01). Both groups were able to venodilate with
sodium nitroprusside. To investigate the effects of
cholesterol reduction on vascular reactivity,
venoreactivity studies were repeated in 12 HC after treatment with 20
to 40 mg/d lovastatin for 6 weeks. There were no
significant venoreactivity changes with the treatment. Plasma LDL
cholesterol concentration was inversely correlated to
venodilator effect of insulin (r=-0.42,
P<0.02). In conclusion, insulin-mediated vasodilation
is impaired in patients with high cholesterol. Absence of
normal insulin-mediated but not sodium nitroprusside–induced
venodilation in hypercholesterolemia
suggests that insulin-mediated vasodilation is endothelium
dependent.
Key Words: hypercholesterolemia • vasoreactivity • insulin • norepinephrine • endothelium
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Introduction
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The importance of
endothelial dysfunction in the regulation of
coronary and systemic arterial vasomotion has been
well established.1 2 3 4 5 6
Hypercholesterolemia, one of the principal risk
factors for coronary artery disease, has been linked to
impaired arterial endothelial function via
impairment in the NO–cyclic GMP pathway.7 8
Recently it has been shown in our laboratory that
hypercholesterolemia causes an exaggerated BP
response to mental arithmetic test and that this enhanced BP response
can be normalized by hepatic HMG CoA reductase inhibitors
in proportion to the degree of lowering of the serum
cholesterol.9 The role of
endothelial dysfunction in this phenomenon is of
considerable interest.
Assessment of endothelial function has been generally
carried out by measuring flow-dependent dilation to acetylcholine in
the human coronary or brachial
arteries10 11 ; however, veins are easily
accessible and share many structural and functional similarities with
arteries. Recently we have developed a technique that provides direct
visualization of veins using cross-sectional and M-mode
ultrasonography. It has the advantage of examining direct local effects
of vasoactive substances in amounts not causing systemic effects. Using
this technique, we have reported that insulin induced a dose-dependent
inhibition of the vasoconstrictor effect of NE and that methylene blue,
a known inhibitor of NO synthase and guanylate
cyclase, inhibited the vasodilator effect of
insulin.12
If insulin exerts its effect by activating either NO synthase or
guanylate cyclase, it would increase levels of cGMP. Thus,
the venodilator effects of insulin may be cGMP dependent. However, our
data do not demonstrate whether the effect of insulin on
guanylate cyclase is a direct one or whether it is mediated
by the generation of NO. Two other groups of
investigators13 14 have recently demonstrated
that the vasodilator effect of insulin on the arterial side
is NO mediated, which further strengthens our hypothesis.
Because hypercholesterolemia is associated with
endothelial dysfunction, we examined whether
insulin-mediated venodilation is impaired in the
hypercholesterolemic population. We chose dorsal hand
veins, substituting infused NE as a surrogate for sympathetic nervous
activity. We also studied vasoreactivity to sodium nitroprusside, an
endothelium-independent vasodilator, to investigate the
underlying mechanism of the defect in insulin-mediated venodilation. In
addition, we examined whether a reduction in cholesterol
with HMG CoA reductase inhibitor improves insulin-mediated
venodilation in hypercholesterolemia.
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Methods
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Study Population
Healthy normotensive volunteers were recruited through
advertisements in the local community. Respondents were initially
interviewed by telephone, and those who met the inclusion criteria
underwent screening and physical examination. Smokers, hypertensives,
diabetics, subjects with known cardiovascular disease,
and those taking medications were excluded. Subjects with homozygous
familial hypercholesterolemia were not included
in the study. Lipid profile and glucose were measured after a 12-hour
fast. Subjects with levels of LDL cholesterol >4.14
mmol/L and triglycerides <350 mg/dL were classified as HC,
and subjects with normal total cholesterol (<5.17
mmol/L) and triglycerides (<170 mg/dL) were classified as
NC.
The final study population consisted of 22 HC and 18 NC. Glucose
tolerance tests were performed in HC to determine possible insulin
resistance. Glucose and insulin levels were measured at 30 minutes, 1
hour, and 2 hours after ingestion of 75 g glucose. Table 1
compares demographic and baseline
hemodynamic variables between HC and NC groups.
Study Protocol
The study protocol was approved by the Human Ethics Committee of
the Millard Fillmore Hospital, and informed consent was obtained from
each volunteer after the procedures were explained. All study subjects
were requested to refrain from alcohol and caffeine for at least 12
hours before the experiment. The experiments were conducted in a quiet
room maintained at 26°C to 28°C.
With the subject supine, one arm was placed on an inclined padded
support at an angle of 30° from the horizontal to empty the
superficial hand vein. A 23-gauge needle was inserted into the dorsal
hand vein, and an intravenous infusion of normal saline was
maintained at 0.5 mL/min. A pneumatic cuff was applied 5 cm above the
elbow and inflated to a pressure of 40 mm Hg.
Two sets of baseline hand vein diameters, one with the cuff uninflated
and another with the cuff inflated at 40 mm Hg, were measured by
ultrasonography. NE (12.5, 25, 50, and 100 ng/min), NE (100 ng/min)
coupled with insulin (8, 16, 24, and 32 µU/min), and NE (100 ng/min)
coupled with sodium nitroprusside (0.01, 0.1, 1, 10, and 100 ng/min)
were infused for 5 minutes at each dose. Vein diameter was measured
during the last 2 minutes of infusion. There was a 10- to 15-minute
washout period with normal saline between drugs. BP and heart rate were
monitored in the contralateral arm by an automated BP monitor (Colin
Press-Mate, Colin Medical Instruments Corp). Readings were obtained
before, during, and after the experiment to assess systemic
hemodynamic changes.
Measurement of Venous Reactivity by Ultrasonography
Dorsal hand vein diameter was measured by ultrasonography as
described previously.12 An Acuson TM 128xp
ultrasound machine with a 7.5-MHz linear array transducer was used. The
transducer was held stationary with a stand specially designed for this
purpose. An interface of gel was applied between the skin and
transducer to improve coupling. Measurements were made 1 cm distal to
the tip of the cannula, showing two-dimensional images of the vein's
cross-section. An M-mode image was generated from which venous diameter
was measured. In our laboratory, this device has been shown to have a
sensitivity of 0.1 mm and an interobserver and intrasubject
coefficient of variation of <5%.
Treatment
To examine whether lowering cholesterol would modify
venous reactivity to NE and insulin, we treated 12 HC with 20 to 40
mg/d lovastatin for 6 weeks. A fasting lipid profile was
performed and a venous reactivity study was repeated after the
treatment.
Statistical Analysis
All data are expressed as mean±SD. The baseline difference
between NC and HC groups in resting hemodynamics and
demographic variables was evaluated by unpaired t test.
Effects of drug treatment with lovastatin on lipid profiles
and vasoreactivity were analyzed by one-way ANOVA. The changes
in venous diameter with NE, insulin, and sodium nitroprusside between
groups were examined by a two-way ANOVA with repeated measures using
Systat software. Multiple regression analysis was performed to
examine the relationship between LDL levels and vasodilator effects of
insulin. A value of P<0.05 was considered to be
significant.
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Results
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As summarized in Table 1
, both groups had similar age and gender
distribution. The HC group was heavier and taller than the NC group,
but body mass index was not significantly different. As expected, HC
had significantly higher total cholesterol levels than NC
(6.93±0.7 versus 4.81±0.46 mmol/L, P<0.001).
Although LDL cholesterol was significantly higher in HC
than NC (4.81±0.52 versus 3.18±0.46 mmol/L,
P<0.001), HDL cholesterol was not significantly
different between the groups. Baseline heart rate (68±7 versus 64±5
bpm, NS), systolic BP (122±11 versus 118±9 mm Hg, NS),
and diastolic BP (74±8 versus 70±5 mm Hg, NS) were
not significantly different between HC and NC groups.
All study subjects had normal fasting glucose (mean, 4.9±0.6
mmol/L) and insulin levels (mean, 8±3.8 µU/mL). To rule out insulin
resistance in the HC group, glucose tolerance tests were performed in
all HC. Their mean glucose levels for 30, 60, 90, and 120 minutes after
glucose challenge were 6.7±1.4, 7.3±1.8, 5.7±1.2, and 5.2±1.7
mmol/L; mean insulin levels were 46±12, 65±14, 50±11, and 28±7
µU/mL. These results confirm that the HC group did not have glucose
intolerance.
Effects of NE and Insulin on Venous Diameter
The mean venous diameter at baseline was similar between NC and HC
(1.6±0.5 and 1.54±0.45 mm, respectively; P=NS). On
cuff inflation, mean resting venous diameter increased to 2.9±0.8
mm for NC and 3.03±0.6 mm for HC. NE caused a dose-dependent
decrease in venous diameter for both groups (significant drug effect,
P<0.001). Although ranges of venoconstriction to NE were
greater in HC than NC (19% to 58% versus 12% to 42%,
P=0.09), these results were not statistically significant.
The highest dose of NE returned venous diameters similar to those
before cuff inflation.
There was a significant difference in venodilatory response to insulin
between HC and NC groups. Infusion of insulin in increasing doses of 8,
16, 24, and 32 µU/min increased venous diameter to 2.17, 2.28, 2.64,
and 2.84 mm (P<0.01) in NC, respectively, whereas
there was an insignificant increase in venous diameter during insulin
infusion in HC (1.67, 1.74, 1.71, and 1.79 mm, respectively;
P=NS). There was a significant drug-by-group interaction
(P<0.01). Thus, NE-mediated venoconstriction was
significantly attenuated by insulin in NC, but this effect was blunted
in hypercholesterolemia. The comparison of
venous diameter changes to NE and insulin between NC and HC is
illustrated in Figure 1.
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Figure 1. Comparison of venous reactivity to NE and insulin
between subjects with normal cholesterol (n=18) and high
cholesterol (n=22). HC had directionally higher
venoconstriction to NE (P=0.09) and significantly
blunted insulin-mediated venodilation (P<0.01).
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Comparison of Vasodilation Mediated by Insulin and Sodium
Nitroprusside
In contrast to the response to insulin, both groups were able to
venodilate with sodium nitroprusside, and there was no significant
group difference in venodilation to sodium nitroprusside between HC and
NC. Vasodilator responses to sodium nitroprusside between HC and NC are
compared in Figure 2. The HC group was
able to venodilate to sodium nitroprusside, an
endothelium-independent vasodilator, but not to
insulin.
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Figure 2. Comparison of sodium nitroprusside–mediated
venodilation between subjects with normal and high
cholesterol. Both groups were able to venodilate to sodium
nitroprusside, an endothelium-independent
vasodilator.
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Effects of Cholesterol Lowering on
Vasoreactivity
The last question we addressed in this study was whether
cholesterol lowering reverses abnormal venoreactivity in
HC. To answer this question, 12 hypercholesterolemic
subjects were treated with 20 to 40 mg/d lovastatin for 6
weeks, and the venoreactivity experiment was repeated. There was
significant reduction in total cholesterol (7.24 to
5.43 mmol/L, P<0.001) and LDL cholesterol
(4.78 to 3.49 mmol/L, P<0.001). Changes in
triglycerides (176 to 155 mg/dL) and HDL
cholesterol (1.34 to 1.5 mmol/L) were not significant.
Table 2 summarizes change in lipid
profile by treatment.
Figure 3 illustrates the effects of
cholesterol lowering on venous reactivity to NE and insulin
among the three groups: NC, HC, and treated HC. Venous diameter change
to NE and insulin of the treated group was between NC and untreated HC.
Although there was a small increase in venous diameter to insulin with
the treatment (average increase of 0.33±0.54 mm to 32 µU/min
insulin), these changes were not statistically significant. Reduction
in LDL cholesterol ranged from 0.75 to 1.55 mmol/L,
with a mean of 1.29 mmol/L. With this narrow range of reduction,
there was no significant relationship between the magnitude of
reduction in LDL cholesterol and change in venous diameter
to insulin with treatment (r=0.25, P=NS).
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Figure 3. Venous reactivity to NE and insulin after the
treatment with HMG CoA reductase inhibitors for 6 weeks
compared among NC, HC, and treated HC.
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Furthermore, we examined the relationship between plasma
cholesterol levels and vasodilator effects of insulin;
there was a significant inverse relationship between plasma LDL
concentration and venous diameter changes with insulin
(r=-0.42, P<0.02). Figure 4 demonstrates this relationship.
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Figure 4. A significant inverse relationship is shown
between venodilator effects of insulin and plasma LDL
cholesterol concentration. Mean±SD values for each group
are superimposed.
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Local infusion of NE alone or combined with insulin or sodium
nitroprusside at the dose ranges used for this study did not
significantly change heart rate or BP.
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Discussion
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The present study demonstrates that insulin-mediated
venodilation is attenuated in HC compared with NC. The nitrate donor
sodium nitroprusside caused equal degrees of venodilation in both
groups. This finding suggests that insulin-mediated venodilation is
dependent on endothelial NO generation. A vasodilatory
effect of insulin has been reported by several investigators, although
underlying mechanisms have not been agreed on. Recent work by Kahn et
al15 has demonstrated that insulin attenuates
vascular smooth muscle calcium influx by means of both voltage-operated
channels and receptor-mediated mechanisms. Creager et
al16 have reported that insulin induces
ß-adrenergic–mediated vasodilation, and Lembo and
colleagues17 suggested that insulin blunts
sympathetic vasoconstriction via an
2-adrenergic pathway. We have previously
reported that insulin attenuates NE-induced vasoconstriction via the
cGMP pathway.12 The present study of blunted
insulin-mediated vasodilation in
hypercholesterolemia further strengthens the
hypothesis that insulin-mediated vasodilation is
endothelium dependent and extends the observations to
veins, which are more easily studied than arteries.
Another noteworthy finding of the present study is that our
hypercholesterolemic subjects had normal glucose and
insulin responses to a glucose challenge but showed abnormal vascular
responses to insulin. Our results clearly demonstrate that impaired
vasodilatory effects of insulin are not always accompanied by glucose
intolerance. This means that selective resistance to insulin action on
vasculature may occur in pathophysiological
conditions that cause abnormal endothelial function.
Thus, altered vasoreactivity to insulin may occur in clinical
populations with or without metabolic insulin
resistance.
The present study used a preconstricted venous model to examine
vasodilator effects of insulin. Previously, we used the venous model
and found that insulin alone did not have a venodilator effect on
relaxed vein.12 Our experience supports earlier
observations in the literature18 that in subjects
who are supine and comfortably relaxed, the forearm veins are usually
fully dilated, in part because of low sympathetic output. In these
circumstances, no response is seen if a dilator substance is given.
Thus, there must be some vasoconstriction to demonstrate any
vasodilator effect. In our studies, the cuff inflation, which was
necessary to minimize measurement variability, may cause "artificial
vasodilation." Consequently, it was necessary to preconstrict vessels
with NE to demonstrate vasodilator effects of insulin.
Assessment of endothelial function has been generally
carried out by measuring flow-dependent dilation to acetylcholine in
the human coronary or brachial
arteries.10 11 Our ultrasonographic method
provides the cross-sectional image of the vein and permits direct
measurement of absolute vein diameter while avoiding systemic effects
of infused drugs. Several animal and human studies have reported that
hypercholesterolemia is associated with
impaired endothelial function and abnormal forearm
vasoreactivity.19 20 21 Our finding in the dorsal
hand vein indicates that the potential effect of insulin on vascular
tone or vascular responses to physiological
vasoconstrictors is not limited to the arterial system and
may be important in the study of phenomena affecting venous return to
the heart.
Although veins are capacitance vessels that have less smooth muscle
than arteries, they are easily accessible and share many structural and
functional similarities with arteries. The role of arterioles in the
regulation of BP has long been the subject of intense investigation. In
contrast, the role of veins has received less attention. Because veins
have sympathetic innervation, there is
physiological variation in venomotor
tone.18 At least two thirds of the circulating
blood volume is normally contained in the venous system, so changes in
venous capacitance will directly affect cardiac filling ("preload")
and may have effects on regional blood flow
patterns.22 Dorsal hand veins have been widely
used for pharmacological studies by measuring changes in venous
diameter as reflected by a linear variable differential
transformer.23 24 25 Venoconstrictor responses to
NE measured by ultrasonography in this study were comparable to those
found in other studies.26 27 In this study,
NE-induced constriction was greater in HC than in NC, although the data
did not reach statistical significance.
Previously we have reported that patients with high
cholesterol show exaggerated BP response to mental
stress.9 The dorsal hand vein responses to NE and
insulin in this population may explain the greater BP response to
stress with hypercholesterolemia. These
findings suggest that venous reactivity to vasoactive substances may
reflect systemic BP regulation. Our venous model was able to identify
abnormal insulin-mediated vasodilation in subjects with high
cholesterol. Thus, an impaired
endothelium-dependent vasodilation may be a mechanism
by which hypercholesterolemia contributes to
increased BP response during stress.
Further, treatment of hypercholesterolemia with
HMG CoA reductase inhibitors reduced BP response to mental
stress.9 Significant improvement of
endothelium-dependent vasodilation has been reported
with cholesterol reduction treatments for 6 months or
longer.28 29 Our high-cholesterol
group was treated with HMG CoA reductase inhibitor for 6
weeks, and it may take longer than 6 weeks of cholesterol
lowering to achieve optimal reversal of endothelial
dysfunction. Nevertheless, there was a significant inverse relationship
between plasma LDL concentration and venodilator effects of insulin.
Therefore, reversing or normalizing endothelial
dysfunction at an early stage with nonpharmacological and
pharmacological interventions may prevent subsequent
endothelial damage and may normalize exaggerated
cardiovascular reactivity and reduce the risk of
cardiovascular disease.
In summary, the present study documents impaired insulin-mediated
vasodilation in patients with high cholesterol.
Furthermore, our study demonstrates a significant inverse relationship
between venodilator effect of insulin and plasma LDL
cholesterol concentration. Our observation that blunted
insulin-mediated vasodilation is not specific for metabolic
insulin resistance and can occur before overt glucose intolerance is a
significant finding and has potential clinical implications.
Metabolic abnormalities are associated with hypertension
and often cluster together. The interaction of these risk factors on
vascular reactivity may be an important component for overall
regulation of BP. The demonstration of impaired vasodilator effect of
insulin in patients with high cholesterol may provide
insight into the possible detrimental interaction of these risk
factors.
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Selected Abbreviations and Acronyms
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| BP |
= |
blood pressure |
| HC |
= |
hypercholesterolemic subjects |
| HMG CoA |
= |
hydroxymethylglutaryl coenzyme A |
| NC |
= |
normal-cholesterol subjects |
| NE |
= |
norepinephrine |
| NO |
= |
nitric oxide |
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Acknowledgments
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This study was supported by National Heart, Lung, and Blood
Institute grant HL-32050 and Food and Drug Administration grant
FD-T-000889. We thank Wendy Orlowski, RN, and Mary Bateson, RN, for
their assistance in this investigation.
Received October 21, 1997;
first decision November 26, 1997;
accepted February 4, 1998.
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Top
Abstract
Introduction
