584
Insulin Does Not Reduce Forearm
«*-Vasoreactivity in Obese Hypertensive
or Lean Normotensive Men
J. Michael Neahring, Konrad Stepniakowski, Andrew S. Greene, Brent M. Egan
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
Evidence supports the hypothesis that an impaired capacity of insulin to antagonize norepinephrineinduced vasoconstriction increases «-adrenergic tone in overweight young men with insulin resistance
and mild hypertension. Therefore, the effects of regionally infused insulin at 100 /iU/mL on forearm blood
flow (mllliliters per deciliter per minute) and responses to norepinephrine were measured in seven obese
hypertensive and eight lean nonnotenslve men younger than 45 years old. The obese hypertensive men
were hyperinsulinemic and insulin resistant compared with the normotensive men, as evidenced by
abnormal values for fasting insulin (15.5±1.6 versus 7.2±0.8 /lU/mL, P<.001), the insulin area under the
curve in response to a 2-hour oral glucose tolerance test (12.0±1.5 versus 6.7±1.1 mUxmin/dL, /><.01),
and the disappearance rate of glucose during a 15-minute insulin tolerance test (2.7±0.3 versus 4.1 ±0.3
mg%/min, P<.05). The logarithm of the norepinephrine ECM was not significantly different in obese
hypertensive men (mean, 95% confidence interval: —8.15, -8.42 to —7.87) versus lean normotensive men
(-7.91, -8.23 to -7.59). The 2-hour regional insulin infusion at 100 /iU/mL did not significantly alter the
EC H for norepinephrine in either group. Insulin at this concentration induced significant and similar
increases of forearm blood flow in the hypertensive and normotensive groups (1.7±0.4 versus 1.7±0.6
mL/100 mL per minute, P=NS). At approximately 100 jiU/mL, insulin does not antagonize norepinephrine-induced vasoconstriction in the forearm circulation of either obese hypertensive or lean normotensive
men. At this dose, the direct forearm vasodilator actions of insulin, in contrast to indexes of
insulin-mediated glucose disposal, are comparatively well preserved in obese young men with mild
hypertension. Thus, abnormalities of the regional vascular actions of insulin do not explain the previously
reported elevation of forearm vascular or-adrenerglc tone in obese, mildly hypertensive young men.
(Hypertension. 1993^2:584-590.)
KEY WORDS • obesity • hypertension, obesity-induced • insulin • vascular resistance • receptors,
adrenergic, alpha
A lthough being overweight is associated with a
/ \
greater prevalence of hypertension in all age
A. A . and gender subgroups, the strongest relation
between obesity and hypertension is observed in men
younger than 45 years old.1 Overweight men younger
than 45 years old have not only threefold more hypertension but also a fivefold greater prevalence of fasting
insulin values greater than 11 /xU/mL compared with
lean men of similar age.2 Euglycemic hyperinsulinemia
stimulates sympathetic activity more in younger versus
older men,3 which implicates a neurogenic link between
excess hyperinsulinemia and hypertension in obese
younger men.
Along this line, insulin-induced sympathetic activation is preserved among obese men younger than 45
Received March 30, 1993; accepted in revised form June 21,
1993.
From the Division of Cardiology-Hypertension (J.M.N., K.S.,
B.M.E.), Department of Medicine and Department of Physiology
(K.S., A.S.G., B.M.E.), Medical College of Wisconsin, Milwaukee.
Preliminary data were presented at the National American
Federation for Clinical Research meeting in Baltimore, Md, May
1992, and published in abstract form (Clin Res. 1992;40:244A.).
Correspondence to Brent M. Egan, MD, Division of Clinical
Pharmacology, Medical University of South Carolina, 171 Ashley
Ave, Charleston, SC 29425.
years old, despite their resistance to insulin-mediated
glucose disposal.4 Thus, hyperinsulinemia may contribute to evidence for greater sympathetic drive,
increased forearm vascular a-adrenergic tone, and
elevated blood pressure in obese young men.5'6 However, insulin also antagonizes a-adrenergic vasoconstriction. 79 Given these opposing actions, if disordered insulin metabolism contributes to an elevated
blood pressure, then the pressor effects of insulin must
outweigh the depressor actions.10 In fact, mildly hypertensive Zucker obese rats are resistant to the
inhibitory effect of insulin on phenylephrine-induced
vasoconstriction.8 This study was designed principally
to test the hypothesis that obese, mildly hypertensive
young men are resistant to the action of insulin to
blunt a-adrenergic vasoconstriction.
Insulin may also act as a direct vasodilator in the
forearm,11'12 although agreement is not uniform.13-14
Impairment of the direct vasodilating action of insulin
could contribute to elevated vascular resistance in
obese, hypertensive young men. The secondary aims of
this study were to determine if insulin directly increases
forearm blood flow (FABF) and to document if this
action is impaired in obese men younger than 45 years
old with mild hypertension.
Neahring et al
Methods
Human Volunteers
Fifteen paid male volunteers, aged 34 to 45 years, were
recruited from the Hypertension Clinic and by advertisement. Each subject signed a written informed consent
document approved by the Human Research Review
Committee. All volunteers underwent a history, physical,
and laboratory examination to exclude health problems
except for obesity and hypertension. Medications were
discontinued a minimum of 3 weeks before the study diet
was begun. Seven white men were categorized as obese
hypertensive, defined as a body mass index greater than 27
kg/m2,15 blood pressure greater than 140 mm Hg systolic
and/or greater than 90 mm Hg diastolic, and a history of
hypertension. Eight men (seven white, one black) were
categorized as lean normotensive, with a body mass index
greater than 25.5 kg/m2,1 blood pressure less than 140/90
mm Hg, and no history of hypertension.
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
Physiological Measurements
Blood pressures at screening were measured in triplicate with a mercury sphygmomanometer after subjects
rested for 5 minutes in a seated position. In the laboratory, mean arterial pressure was measured directly from
the brachial artery by electronic integration of the
arterial pulse waveform.5 FABF (in millimeters per 100
mL forearm volume per minute) was obtained by mercury-in-Silastic strain-gauge venous occlusion plethysmography using the Hokanson EC-4.5 A cuff on the arm
was inflated to 50 mm Hg for 15 seconds and deflated 5
seconds over four cycles using the Hokanson E-20 rapid
cuff inflator. A separate cuff around the wrist was
inflated to 50 mm Hg and deflated simultaneously with
the arm cuff to prevent venous return from the hand
circulation during the FABF measurement. Forearm
vascular resistance was calculated as mean arterial
pressure/FABF. Hyperemic FABF was measured after
10 minutes of ischemic forearm exercise.16 Stroke volume (in milliliters) was measured by thoracic impedance.17 Ensemble averaging of 10 cardiac cycles was
used18 to reduce variability of stroke volume caused by
respiration. Cardiac output (in liters per minute) was
calculated as heart rate x stroke volume/1000.
Biochemical Measurements
Serum insulin was measured by radioimmunoassay
(Coat-A-Count Insulin, Diagnostic Products Corp, Los
Angeles, Calif) with a sensitivity of 1 /iU/mL and a
coefficient of variation of 6.5% at insulin values of 1 to
20 fiU/mh and 3.7% at 100 to 300 jiU/mL.19 Glucose
was measured with a glucose analyzer (Beckman Instruments, Brea, Calif). Plasma norepinephrine was measured by single-isotope radioenzymatic assay,20 with
intra-assay and interassay coefficients of variation of 5%
and 8%, respectively. Plasma renin activity was determined by radioimmunoassay.21
Anthropometric Measurements and Calculations
Height and weight were measured in lightly clothed
subjects without shoes. Triceps, biceps, subscapular,
and iliac skinfold thicknesses were obtained with Lange
calipers (Cambridge Scientific Instruments, Cambridge,
Mass). Percent body fat was calculated from the skinfold data.22 Waist and hip circumferences were measured with subjects in the standing position,23 and the
waist-to-hip ratio was calculated.
Insulin and cr-Adrenergic Reactivity
585
Dietary Control
Volunteers were interviewed by the Clinical Research Center (CRC) dietitian to determine their usual
diet. An isocaloric diet was calculated for each subject
using the NUTRITIONIST HI DIET ANALYSIS software (NSquared Computing, Salem, Ore). The diet was controlled for Na+ (500 mg/d), K+ (2500 mg/d), Ca 2+ (800
mg/d), and Mg 2+ (300 mg/d). The caloric composition
of the diet was 45% to 50% carbohydrate, 35% to 40%
fat, and 15% protein. The diet was supplemented with
18 600-mg NaCl tablets daily (approximately 184 mEq).
Subjects came to the CRC on alternate days during the
week before the lab study to be weighed and to obtain
all food and beverages, which were prepared by trained
metabolic cooks in the CRC kitchen under the direction
of the dietitian. The caloric intake was adjusted to
maintain body weight within 1.5% of baseline. Compliance with the diet was verified by 24-hour urinary Na + .
Protocol 1
Seven obese hypertensive and eight lean normotensive subjects completed this protocol. The subject began
a urine collection at 7 AM after 6 days on the study diet,
reported to the CRC at 7 AM the following morning, and
closed the urine collection. Forearm volume by water
displacement and body weight were measured. Electrodes were positioned for impedance cardiography.
The brachial artery catheter was placed under sterile
conditions. Intravenous catheters were inserted retrogradely into a deep vein of the study (ipsilateral)
forearm and in a vein of the contralateral forearm for
blood sampling. Room temperature was controlled to
maintain stable baseline FABF. After 30 minutes of
supine rest, FABF was measured in both arms. Once
three consecutive measurements of FABF were within
±10%, blood samples for glucose, insulin, catecholamines, and plasma renin activity were obtained.
Norepinephrine was infused regionally in seven sequential ascending doses of 3xlO"10, 10"9, 3x10"', 10"8,
3xl0~\ 10"7, and 3xlO" 7 mol/L for 5 minutes each.
FABF was measured during the final 90 seconds of each
infusion. The norepinephrine infusion rate for each dose
was calculated based on FABF ([miUiliter per deciliter per
minute] x [forearm+hand volume (deciliters)]).
After the norepinephrine infusion was completed, baseline FABF was generally reestablished within 40 minutes.
During this time, insulin was diluted to 25 000 /xU/mL in
95 mL 0.9% NaCl with 5 mL of 5% albumin. FABF was
measured every 10 minutes and the infusion rate adjusted
to maintain a regional insulin concentration 100 /xU/mL
above basal levels for 2 hours. Venous glucose and insulin
samples were obtained from both forearms at 30-minute
intervals. After 2 hours, the insulin infusion was continued
while norepinephrine was repeated. The norepinephrine
and insulin were calculated for each dose based on the
preceding FABF value. FABF was then measured after 10
minutes of ischemic exercise.
Subprotocol la. In five obese hypertensive and three
lean normotensive subjects, the diet and study were
repeated. However, 0.9% NaCl plus albumin (vehicle)
without insulin was given (sham procedure) for 2 hours
after the sequential norepinephrine infusion and continued while norepinephrine was repeated. Studies in
the same subject requiring brachial artery catheterization were separated by at least 3 weeks.
586
Hypertension
Vol 22, No 4 October 1993
Subprotocol lb. Four volunteers (three lean, one
obese) followed the study diet for 7 days. They received
a brachial artery infusion of methoxamine at 10"8 to
3xlO~ 6 mol/L. After a second baseline measurement,
insulin was infused at 100 /xU/mL FABF for 2 hours and
continued while methoxamine was repeated.
Subprotocol lc. Four lean volunteers followed the
study diet for 7 days and underwent a regional hemodynamic study in which the FABF response to regional
norepinephrine (3xl0~ 10 to 3xlO~ 7 mol/L) was obtained. After a second baseline measurement, 3xlO~9
mol/L nitroprusside per milliliter FABF was infused
and continued while norepinephrine was repeated.
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Protocol 2
After 6 days on the study diet, all volunteers had
fasting measurements of glucose and insulin on arterialized venous blood24 at baseline (-20, - 1 0 , and 0
minutes) and at 15, 30, 60, 90, and 120 minutes after a
75-g oral glucose load. The following morning, glucose
and insulin measurements were obtained in triplicate in
the fasting state and again 3, 6, 9, 12, and 15 minutes
after an intravenous bolus of human insulin at 0.1 U/kg
(insulin tolerance test).25
Data Analysis
Data are reported as mean±SEM. Analyses were
performed using SPSS 5.0 (Chicago, 111). A comparison of
descriptive variables in hypertensive and normotensive
subjects was made with the Student's unpaired t test.
The insulin and glucose areas under-the-curve (AUC)
were calculated. The dose-response curves to norepinephrine, both with and without insulin, and to nitroprusside were assessed with repeated-measures analysis
of variance for determination of the separate and
interactive effects of diagnosis (hypertensive versus normotensive), dose or time, and insulin. The effective
concentration of norepinephrine inducing 50% of the
maximum response (EG*,) was calculated for each individual using GRAPHPAD 4.0 software (San Diego, Calif).
The fit of the curve to the actual data without and with
insulin, respectively, was i?2=.89±.O6 and .93±.04 in
normotensive subjects and i? 2 =.95±.01 and .96±.03 in
hypertensive subjects. The mean and 95% confidence
intervals for the norepinephrine EQo were calculated
from the group data for hypertensive and normotensive
subjects. Because the differences in venous glucose
values between the two forearms during the regional
insulin infusion were not normally distributed, these
data were analyzed using the nonparametric Wilcoxon
rank-sum test. Three consecutive FABF values were
averaged at baseline and at 30-minute intervals during
the 120-minute insulin infusion. For example, the 30minute value represents the mean of FABF at 20, 30,
and 40 minutes, etc. Analysis of covariance was used to
assess the FABF response to insulin in obese hypertensive versus lean normotensive subjects, while controlling
for differences in basal FABF.
Results
As summarized in Table 1, the hypertensive and
normotensive groups were not significantly different for
age or height. Based on the selection process, the
hypertensive subjects had greater values than normotensive subjects for systolic and diastolic blood pressures as well as body mass index. Percent body fat and
1. Baseline Values for Obese
Hypertensive Patients and Lean
Normotensive Volunteers
TABLE
Variable
Age, y
Height, cm
Body mass index,
kg/m 2
Normotensive
Hypertensive
P
40±1
39±2
NS
180±2
176±3
NS
23.3±0.3
39.0±2.3
<.001
Body fat, %
18.3±1.2
30.7±1.6
<.001
Waist-to-hip ratio
0.85±0.01
0.99±0.02
<.001
Systolic BP, mm Hg
120±3
147±6
<.0O5
Diastolic BP, mm Hg
76±2
95±2
<.0O1
BP Indicates blood pressure. Values are mean±SEM.
the waist-to-hip ratio were increased in hypertensive
subjects. As shown in Table 2, mean intra-arterial
pressure, heart rate, and FABF were significantly higher
in the hypertensive subjects. Cardiac output, hematocrit, and 24-hour urinary Na+ were not significantly
different in the two groups. Postischemic forearm vascular resistance was higher in the obese hypertensive
subjects. Plasma renin activity was significantly higher in
obese hypertensive versus lean normotensive subjects,
which confirms a previous report.26 The comparatively
low values for plasma renin activity in both groups
reflect the high-sodium diet and supine position under
which samples were obtained. Plasma norepinephrine
was not significantly different in the two groups.
Metabolic Characteristics
As shown in Table 3, fasting glucose and insulin levels
were elevated in the hypertensive subjects. Although
the glucose AUC values were not different during the
2-hour oral glucose tolerance test, the insulin AUC was
TABLE 2. Baseline Laboratory Data In Obese
Hypertensive and Lean Normotensive Men
Variable
Normotenslve
Hypertensive
P
Mean BP, mm Hg
79±3
92±4
<.O5
Heart rate, bpm
56±4
69+4
<.01
Cardiac output,
L/min
5.6±0.2
6.2±0.5
NS
(mL/100 mL)/min
2.7±0.2
5.5+0.8
<.005
FABF,,
(mL/100 mL)/min
55.8±6.6
40.6±4.6
NS
1.7±0.2
2.7±0.3
<.O2
FAVR;, U
Hematocrit
0.40±0.01
0.42+0.01
NS
Urine Na + ,
mmol/24 h
207±10
179±9
NS
Plasma NE,
pg/mL
205+11
240 ±27
NS
PRA,
(ng Ang l/mL)/h
0.95±0.15
1.64±0.19
<.O2
BP indicates blood pressure; bpm, beats per minute; FABF,
forearm blood flow; b, baseline; i, after 10 minutes of ischemia;
FAVR, forearm vascular resistance; NE, norepinephrine; PRA,
plasma renin activity; and Ang I, angiotensin I. Values are
mean±SEM.
Neahring et al
Insulin and or-Adrenergic Reactivity
587
3. Glucose and Insulin Metabolism in Obese Hypertensive and
Lean Normotenslve Men
TABLE
Variable
Normotenslve
Hypertensive
P
Fasting plasma insulin, /ill/mL
7.2+0.8
1.5+1.6
<.001
Fasting plasma glucose, mg/dL
86±1
95±2
<.01
11 980±1 536
<.01
18601±1 048
NS
2.7±0.3
<.05
Insulin AUCOGTT, ^Uxmin/mL
Glucose AUCOQTT. mgxmin/dL
Knr, mg%/min
6 678 + 1 124
17 203±703
4.1 ±0.3
Insulin AUCrrr, /iUxmin/mL
5 777±663
7 439±370
Glucose AUCm, mgxmin/dL
1 196±26
1 312±39
<.O5
9.7±3.0
0.0±0.7
<.O3
Gluvoa.-Gluv^,,, mg/dL
NS
AUC Indicates area under-the-curve; OGTT, oral glucose toterance test; K, disappearance rate constant
for glucose during insulin toterance test (ITT); and Gluvom-Gluv**, venous glucose concentrations in the
contralateral minus ipsilateral forearm during 2-hour regional insulin infusion. Values are mean±SEM.
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
greater in hypertensive subjects. During the 15-minute
insulin tolerance test,25 the disappearance rate of
plasma glucose was significantly slower in hypertensive
subjects, despite a tendency to a higher insulin AUC.
The difference between the contralateral and ipsilateral
forearm venous glucose concentration was significantly
greater in normotensive versus hypertensive subjects
during the final 60 minutes of the regional insulin
infusion.
glucose in the contralateral forearm (Fig 4). Although
the sham procedure increased FABF, this was significantly less than the rise of FABF observed with insulin
(Fig 4). Heart rate, mean arterial pressure, and cardiac
O
•
NE
Normotenslve
Hypertemive
NE + Insulin
Effects of Regional Hyperinsulinemia on Forearm
Vascular Reactivity to Norepinephrine
The absolute norepinephrine-induced reduction in
FABF was greater in hypertensive than normotensive
subjects, whereas the relative (log) flow responses were
parallel (Fig 1). As shown, the logarithm of the norepinephrine EQo was not significantly different in the
obese hypertensive (mean, 95% confidence interval:
-8.15, -8.42 to -7.87) versus the lean normotensive
(-7.91, -8.23 to -7.59) groups. Insulin did not significantly alter the norepinephrine ECw either within or
between the hypertensive (-8.08, -8.34 to -7.82) and
normotensive (-8.01, -8.43 to -7.58) groups. Insulin
did not antagonize methoxamine-mediated constrictor
responses (Fig 2). In fact, insulin augmented (significantly steeper slope) the absolute but not the relative
(log) norepinephrine-induced decline of FABF. This
apparent enhancement of forearm vascular responsiveness to a-agonists was likely a nonspecific effect of the
higher initial FABF, because nitroprusside also significantly increased the slope of the FABF response to
norepinephrine.
Effects of Regional Hyperinsulinemia on Forearm
Blood Flow and Comparison of Responses in Obese
Hypertensive and Lean Normotensive Subjects
The regional insulin infusion produced mean venous
plasma insulin concentrations in the ipsilateral forearm
vein of 104±12 fiU/mL in normotensive subjects and
100 ±10 /xU/mL in hypertensive subjects. Blood flow
increased within 30 minutes and was maintained for the
duration of the 2-hour infusion in the ipsilateral but not
the contralateral forearm of both groups (Fig 3). The
regional insulin infusion tended to raise systemic insulin, as measured in the contralateral forearm, in hypertensive and normotensive subjects. However, this did
not alter cardiac output, heart rate, or blood flow and
LogNE
FIG 1. Plots show forearm blood flow (FABF) responses
and calculated group mean ECX values in hypertensive and
normotensive subjects to norepinephrine (NE) alone and with
insulin. Left: Mean arterial pressure (MAP), heart rate (HR),
cardiac output (CO), and absolute and natural log values for
FABF at baseline and during regional NE infusion for
hypertensive and normotensive subjects. Right: Same as left,
but insulin was infused with NE. *P<.05 for indicated time
point vs baseline value; + indicates the two series of data are
different but parallel (no significant effect ofdosexdiagnosis);
and t, the two curves are different and not parallel (significantly different effect, dose x diagnosis).
588
Hypertension
Vol 22, No 4
October 1993
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Log Methoxamine
-10
100 -
LogNE
FlG 2. Plots show effect of insulin and nitroprusside on
forearm blood flow (FABF) responses to norepinephrine (NE)
or methoxamine.
Top: FABF responses to NE and
NE+insulin. Middle: FABF responses to methoxamine and
methoxamine + insulin. Bottom: FABF responses to NE and
NE+nitroprusside. t Indicates the two curves are different and
not parallel (significantly different effect, dosexdiagnosis).
output did not change during the sham procedure. The
absolute mean increase of FABF during the 2-hour
regional infusion of insulin, although significant within
each group, was similar in hypertensive versus normotensive subjects (1.7±0.4 versus 1.7±0.6 mL/100 mL
per minute). The absence of significant differences in
the FABF response to insulin in hypertensive versus
normotensive subjects persisted when controlling for
baseline FABF in covariate analysis.
Discussion
Effect of Regional Insulin on Forearm Vascular
Reactivity to Norepinephrine
The primary objective of this study was to determine
if an impairment of the capacity of insulin to antagonize
reactivity to norepinephrine could contribute to the
increased forearm vascular a-adrenergic tone observed
in our previous studies.5-6 The norepinephrine ECJO was
similar in obese hypertensive versus lean normotensive
subjects (Fig 1). These findings are consistent with our
earlier report that forearm vascular sensitivity to norepinephrine is similar in an overweight group of mildly
hypertensive young men versus normotensive control
subjects of similar age and weight.5 Regional insulin at
approximately 100 ^.U/mL for 2 hours did not antago-
90
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30
60
Time (min)
90
120
FIG 3. Plots show forearm blood flow (FABF) response to
insulin in hypertensive and normotensive subjects. Mean
arterial pressure (MAP), heart rate (HR), cardiac output
(CO), insulin, and FABF in the contralateral (con) and
ipsilateral (ips) forearms are shown at baseline and during
insulin. *¥<.O5 for indicated time point vs baseline value; +
indicates the two series of data are different but parallel (no
significant effect of dosexdiagnosis).
nize forearm vascular a-adrenergic responses, as assessed by changes of the EQo or the absolute reduction
of FABF in response to norepinephrine in either obese
young men with mild hypertension or lean normotensive
control subjects. Thus, we cannot attribute the increased forearm vascular a-adrenergic tone observed in
our previous studies in a predominantly overweight
group of hypertensive5 and obese6 men to an impairment of the local action of insulin to antagonize regional
vascular reactivity to norepinephrine.
Although lean hypertensive and obese normotensive
men were not included in this study, it is unlikely that
insulin would have antagonized their vascular a-adren-
Neahring et al
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FIG 4. Plots show forearm blood flow (FABF) during
insulin vs sham procedure. Heart rate (HR), cardiac output
(CO), systemic glucose (contralateral forearm venous levels),
and FABF values in eight men are shown for the 0.9%
NaCl+albumin (vehicle [sham]) and insulin infusions.
# Indicates that the change in FABF from baseline is greater
(P<.05) during insulin vs sham.
ergic reactivity when such effects were not observed in
either lean normotensive subjects or obese hypertensive
subjects. The failure of insulin to blunt a-adrenergic
vasoconstriction in the forearm was not explained by
major differences of insulin on FABF responses to a
selective ^-receptor agonist (methoxamine) versus a
nonselective ar and a2-receptor agonist (norepinephrine, Fig 2).
We elected to study the effects of a single dose of
insulin on regional reactivity to norepinephrine for two
reasons. First, the investigation by Alexander and Oake7
showed that the capacity of insulin at 150 /xU/mL to
antagonize reactivity to norepinephrine in tail arteries
isolated from male rats was progressively greater over
120 minutes. These data suggest that studying the
effects of multiple insulin doses over briefer time periods may underestimate the effects of insulin on vascular
a-adrenergic reactivity. Second, in most healthy subjects, insulin levels do not exceed 100 jiU/mL even after
a 100-g oral glucose load.2 Thus, if insulin is a physiologically important modulator of vascular a-adrenergic
reactivity, then this effect should be apparent at levels
of 100 /iU/mL or less. Moreover, none of the previous
studies observed both an antagonistic action of insulin
on vascular a-adrenergic reactivity at low doses and a
facilitatory or no effect at higher doses.7-8
Previous studies suggest that the effects of insulin on
vascular responses to a-agonists may be influenced by
multiple factors, including species and gender, regional
versus systemic infusions, physiological versus pharmaco-
Insulin and or-Adrenergic Reactivity
589
logic doses, the presence or absence of endothelium, and
in vitro versus in vivo measurements. For example,
insulin antagonizes pressor responses to norepinephrine
in isolated tail arteries from male but not female rats.7
Insulin also blunts phenylephrine-mediated contractions
in deendothelialized rat aorta.8 Similarly, pharmacologic
doses of insulin antagonize reactivity to norepinephrine,
serotonin, and potassium in the rat mesenteric circulation in vitro.9 However, physiological hyperinsulinemia
enhances rat mesenteric vascular reactivity to norepinephrine but not angiotensin or serotonin.27 Euglycemic
hyperinsulinemia in humans similarly augments pressor
responses to norepinephrine but not angiotensin II.28
Thus, we cannot extrapolate from the forearm to other
regional beds or the systemic circulation.
Effects of Insulin on Forearm Blood Flow and
Comparison of the Flow Responses in Hypertensive
and Normotensive Subjects
In this study, insulin at 100 /xU/mL with its vehicle
(saline plus albumin) was a direct vasodilator in the
regional forearm circulation, because blood flow increased in the ipsilateral (infused) but not the contralateral forearm (Fig 3). Moreover, the vasodilation
induced by insulin was greater than the response to the
sham procedure (Fig 4). Thus, insulin can increase
blood flow by local actions in the forearm.
Andres et al11 reported that locally infused insulin
dilated the forearm circulation in humans. They also
observed a nonspecific vasodilation during the regional
infusion that establishes the requirement for a sham
procedure. Creager and colleagues12 reported that the
forearm vasodilator response to regional insulin was
blocked by propranolol but not by phentolamine. This
suggests that the vasodilator effect of insulin is directly
or indirectly dependent on /3-receptors. Along this line,
preliminary reports indicate that insulin enhances the
cyclic AMP response of human leukocytes to /3-adrenergic receptor agonists.29
Other reports indicate that insulin does not increase
FABF.13-14 One explanation for the incongruity of the
forearm vascular actions of insulin may be the relatively
large variability of basal FABF and the relatively modest local vasodilating action of insulin. In other words,
the vasodilator response to regional insulin in this study,
after correcting for the nonspecific effect of the sham
procedure, was approximately 20%. The minimal decline of systemic glucose levels during the regional
insulin infusion (Fig 3) probably does not reduce the
forearm vasodilator response, because glucose clamping
did not enhance the local vascular response to regional
insulin in a previous study.12 In our experience, very
careful control of the laboratory environment is required to maintain basal FABF within ±10%.5-6-16-30
Therefore, the modest regional vasodilator action of
insulin may be difficult to document. In contrast, systemic hyperinsulinemia appears to increase leg blood
flow and FABF31-32 more than that observed during our
regional insulin infusion. Thus, insulin probably dilates
by systemic or central effects in addition to local actions.
The obese hypertensive subjects had an increased
body mass index and an elevated waist-to-hip ratio,
which are associated with insulin resistance.19-33 They
had evidence for resistance to insulin-mediated glucose
disposal (Table 3) with elevated fasting insulin, a
greater insulin response to oral glucose,34 and a reduced
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Hypertension
Vol 22, No 4
October 1993
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rate of glucose disappearance during an insulin tolerance test.25 Despite systemic evidence for insulin resistance, the absolute increase of FABF during the regional insulin infusion was similar in both groups. In
view of the link between flow and metabolic responses
to insulin in the leg,31 one explanation for our data is
that the systemic evidence for insulin resistance in obese
hypertensive subjects does not include their forearms.
Arterial glucose values were not obtained during the
regional insulin infusion because our pilot studies indicated that the arterial sampling with flushing of the
catheter increased the nonspecific vasodilation, as
noted in previous studies.11 However, venous glucose
levels were measured in both forearms at 30-minute
intervals during the regional insulin infusion. The difference between the contralateral and ipsilateral forearm glucose concentrations during the final 60 minutes
of the 2-hour regional insulin infusion would predominantly reflect the effect of insulin in the ipsilateral
forearm. Although this is not a classic regional metabolic "clamp" study and interpretation is limited, the
findings were consistent with previous reports.14 Lean
normotensive subjects had a greater difference between
the contralateral minus ipsilateral venous glucose values
compared with hypertensive subjects (Table 3). Despite
indirect evidence for resistance to insulin-mediated
glucose uptake in the forearm, insulin at 100 jiU/rnL
induced similar absolute increases of FABF in obese
hypertensive and lean normotensive subjects.
Acknowledgments
This work was supported by grant HL-R01-43164 from the
National Institutes of Health; Clinical Investigator and Postdoctoral Fellowship awards from the American Heart Association, Wisconsin Affiliate; and General Clinical Research
Center (GCRC) Grant M01-RR58 to the Medical College of
Wisconsin. The authors thank the GCRC nursing and nutrition staff for superb support.
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J M Neahring, K Stepniakowski, A S Greene and B M Egan
Hypertension. 1993;22:584-590
doi: 10.1161/01.HYP.22.4.584
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