(Circulation. 1996;93:1403-1410.)
© 1996 American Heart Association, Inc.
Articles |
Insulin Modulation of ß-Adrenergic Vasodilator Pathway in Human Forearm
From the Istituto Neurologico Mediterraneo, Neuromed, Pozzilli (IS) (G.L., C.V., B.T.), and the Department of Internal Medicine, School of Medicine, Federico II University, Naples (G.I., V.R., L.P., B.T.), Italy.
Correspondence to Bruno Trimarco, MD, Medicina Interna, Università di Napoli Federico II, Via S Pansini 5, 80131 Napoli, Italy. E-mail trimarco@ds.cised.unina.it.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background Insulin modulates sympathetic vasoconstriction, but the mechanisms underlying this effect are not completely elucidated. We have recently investigated the insulin effect on the
1- and 2-adrenergic
vasoconstriction pathway, where it is still conflicting with the
possible insulin influence on the ß-adrenergic vasodilator
pathway. The aim of the present study was to investigate this
issue.
Methods and Results The study was performed on the forearm
of healthy humans, and all test substances were infused into the
brachial artery at systemically ineffective rates. In five subjects, we
evaluated isoproterenol-induced vasodilation (1, 3, 6, and 9
ng·kg-1·min-1)
both under control conditions and during insulin infusion (0.05
mU·kg-1·min-1).
In another group of five subjects, we tested whether the vasorelaxant
effect of sodium nitroprusside (1, 2, 4, and 8
ng·kg-1·min-1)
was modified by insulin. Moreover, to explore whether the interaction
between insulin and forearm ß-adrenergic pathway participates in
insulin modulation of sympathetic-evoked vasoconstriction, we
measured in six normal subjects the forearm vascular response to
lower-body negative pressure under control conditions and during
intrabrachial infusion of insulin alone and in combination with a
selective ß-adrenergic blocking agent (propranolol 10
µg/100 mL per minute). Finally, to verify whether insulin interaction
with the ß-adrenergic pathway may also account for insulin
modulation of 2-adrenergic vasoconstriction, we assessed
the vascular response to a selective 2-adrenergic
agonist before and after propranolol administration.
Insulin exposure potentiated the vascular responsiveness to
isoproterenol but did not affect the vasodilator response to sodium
nitroprusside. Furthermore, the insulin-induced attenuation of
sympathetic vasoconstriction was partially corrected by
propranolol. In contrast, the insulin modulation of
2-adrenergic vasoconstriction was not influenced by
ß-adrenergic blockade.
Conclusions Taken together, our results suggest that
insulin modulation of sympathetic-induced vasoconstriction is
carried out through an interaction of the hormone with the pathways of
both 2- and ß-adrenergic receptors.
Key Words: forearm vascular resistance • nervous system • receptors, adrenergic, alpha
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The actions of insulin are characterized by a wide variety of effects, including modulation of glucose and amino acid transport, activities of key enzymes in intermediary metabolism, rates of protein, DNA and RNA synthesis, transcription of specific genes, and cellular growth and differentiation. Recently, a large body of studies clearly showed that insulin also has relevant effects on the cardiovascular function through both a direct vasorelaxant action on peripheral vasculature1 2 3 and an indirect effect on the autonomic nervous system.4 5 6 In humans, in particular, although insulin evokes a net reflex increase in sympathetic outflow, it coincidentally can blunt the vasoconstrictive effect resulting from the reflex sympathetic activation.7 The balance between these different insulin actions might play an important role in the setting of hypertensive conditions.8 Thus, understanding the precise mechanisms by which insulin exerts its cardiovascular effects represents a significant challenge.
Recent studies clarified that insulin affects sympathetic outflow
by a central neural mechanism6 acting on the anteroventral
third ventricle.9 On the contrary, the mechanism by which
insulin exerts its modulating action on reflex sympathetic
vasoconstriction is not completely elucidated, but new knowledge is
shedding light on this issue. In particular, we recently explored in
humans the interaction between insulin and sympathetic
vasoconstrictive pathways, demonstrating that insulin
interacts selectively with the 2-adrenergic
pathway.10 However, a recent study on aortic rings of
normotensive rats also indicated that part of the modulating effect of
insulin on adrenergic vasoconstriction could be ascribed to a
facilitating effect on the ß-adrenergic vasodilator
pathway.11 Conflicting results have been described in
humans. In particular, Creager et al12 reported in 1985
that the vasorelaxant effect of insulin was abolished by a
ß-adrenergic receptor blocking agent; more recently, Randin et
al13 showed that propranolol administration
could not modify the vascular action of insulin.
Therefore, we planned the present study to clarify whether insulin
interacts with the ß-adrenergic pathway in the human forearm and
eventually to verify whether the interaction between insulin and the
ß-adrenergic pathway may also account for the modulation of
2-adrenergic vasoconstriction.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
The study group consisted of 28 normal volunteers (22 men, 6 women) ranging from 19 to 40 years of age (average, 30±1 years). Medical history, physical examination, and laboratory analyses were performed to evaluate the subjects' normalcy. Renal, liver, and endocrine functions were normal. Body weight was 77±2 kg; body mass index was 24.7±0.5 kg/m2. No subject had had recent changes in body weight or dietary habits. All subjects had a normal tolerance to a 75-g oral glucose load (according to the criteria of the National Diabetes Data Group).14 No subject was engaged in competitive sports or did intense physical activity during the days immediately before the study. Written informed consent was obtained from all participants. The experimental protocol was in accordance with institutional guidelines for human research.
Procedures
The study began at 8 AM in a quiet room with a
constant temperature of 22°C to 24°C. All subjects were studied in
a postabsorptive state in the supine position after a 12- to 15-hour
overnight fast. No premedication was administered. On a subject's
arrival at the laboratory, forearm volume was measured by water
displacement. The forearm perfusion technique was performed as
previously described.15 A plastic cannula was introduced
in a retrograde manner into a large antecubital vein and threaded as
deeply as possible. In the same arm, a second double-lumen catheter
with the distal and proximal holes separated by 
3 cm (Arrow
International Inc) was introduced into the brachial artery. The distal
hole was used to infuse insulin and other test substances, and the
proximal lumen was used to sample arterial blood entering
the forearm that was uncontaminated by solutions infused downstream and
to measure arterial blood pressure by means of a Statham
P23Db pressure transducer. Systolic and diastolic
pressures were recorded on a multichannel polygraph (Gould
Instruments). Heart rate was determined from a
simultaneously obtained ECG signal and calculated from the
R-R interval. Bilateral blood flow (expressed in milliliters per 100 mL
of tissue per minute) was measured by strain-gauge
plethysmography16 with a Digimatic DM2000 (Medimatic)
instrument with a calibrated mercury-in-Silastic strain gauge
applied on each arm 5 cm below the antecubital crease. Both arms
were supported above heart level. Forearm blood flow (FBF) was measured
simultaneously in both arms from the rate of the increase
in forearm volume while venous return from the forearm was prevented by
inflating a cuff around the upper arm. Forearm vascular resistance was
calculated as the ratio of mean arterial pressure
(diastolic pressure plus one third of the pulse pressure)
to the FBF and expressed as arbitrary units reflecting millimeters of
mercury per milliliter per 100 mL of tissue per minute. The
intrasubject coefficient of variation was 7% based on two consecutive
measurements taken at 1-minute intervals.
Protocols
All test substances were dissolved in NaCl 0.9% on the day of
the study. The infusion rate of all substances into the brachial artery
was chosen to act selectively in the experimental forearm without
causing systemic effects.
The intra-arterial infusion of insulin (0.05 mU·kg-1·min-1), insulin plus propranolol (10 µg/100 mL per minute), or propranolol alone was performed 30 minutes before and throughout the application of the various vasoactive tests. Insulin infusion induced an increase in deep venous insulin concentration (from 51±6 to 506±35 pmol/L, n=22, P<.01) without affecting the systemic levels of the hormone (from 50±7 to 51±7 pmol/L, n=22, P=NS).
After complete instrumentation, all subjects rested at least 30 minutes
to establish a stable baseline before data collection. Fig 1
shows flow diagrams of the protocols.
|
Series 1: Effects of Insulin on Isoproterenol- and Sodium
Nitroprusside–Induced Forearm Vasodilation
To evaluate the effect of insulin on the forearm vasodilation
induced by the ß-adrenergic receptor selective stimulation, we
assessed in five subjects the responses to intrabrachial infusion of
isoproterenol before and during intrabrachial infusion of insulin.
Isoproterenol was administered at 1, 3, 6, and 9
ng·kg-1·min-1.
Each drug dose was maintained for 10 minutes to analyze the
vascular steady state response. To rule out the hypothesis that insulin
could not specifically interact with the isoproterenol-induced
vasodilation, we tested in another group of five subjects the
hemodynamic effect of intra-arterial
infusion of sodium nitroprusside17 18 (1, 2, 4, and 8
ng·kg-1·min-1)
before and during insulin administration.
Series 2: Effects of Insulin and Insulin Plus
Propranolol on Forearm Neurogenic
Vasoconstriction
Lower-body negative pressure (LBNP; applied incrementally at
5, 10, 15, and 20 mm Hg for 5 minutes each) was used to cause a graded
reflex forearm sympathetic vasoconstriction. An airtight chamber,
similar to that described by Mark and Kerber,19 was placed
over the lower portion of each subjects' body from the iliac crest
down. Negative pressure applied to the chamber was monitored by a
pressure transducer. FBF was measured in both arms during the last 90
seconds of each level of LBNP. To simplify the experimental protocol,
we decided not to measure the changes in central venous pressure
induced by LBNP, which represent the stimulus for sympathetic
reflex activation. Thus, we used the simultaneous
assessment of FBF in the contralateral arm to rule out the possibility
that the changes in the vascular response in the experimental arm could
result from a different decrease in central venous pressure during
LBNP.
To verify the possible interaction between insulin and forearm ß-adrenergic pathways during insulin modulation of the forearm neurogenic vasoconstriction, we evaluated in six normal subjects LBNP-evoked hemodynamic responses under control conditions, during intrabrachial insulin infusion, and during simultaneous administration of insulin and propranolol, a ß-adrenergic receptor blocking agent. In addition, we evaluated the effect of propranolol on LBNP-evoked vasoconstriction in another group of six subjects.
Series 3: Effects of Insulin and Insulin Plus
Propranolol on Forearm Vasoconstrictive
Responses Induced by BHT-933
To rule out the possibility that an interaction between
insulin and ß-adrenergic pathways may contribute to the insulin
modulation of the 2-adrenergic vasoconstriction, we
assessed the vascular response to intrabrachial infusion of the
2-adrenoceptor selective agonist BHT-933 under control
conditions, during intrabrachial infusion of insulin, and during
simultaneous intra-arterial infusion of
insulin and propranolol in a group of six subjects.
Dose-response curves were generated for each period. In particular,
BHT-933 was infused at 0.5, 1, 2, and 4
µg·kg-1·min-1.
Each drug dose was maintained for 10 minutes to analyze the
vascular steady state response.
Analytical Methods
Plasma insulin was measured by
radioimmunoassay.20
Data Analysis
Comparison of plasma insulin levels obtained in basal state and
during intra-arterial infusion of the hormone was
evaluated by Student's t test. One-way
repeated-measures ANOVA was used to evaluate the responses to
graded LBNP, isoproterenol, sodium nitroprusside, and BHT-933. To
estimate the effect of insulin, insulin plus propranolol,
or propranolol alone on the responses to LBNP,
isoproterenol, sodium nitroprusside, and BHT-933, repeated-measures
ANOVA with a grouping factor was performed. Post hoc
simultaneous multiple comparisons were done by
Bonferroni's analysis.21 Results are
presented as mean±SE.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Effects of Insulin on Isoproterenol or Sodium Nitroprusside Forearm Vasodilation
The infusion of increasing amounts of isoproterenol in the brachial artery did not modify arterial blood pressure and heart rate but induced a dose-dependent vascular response in the experimental arm (Table 1
and Fig 2).
During insulin infusion, no significant difference could be detected in
the hemodynamic parameters. Under these
conditions, isoproterenol administration also induced significant
vasodilation. However, the isoproterenol-induced vasodilator
response was significantly increased in the presence of insulin
(F=3.285, P<.05 by ANOVA; Fig 2).
|
|
) and during
insulin administration (
). Bases 1 and 2 represent values
before and 30 minutes after the start of vehicle or insulin infusion,
respectively. Each point represents mean±SEM.
*P<.05 vs the same situation under control conditions.
In another set of experiments, the infusion of increasing amounts
of sodium nitroprusside in the brachial artery did not influence
arterial blood pressure (from 95±3 to 98±4 mm Hg,
P=NS) and heart rate (from 81±3 to 77±7 beats per minute,
P=NS) but induced a dose-dependent vasodilation in the
experimental arm (Fig 2
). In the same way, during insulin exposure
sodium nitroprusside administration induced a dose-dependent
vasodilation comparable in magnitude with that observed earlier
(F=0.358, P=NS; Fig 2).
Effects of Insulin and Insulin Plus Propranolol on
Forearm Neurogenic Vasoconstriction
As Table 2 shows, mean blood pressure and
heart rate remained substantially unmodified during graded LBNP both
under control conditions and during infusion of insulin alone or
insulin combined with propranolol. In contrast, LBNP
induced a significant decrease in FBF and consequently an increase in
forearm vascular resistance in both the experimental and contralateral
arms (Fig 3). Furthermore,
intra-arterial insulin infusion did not affect systemic
and forearm hemodynamics. During insulin
administration, however, LBNP induced a vascular response in the
experimental arm that was significantly decreased compared with that
observed when LBNP was applied under control conditions
(F=19.683, P<.01; Fig 3). In contrast, the
LBNP-induced forearm vascular response in the contralateral arm was
comparable to that observed previously (F=0.485,
P=NS). Finally, during intrabrachial infusion of both
insulin and propranolol, LBNP induced a forearm vascular
response in the contralateral arm that was comparable in magnitude to
those observed both under control conditions and during infusion of
insulin alone (F=0.634, P=NS; Fig 3), whereas in
the experimental arm, LBNP-induced vasoconstriction was potentiated
compared with that recorded during infusion of insulin alone
(F=4.250, P<.05; Fig 3) but still blunted
compared with that observed under control conditions
(F=2.976, P<.05; Fig 3).
|
|
).
Bases 1 and 2 represent values before and 30 minutes after the
start of vehicle, insulin, or insulin plus propranolol
infusion, respectively. Each point represents mean±SEM.
*P<.05 vs the same situation under control conditions.
P<.05 vs the same situation during insulin alone.
In another set of experiments, intrabrachial propranolol
infusion was not able to modify the LBNP-induced forearm vascular
response (Table 3).
|
Effects of Propranolol on Insulin Modulation of the
Forearm Vasoconstrictive Responses Induced by
BHT-933
Under control conditions, the intrabrachial infusion of increasing
amounts of BHT-933 did not modify blood pressure and heart rate but
induced a dose-dependent decrease in FBF (Table 4)
and consequently an increase in forearm vascular resistance in the
experimental arm (Fig 4). During insulin administration,
the intra-arterial infusion of increasing doses of
BHT-933 still induced a dose-dependent vasoconstriction, but this
response was significantly blunted compared with that produced by
infusion of the same agent under control conditions
(F=7.380, P<.05; Fig 4). During
simultaneous intrabrachial infusion of insulin and
propranolol, arterial blood pressure, heart
rate, and FBF remained substantially unmodified (Table 4). Under these
conditions, administration of BHT-933 induced a
vasoconstrictive response similar to that observed
during infusion of insulin alone (F=0.060, P=NS;
Fig 4) and still significantly blunted compared with that observed
under control conditions (F=6.319, P<.01; Fig 4).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present results in humans show that forearm insulin exposure can sensitize the vascular ß-adrenergic receptor responsiveness. Furthermore, the interaction between insulin and ß-adrenergic signal pathways also is supported by the evidence that insulin-induced attenuation of sympathetic vasoconstriction is partially reduced by a selective ß-adrenergic blockade.
There is much evidence in humans that insulin stimulates peripheral sympathetic efferent outflow but is simultaneously able to attenuate the vascular effects of sympathetic overactivity. One potential mechanism by which insulin modulates the vasoconstrictive effects of sympathetic nervous system activation could be a sensitizing action on the vascular ß-adrenergic receptor pathway. In vitro studies seem to support this hypothesis because an insulin-induced enhancement of vascular ß-adrenergic responsiveness was shown recently in aortic rings.11 Moreover, the interaction between insulin and the ß-adrenergic signal pathway also has been described in other cellular systems,22 23 24 further encouraging us to verify in humans the possible interaction between these two signal pathways at the vascular level.
On this issue, it is critical to consider the results of two previous studies reporting conflicting conclusions. Creager et al12 evaluated the cardiovascular response to insulin by administering increasing amounts of the hormone into the brachial artery, starting from 0.1 mU·kg-1·min-1, which was twofold higher than the dose used in our and similar studies designed to investigate the effects of physiological increases of insulin levels.6 10 25 26 Under these conditions, insulin spilled significantly into the systemic circulation, resulting in hypoglycemia and epinephrine release, and the forearm vasodilator response was completely abolished by the intrabrachial infusion of a ß-adrenergic blocking agent. In this setting, the conclusion that insulin-induced vasodilation was mediated through a ß-adrenergic mechanism was troubled by the concomitant confounding effect of hypoglycemia. Subsequently, to avoid the effects of systemic insulinization, Creager et al clamped blood glucose at its basal values. Under these conditions, a significant increase in FBF was observed only at the highest level of intrabrachial insulin infusion rate (1 mU·kg-1·min-1), which obviously exposed the forearm at elevated pharmacological amounts of insulin. In contrast, Randin et al13 recently reported that insulin, delivered intravenously and maintaining euglycemic conditions, could evoke an increase in calf blood flow and that such an effect was completely unaltered by systemic propranolol administration. In this setting, the conclusion that ß-adrenergic mechanisms were not involved in the vasodilator effect of insulin was troubled by the systemic infusion of propranolol, which has been reported to interfere heavily with the vascular response.27 28 In particular, systemic ß-blockade dissociates the response of calf vascular resistance from activation of muscle sympathetic nervous system,29 which represents the main component of the complex insulin action on the cardiovascular system. Thus, such an experimental approach cannot verify whether the vascular effects of insulin are mediated at least in part by an interaction between the hormone and the ß-adrenergic receptors.
Our approach takes into account the pitfalls of the above-mentioned
studies and tries to overcome them by providing a model in which both
insulin and propranolol are infused into the brachial
artery at rates that do not induce systemic effects. Under these
conditions, we could better evaluate the interaction of insulin and the
sympathetic control of vascular function without the complex effects
evoked by systemic insulinization. Confirming our
findings6 7 10 and other
observations,25 30 31 32 33 we could not detect significant
changes in vascular resistance during forearm insulin exposure, whereas
the vascular effects of the hormone were recognized only during forearm
vasoconstriction evoked by sympathetic nervous system activation. In
this study, we have observed that insulin potentiates the
vasodilatation elicited by a selective pharmacological stimulation of
ß-adrenergic receptors. Moreover, the parallel observation that
insulin does not affect the vasodilation induced by sodium
nitroprusside rules out the hypothesis that the hormone may elicit a
generalized facilitation of vasodilation and suggests a specific
interference with the ß-adrenergic receptor response. Our results
also support the possibility that insulin-induced enhancement of
the ß-adrenergic vascular response may play a role in a
physiological recruitment of sympathetic
vasoconstriction. Actually, the combined observations that
intrabrachial propranolol administration partially restores
the forearm vasoconstrictive response to LBNP during
insulin infusion but could not influence the LBNP-evoked
vasoconstriction per se further support the hypothesis that the
interaction between insulin and ß-adrenergic pathways plays a
role in insulin modulation of sympathetic-evoked vascular response.
However, we have recently observed that the vascular
2-adrenergic pathway also is modulated by insulin;
consequently, it was imperative to discern whether our previous
observation should be at least partially modified after the disclosure
of the relationship between insulin and ß-adrenergic pathways at
the vascular level. Our data with the selective
2-adrenergic receptor agonist BHT-933 during
propranolol administration clearly indicate that insulin
modulation of 2-adrenergic vasoconstriction is not
affected by simultaneous ß-adrenergic blockade. Taken
together, our findings suggest that insulin exerts its modulatory role
on sympathetic vasoconstriction through both a facilitation of
ß-adrenergic signal and an impairing of
2-adrenergic vasoconstriction. On this issue, we also
must emphasize that during insulin infusion ß-adrenergic blockade
was able to restore the sympathetic-evoked vasoconstriction only
partially, further suggesting that the 2-adrenergic
component was still sensitive to the insulin-modulating action.
Several hypothetical mechanisms can be suggested to explain how insulin
interacts with 2- and ß-adrenergic signals. In
particular, both these adrenergic receptors regulate the intracellular
level of cAMP, the second messenger in the transduction of these two
signal pathways, and studies in cell culture systems indicate insulin
to be a primary regulator of receptor-stimulated adenylyl
cyclase activity.22 34 35 36 37 Moreover, a growing body of
evidence suggests that the hemodynamic effect of
insulin may be mediated by an enhanced endothelial
function.38 39 In particular, a recent study on rat aortic
rings preconstricted with norepinephrine showed that the
ability of insulin to attenuate the adrenergic vasoconstriction is
abolished when
NG-monomethyl-L-arginine
was used to inhibit nitric oxide synthase.40 In the same
way, it should be mentioned that the ß-adrenergic potentiation
observed in vitro during insulin exposure is not observed after
endothelium stripping of aortic rings, thus indicating
that insulin modulation of the ß-adrenergic vasodilation is
endothelium dependent.11 Furthermore, the
relevance of the insulin-enhanced
endothelium-dependent vasorelaxation might be taken
into account even for the modulation of the 2-adrenergic
vasoconstriction. Actually, the 2-adrenergic receptors
also are present on endothelial cells, and
activation of the 2-adrenergic receptor signal
transduction pathway represents a strong stimulus for
endothelium-derived relaxing factor
release.41 42 Thus, it could be reasonable to hypothesize
a potential interaction of insulin at the
endothelial 2- and
ß-adrenergic signal transduction levels that promotes the
generation of vasorelaxing products, which may modulate the
vascular effects of sympathetic overactivity simultaneously
evoked by insulin.
The strong epidemiological evidence linking essential hypertension to
insulin resistance8 43 44 and the recent observations that
this abnormality of insulin action is an inherited trait detected
before the development of high blood pressure44 45 46
obviously encourage us to identify the precise
physiological relationships between insulin effects
and cardiovascular functions. Our current results,
reporting a specific interaction between insulin and vascular
2- and ß-adrenergic signal pathways, may address
in a more detailed way the next studies in hypertensive patients in
whom a loss of insulin-induced attenuation of the
sympathetic-evoked vasoconstriction has been
reported.47 48
Received September 13, 1995; revision received October 30, 1995; accepted October 31, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Alexander WD, Oake RJ. The effect of insulin on vascular reactivity to norepinephrine. Diabetes. 1977;26:611-614. [Abstract]
2. Yagi S, Takata S, Kiyokawa H, Yamamoto M, Noto Y, Ikeda T, Hattori N. Effects of insulin on vasoconstrictive responses to norepinephrine and angiotensin II in rabbit femoral artery and vein. Diabetes. 1988;37:1064-1067. [Abstract]
3. Standley PR, Zhang F, Ram JL, Zemel MB, Sowers JR. Insulin attenuates vasopressin-induced calcium transient and voltage-dependent calcium response in rat vascular smooth muscle cells. J Clin Invest. 1991;88:1230-1236.
4. Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991;87:2246-2252.
5. Berne C, Fagius J, Pollare T, Hjemdahl P. Sympathetic response to euglycaemic hyperinsulinemia. Diabetologia. 1992;35:873-879. [Medline] [Order article via Infotrieve]
6. Lembo G, Napoli R, Capaldo B, Rendina V, Iaccarino G, Volpe M, Trimarco B, Saccà L. Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension. J Clin Invest. 1992;90:24-29.
7.
Lembo G, Rendina V, Iaccarino G, Lamenza F, Volpe M,
Trimarco B. Insulin reduces reflex forearm sympathetic
vasoconstriction in healthy humans.
Hypertension. 1993;21:1015-1019.
8. Welborn TA, Breckenridge A, Rubinstein AH, Dollery CT, Fraser TR. Serum insulin in essential hypertension and in peripheral vascular disease. Lancet. 1966;1:1336-1337. [Medline] [Order article via Infotrieve]
9.
Muntzel M, Beltz T, Mark AL, Johnson AK.
Anteroventral third ventricle lesions abolish lumbar sympathetic
responses to insulin. Hypertension. 1994;23:1059-1062.
10.
Lembo G, Iaccarino G, Rendina V, Volpe M, Trimarco
B. Insulin blunts sympathetic vasoconstriction through the
2-adrenergic pathway in humans.
Hypertension. 1994;24:429-438.
11.
Gros R, Borkowski KR, Feldman RD. Human
insulin-mediated enhancement of vascular ß-adrenergic
responsiveness. Hypertension. 1994;23:551-555.
12.
Creager MA, Liang CS, Coffman JD.
ß-Adrenergic-mediated vasodilator response to insulin in the
human forearm. J Pharmacol Exp Ther. 1985;235:709-714.
13.
Randin D, Vollenweider P, Tappy L, Jequier E, Nicod P,
Scherrer U. Effects of adrenergic and cholinergic blockade on
insulin-induced stimulation of calf blood flow in humans.
Am J Physiol. 1994;266:R809-R816.
14. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28:1039-1057. [Medline] [Order article via Infotrieve]
15.
Lembo G, Capaldo B, Rendina V, Iaccarino G, Napoli R,
Guida R, Trimarco B, Saccà L. Acute
noradrenergic activation induces insulin resistance in
human skeletal muscle. Am J Physiol. 1994;266:E242-E247.
16.
Trimarco B, Lembo G, Ricciardelli B, De Luca N, Rendina
V, Condorelli GL, Volpe M. Salt-induced plasticity in
cardiopulmonary baroreflexes in salt-resistant
hypertensives. Hypertension. 1991;18:483-493.
17. Bruning TA, Chang PA, Blauw GJ, Vermeij P, van Zwieten PA. Serotonin-induced vasodilation in the human forearm is mediated by the "nitric oxide-pathway": no evidence for involvement of the 5-HT3-receptor. J Cardovasc Pharmacol. 1993;22:44-51.
18. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of forearm resistance vessel in hypercholesterolemic humans. J Clin Invest. 1990;86:228-234.
19.
Mark AL, Kerber RE. Augmentation of
cardiopulmonary baroreflex control of forearm vascular
resistance in borderline hypertension.
Hypertension. 1982;4:39-46.
20.
Debuquois B, Aurbach GD. Use of polyethylene
glycol to separate free and antibody bound peptide hormones in
radioimmunoassay. J Clin Endocrinol Metab. 1971;33:732-738.
21. Wilkinson L. SYSTAT: The System for Statistics. Evanston, Ill: Systat, Inc; 1990.
22. Feldman RD. Insulin mediated sensitization of adenylyl cyclase activation. Br J Pharmacol. 1993;110:1640-1644. [Medline] [Order article via Infotrieve]
23.
Hadcock JR, Ports JD, Gelman MS, Malbon CC.
Cross-talk between tyrosine kinase and G-protein-linked
receptors. J Biol Chem. 1992;267:26017-26022.
24. Bahouth SW, Lopez S. Insulin desensitizes ß1-adrenergic receptor-mediated stimulation of adenylyl cyclase in SK-N-MC cells. Life Sci. 1992;51:271-276.
25.
Capaldo B, Napoli R, Di Bonito P, Albano G, Saccà
L. Dual mechanism of insulin action on human skeletal muscle:
identification of an indirect component not mediated by FFA.
Am J Physiol. 1991;260:E389-E394.
26.
Ferrannini E, Taddei S, Santoro D, Natali A, Boni C,
Del Chiaro D, Buzzigoli G. Independent stimulation of glucose
metabolism and Na+-K+ exchange by
insulin in the human forearm. Am J Physiol. 1988;255:E953-E958.
27.
Ferguson DW, Thames MD, Mark AL. Effects of
propranolol on reflex vascular responses to
orthostatic stress in humans.
Circulation. 1983;67:802-807.
28. Best JD, Halter JB. Blood pressure and norepinephrine spillover during propranolol infusion in humans. Am J Physiol. 1985;248:R400-R406.
29.
Jacobsen TN, Converse RL Jr, Victor RG.
Contrasting effects of propranolol on sympathetic nerve
activity and vascular resistance during orthostatic
stress. Circulation. 1992;85:1072-1076.
30. Louard RJ, Fryburg DA, Gelfand RA, Barrett EJ. Insulin sensitivity on protein and glucose metabolism in human forearm skeletal muscle. J Clin Invest. 1992;90:2348-2352.
31. Yki-Järvinen H, Young AA, Lankin C, Foley JE. Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest. 1987;79:1713-1719.
32. Andres R, Baltzan MA, Cader G, Zierler KL. Effect of insulin on carbohydrate metabolism and on potassium in the forearm of man. J Clin Invest. 1962;41:108-115.
33. Buchanan TA, Thawani H, Kades W, Modral JG, Weaver FA, Laurel C, Poppiti R, Xiang A, Hsueh W. Angiotensin II increases glucose utilization during acute hyperinsulinemia via a hemodynamic mechanism. J Clin Invest. 1993;92:720-726.
34.
Kahn NN, Sinha AK. Stimulation of
prostaglandin E1 binding to human blood
platelet membrane by insulin and the activation of
adenylate cyclase. J Biol
Chem. 1990;265:4976-4981.
35. Begeot M, Langlois D, Saez JM. Insulin-like growth factor-1 and insulin increase the stimulatory guanine nucleotide binding protein (Gs) in cultured bovine adrenal cells. Mol Cell Endocrinol. 1989;66:53-57. [Medline] [Order article via Infotrieve]
36.
Devedjian JC, Fargues M, Denis-Prouxviel C, Daviaud D,
Prats H, Paris H. Regulation of 2A-adrenergic
receptor in the HT29 cell line. J Biol
Chem. 1988;263:15553-15580.
37. Irvine FJ, Housley MD. Insulin and glucagon attenuate the ability of cholera toxin to activate adenylate cyclase in intact hepatocytes. Biochem J. 1988;251:447-452. [Medline] [Order article via Infotrieve]
38. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest. 1994;94:1172-1179.
39. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest. 1994;94:2511-2515.
40. Wu H, Jeng YY, Yue C, Chyu KY, Hsueh W, Chan T. Endothelial-dependent vascular effects of insulin and insulin-like growth factor I in the perfused rat mesenteric artery and aortic ring. Diabetes. 1994;43:1027-1032. [Abstract]
41. Cocks TM, Angus JA. Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin. Nature. 1983;305:627-630. [Medline] [Order article via Infotrieve]
42. Vanhoutte PM, Miller VM. Alpha-2 adrenoceptors and endothelium derived relaxing factor. Am J Med. 1989;87(suppl 3C):1S-5S.
43. Modan M, Halkin H, Almog S, Lusky A, Eskol A, Shefi M, Shitrit A, Fuchs Z. Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest. 1984;75:809-817.
44. Reaven GM. Insulin resistance, hyperinsulinemia, and hypertriglyceridemia in the etiology and clinical course of hypertension. Am J Med. 1991;90(suppl 2):7S-12S.
45. Ferrari P, Weidmann P, Shaw S, Giachino D, Riesen W, Allemann Y, Heynen G. Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent. Am J Med. 1991;91:589-596. [Medline] [Order article via Infotrieve]
46.
Lembo G, Iaccarino G, Vecchione C, Rendina V, Trimarco
B. Insulin modulation of vascular reactivity is already impaired
in prehypertensive SHR. Hypertension. 1995;26:290-293.
47. Feldman RD, Bierbrier GS. Insulin mediated vasodilation: impairment with increased blood pressure and body mass. Lancet. 1993;342:707-709. [Medline] [Order article via Infotrieve]
48. Lembo G, Rendina V, Iaccarino G, Lamenza F, Volpe M, Trimarco B. Insulin does not modulates reflex forearm sympathetic vasoconstriction in patients with essential hypertension. J Hypertens. 1993;11(suppl 5):S272-S273.
This article has been cited by other articles:
 |
|
 |
|
  G. de Simone, F. Pasanisi, and F. Contaldo Link of Nonhemodynamic Factors to Hemodynamic Determinants of Left Ventricular Hypertrophy Hypertension, July 1, 2001; 38(1): 13 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Laine, M. J. Knuuti, U. Ruotsalainen, T. Utriainen, V. Oikonen, M. Raitakari, M. Luotolahti, O. Kirvela, P. Vicini, C. Cobelli, et al. Preserved Relative Dispersion but Blunted Stimulation of Mean Flow, Absolute Dispersion, and Blood Volume by Insulin in Skeletal Muscle of Patients With Essential Hypertension Circulation, June 2, 1998; 97(21): 2146 - 2153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Scherrer and C. Sartori Insulin as a Vascular and Sympathoexcitatory Hormone : Implications for Blood Pressure Regulation, Insulin Sensitivity, and Cardiovascular Morbidity Circulation, December 2, 1997; 96(11): 4104 - 4113. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||