(Circulation. 1995;92:2911-2918.)
© 1995 American Heart Association, Inc.
Articles |
Effect of Insulin on Acetylcholine-Induced Vasodilation in Normotensive Subjects and Patients With Essential Hypertension
From I Clinica Medica, University of Pisa, and the Metabolism Unit, CNR Institute of Clinical Physiology (A.N., E.F.), Pisa, Italy.
Correspondence to Dr Stefano Taddei, I Clinica Medica, University of Pisa, Via Roma 67, 56100 Pisa, Italy.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background The present study was designed to directly test the vasodilation action of insulin and its relation to endothelium-dependent mechanisms.
Methods and Results In 18 normotensive subjects and 27 patients with untreated mild to moderate essential hypertension, we studied the effect of intrabrachial insulin on the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (at doses of 0.15, 0.45, 1.5, 4.5, and 15 µg · min-1 · dL-1), an endothelium-dependent vasodilator, or sodium nitroprusside (at doses of 1, 2, and 4 µg · min-1 · dL-1), an endothelium-independent vasodilator. Local hyperinsulinemia (deep venous plasma insulin, 48±6 and 51±5 µU/mL in control subjects and hypertensive patients, respectively) did not affect basal forearm blood flow and stimulated forearm glucose extraction (control subjects, 3±1% to 11±2%, P<.001; hypertensive patients, 3±1% to 6±1%, P<.001; P<.01 for the between-group difference). In both normotensive and hypertensive subjects, insulin significantly potentiated acetylcholine-induced vasodilation, whereas it did not alter the vasodilatory response to sodium nitroprusside. NG-monomethyl-L-arginine, an inhibitor of endothelial nitric oxide synthesis, blunted insulin-induced facilitation of acetylcholine vasodilation in normotensive but not in hypertensive subjects. In contrast, in hypertensive patients but not in normotensive control subjects, the potentiation of the vascular response to acetylcholine induced by local hyperinsulinemia was abolished by intrabrachial ouabain, an inhibitor of Na+-K+ pump.
Conclusions In healthy humans and essential hypertensive patients alike, local physiological hyperinsulinemia per se does not increase forearm blood flow but potentiates the vasodilation induced by acetylcholine regardless of metabolic insulin resistance. This effect is endothelium-dependent because it is not seen with nitroprusside and is related to the L-arginine–nitric oxide pathway in normotensive subjects and to smooth muscle cell hyperpolarization in essential hypertensive patients.
Key Words: insulin • acetylcholine • blood flow • endothelium-derived factors
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Although the possibility that insulin may have vasoactive properties has been recognized for many years, the recent demonstration1 2 that essential hypertension is associated with insulin resistance has rekindled interest in the vascular effects of the hormone. In both animals3 4 and humans,5 6 systemic hyperinsulinemia decreases peripheral vascular resistance by causing some degree of limb (leg or forearm) vasodilation. This finding is in contrast to the negative results of several studies that tested the vasodilating effects of the local administration of insulin in the human forearm.7 8 9 10 This conflict has cast doubt on a direct vasodilating action of the hormone and has raised the possibility that insulin has different hemodynamic effects according to the route of administration, systemic or local.
Endothelial cells play a key role in modulating vascular tone through the production of relaxing substances, the most important of which are the EDRF nitric oxide, a product of the degradation of L-arginine into citrulline, a still-unidentified EDHF, and prostacyclin.11 It recently was documented that in normotensive humans, leg12 vasodilation induced by methacholine, an endothelium-dependent vasodilator,11 is enhanced during systemic hyperinsulinemia, whereas the vasodilating effect of sodium nitroprusside, an SMC relaxant,13 is not affected. Thus, these observations suggest that in healthy subjects the vasorelaxant effects of systemic hyperinsulinemia are dependent, at least in part, on the endothelium. However, as mentioned above, the vascular effects of systemic and local insulin can be different. In particular, systemic insulin appears to be sympathoexcitatory,3 5 probably by direct action on the central nervous system.14
Therefore, the present study using the perfused forearm technique was undertaken to test whether local hyperinsulinemia modulates endothelial function in healthy humans and in patients with essential hypertension and, if so, by what mechanism.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Subjects
The study group included 27 patients with mild to moderate, uncomplicated essential hypertension and 18 healthy subjects matched for sex, age, and body weight (Table 1
). The
hypertensive patients either were untreated or had stopped
antihypertensive therapy at least 2 weeks before the study. The study
protocol was approved by the Institutional Ethics Committee; informed
consent was obtained from all subjects before their participation in
the study.
|
Experimental Procedure
All studies were performed at 8AM, after an
overnight fast, with the subjects lying supine in a quiet,
air-conditioned room (22°C to 24°C). A polyethylene cannula (21
gauge, Abbot) was inserted into the brachial artery under local
anesthesia (2% lidocaine). The cannula was connected
through stopcocks to a pressure transducer (model MS20, Electromedics)
for the determination of systemic mean arterial blood
pressure (one third pulse pressure plus diastolic pressure)
and heart rate (model VSM1, Physiocontrol) and for
intra-arterial infusions. In 16 of the 18 normotensive
subjects and 24 of the 27 hypertensive patients, another cannula (6 cm
long) was advanced into an ipsilateral deep forearm vein retrogradely.
FBF was measured in both forearms (experimental and contralateral) by
strain-gauge venous occlusion plethysmography (LOOSCO, GL
LOOS).15 Circulation to the hand was excluded 1 minute
before each measurement of FBF by inflation of a pediatric cuff around
the wrist at suprasystolic pressure. Earlier work
determined the sensitivity and reproducibility of the
method.16 Forearm volume was measured by the water
displacement technique. Infusion rates of drugs were normalized to 100
mL tissue by alteration of the drug concentration in the solvent while
the pump flow rate was kept constant. The drugs used were infused
through separate ports through three-way stopcocks at
concentrations that had no systemic effects.
Experimental Design
Protocol A
In 6 healthy
subjects and 8 hypertensive patients, the effect of
insulin on endothelium-dependent and
endothelium-independent vasodilation was assessed
by a dose-response curve to intra-arterial
acetylcholine11 (at infusion rates of 0.15, 0.45, 1.5,
4.5, and 15
µg · min-1 · dL-1
forearm tissue, 5 minutes for each dose) and sodium
nitroprusside13 (at infusion rates of 1, 2, and 4
µg · min-1 · dL-1, 5
minutes
for each dose). Drugs were administered both under control conditions
(ie, during the intrabrachial infusion of saline at 0.2 mL/min) and in
the presence of an intrabrachial infusion of insulin. The insulin
infusion rate was calculated in each subject (from the mean basal FBF
and forearm volume) to produce increments in local arterial
plasma insulin level of approximately 60 µU/mL (420 pmol/L) and was
started 20 minutes before each drug dose response (insulin prime). For
each insulin infusion, simultaneous arterial
and venous samples were obtained before the start and at the end of the
20-minute prime for the measurement of plasma insulin and glucose
concentrations. The sequence of infusion of acetylcholine and sodium
nitroprusside was randomized, and 1 hour of washout was allowed between
each dose-response curve. Fig 1 shows the
experimental designs.
|
Protocol B
To test whether
insulin increases the
endothelium-dependent release of nitric oxide, we
used the arginine analogue L-NMMA, which antagonizes the synthesis of
nitric oxide from L-arginine in a competitive
manner.11 17 In 6 normotensive subjects and 7
hypertensive
patients, the dose-response curve to intra-arterial
acetylcholine at the same doses as in protocol A was performed
according to the following design: during saline (0.2 mL/min), in
the presence of insulin as in protocol A, in the presence of
intra-arterial L-NMMA (100
µg · min-1 · dL-1 started
5 minutes
before acetylcholine and continued throughout), and finally in the
presence of simultaneous infusions of insulin and L-NMMA.
Again, 1 hour of washout was allowed between each dose-response
curve.
Protocol C
Finally, to assess whether
insulin-induced
hyperpolarization can affect the vascular
response to acetylcholine infusion, in another group of 6 normotensive
subjects and 7 essential hypertensive patients, protocol B was modified
by replacing L-NMMA with ouabain18 infused intrabrachially
at 0.72 µg · min-1 · dL-1.
Because
the insulin-induced hyperpolarizing effect is quite rapid in
onset,19 ouabain was infused 20 minutes before
acetylcholine was added (ie, it was coinfused with insulin).
Protocol D
To rule out the possible interference
caused by L-NMMA– or
ouabain-induced vasoconstriction on the response to
acetylcholine, in an additional 4 normotensive subjects and 4
hypertensive patients, we tested the effect of
norepinephrine infused into the brachial artery at doses
(0.015 and 0.05
µg · min-1 · dL-1)
titrated to induce an FBF decrement comparable to that obtained with
ouabain (
35%) or L-NMMA (50%). The experimental design was
similar to protocol C or B, with L-NMMA or ouabain replaced with
norepinephrine.
Analytical Procedures
Insulin was measured in plasma by a
standard radioimmunoassay
method (INSKIT, Sorin). Plasma glucose was assayed by an enzymatic
method (glucose oxidase, Beckman Glucose Analyzer).
Drugs
Acetylcholine hydrochloride (Farmigea SpA), L-NMMA
(Clinalfa
AG), insulin (Actrapid), ouabain (Ouabaine Arnaud), and sodium
nitroprusside (Malesci) were obtained from commercially available
sources and diluted freshly to the desired concentration by the
addition of normal saline. To avoid adsorption to syringe and
connecting line, insulin was dissolved in saline plus 1%
albumin. Sodium nitroprusside was dissolved in a dextrose
solution and protected from light by aluminum foil.
Data Analysis
Forearm glucose balance was obtained as the
product of the
AV plasma glucose concentration gradient and forearm plasma flow.
Plasma flow rates were calculated to be the product of FBF and
(1-hematocrit). Glucose extraction ratio was computed as the ratio of
the AV difference to the arterial concentration. Because
mean arterial blood pressure did not change significantly
during the study, data were analyzed in terms of changes in
FBF. Because L-NMMA and ouabain altered resting FBF, data were
analyzed as percent increase from baseline. Contralateral FBF
changed slightly but not significantly during the experimental period.
Nonetheless, to account for these changes, data also were expressed as
the I/C ratio. Results are expressed as mean±SEM. Statistical
analysis was done by two- or three-way ANOVA. Differences
were considered to be statistically significant only when
P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Table 1
summarizes the characteristics of the normotensive
subjects and essential hypertensive patients. Except for
arterial blood pressure, there were no significant
differences between the two study groups. Twenty minutes of intrabrachial insulin preinfusion raised deep venous plasma insulin concentrations into the physiological range of postcibal values (normotensive subjects, from 10±1 to 48±6 µU/mL, P<.001; hypertensive patients, from 10±1 to 51±5 µU/mL, P<.001) and caused a decrease in deep venous plasma glucose levels (normotensive subjects, from 4.45±0.09 to 4.06±0.10 mmol/L, P<.01; hypertensive patients, from 4.52±0.06 to 4.32±0.07 mmol/L, P<.05). In both groups, arterial plasma glucose levels did not change during the experiment. Forearm glucose extraction was stimulated by insulin administration in both control subjects (from 3.3±0.8% to 11.3±1.5%, P<.001) and hypertensive patients (from 2.7±0.5% to 6.0±1.1%, P<.001). This degree of insulin-stimulated forearm glucose extraction was significantly (P<.01) greater in control subjects than in hypertensive patients.
Effect of Insulin on Vasodilatory Response to Acetylcholine and
Sodium Nitroprusside (Protocol A)
In normotensive subjects under
control conditions,
acetylcholine and sodium nitroprusside led to similar forearm
vasodilation (FBF rose from 3.5±0.2 to a maximum of 24.9±1.9
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 7.1±0.8] and from 3.6±0.3 to
22.1±1.7
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 6.0±0.6], respectively; see Fig
2).
Insulin administration did not alter basal FBF (3.6±0.2
versus 3.7±0.2
mL · min-1 · dL-1
[I/C, 1.0±0.1 versus 1.1±0.1], P=NS)
but significantly
(P<.01) increased acetylcholine-induced vasodilation
(from 3.7±0.2 to a maximum of 34.9±3.3
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 10.1±1.2], P<.01 versus saline),
whereas it
did not alter the response to sodium nitroprusside (from
3.7±0.3 to 21.7±1.8
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 5.7±0.6], P=NS versus saline).
|
, saline
infusion at 0.2 mL/min) and in the presence of local
hyperinsulinemia (
) in normotensive subjects
(n=6, left) and hypertensive subjects (right). Data are shown as
mean±SEM and expressed as percent increase above basal. Asterisks
denote significant differences between infusions with and without
insulin (P<.05 or less).
In essential hypertensive patients, the vasodilating effect of
acetylcholine (from 3.4±0.4 to a maximum of 16.8±3.1
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 4.7±0.4]) was significantly (P<.05)
less than
in normotensive control subjects. Nevertheless, the FBF response to
acetylcholine was significantly potentiated by insulin (from 3.5±0.5
to a maximum of 25.1±4.1
mL · min-1 · dL-1 [I/C,
from
1.1±0.1 to 7.4±0.8], P<.01 versus saline). This
facilitatory effect of insulin on acetylcholine-induced
vasodilation was not statistically different between normotensive
subjects and essential hypertensive patients (Fig 3).
The response to sodium nitroprusside (from 3.3±0.4 to 18.7±3.1
mL · min-1 · dL-1 [I/C,
from 1±0.1
to 6.1±0.7]) was not statistically different from that observed in
the control subjects, and insulin likewise failed to affect the
vasodilatory response to sodium nitroprusside (from 3.4±0.4 to
18.1±3.1
mL · min-1 · dL-1 [I/C,
from 0.94±0.1 to 5.3±0.4], P=NS versus
saline; Fig 2). As
in control subjects, insulin administration did not alter basal
FBF.
|
, n=22) and essential hypertensive patients (
,
n=31). Data are shown as mean±SEM and expressed as percent
increase of
acetylcholine-induced vasodilation in the presence of insulin
compared with acetylcholine-induced vasodilation under control
conditions. The facilitatory effect of insulin on
acetylcholine-induced vasodilation was not statistically different
between the two groups.
L-NMMA Infusion (Protocol B)
In this group of normotensive
control subjects,
acetylcholine-dependent vasodilation (from 3.6±0.3 to 25.5±1.9
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 6.9±0.7]) again was significantly
(P<.01) increased by the simultaneous infusion
of insulin (from 3.7±0.3 to 35.9±2.3
mL · min-1 · dL-1 [I/C,
from
1.1±0.1 to 10.6±1.3]; see Fig 4). L-NMMA
infusion
caused a decrease in basal FBF (from 3.8±0.3 to 2.0±0.2
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 0.5±0.3], P<.01) and significantly
blunted the vasodilating effect of acetylcholine both under
control conditions (from 2.0±0.2 to 7.7±2.2
mL · min-1 · dL-1 [I/C,
from
0.5±0.3 to 2.2±0.3], P<.001 versus saline) and
during insulin administration (from 2.1±0.3 to 15.5±3.4
mL · min-1 · dL-1 [I/C,
from
0.6±0.4 to 4.3±0.5], P<.01 versus insulin
alone). Of
note is that at the two lower rates of acetylcholine infusion, L-NMMA
abolished the potentiating effect of insulin.
|
Different results were obtained in patients with essential hypertension. Acetylcholine infusion again caused a dose-dependent vasodilation (from 3.2±0.5 to 18.1±2.6 mL · min-1 · dL-1 [I/C from 1.0±0.1 to 6.1±0.7]), which was significantly (P<.01) increased by insulin (from 3.1±0.4 to 23.9±3.1 mL · min-1 · dL-1 [I/C, from 1.0±0.1 to 7.9±0.9], P<.001 versus saline). L-NMMA infusion caused a decrease in basal FBF (from 3.1±0.4 to 2.3±0.3 mL · min-1 · dL-1 [I/C, from 1.0±0.1 to 0.8±0.1], P<.01), which was significantly (P<.01) smaller than that observed in normotensive control subjects. Moreover, L-NMMA failed to blunt the response to acetylcholine either when infused alone (from 2.3±0.3 to 11.8±2.4 mL · min-1 · dL-1 [I/C, from 0.8±0.1 to 5.6±0.6], P=NS versus saline) or when coinfused with insulin (from 2.3±0.5 to 18.7±3.3 mL · min-1 · dL-1 [I/C, from 0.7±0.1 to 8.5±0.9], P=NS versus saline).
To rule out the possibility of insufficient L-NMMA blockade, in another
group of 5 hypertensive patients, the L-NMMA dose was doubled (200
µg · min-1 · dL-1).
Nonetheless,
the nitric oxide synthase antagonist did not affect the
response to acetylcholine either under control conditions or in the
presence of insulin (Table 2, protocol 1).
|
Ouabain Infusion (Protocol C)
In this group of control
subjects, vasodilation to acetylcholine
(from 3.9±0.4 to 25.3±2.1
mL · min-1 ·dL-1 [I/C,
from
1.0±0.1 to 6.6±0.7]) was still significantly
(P<.001) increased by the simultaneous
infusion of insulin (from 3.7±0.3 to 34.1±4.6
mL · min-1 · dL-1 [I/C,
from
9.5±0.1 to 9.2±1.1], P<.001 versus saline; Fig
5). Ouabain administration decreased basal FBF (from
3.7±0.5 to 2.6±0.4
mL · min-1 · dL-1 [I/C,
from
1.0±0.1 to 0.6±0.5], P<.01) but failed to
affect the
response to acetylcholine infused either alone (from 2.6±0.4 to
17.3±2.7
mL · min-1 · dL-1 [I/C,
from 0.6±0.5 to 4.7±0.6], P=NS versus
acetylcholine
during saline infusion) or during insulin administration (FBF, from
3.0±0.5 to 24.7±4.1
mL · min-1 · dL-1 [I/C,
from
0.7±0.1 to 6.2±0.7], P=NS versus
acetylcholine during
saline and insulin infusion).
|
In the essential hypertensive patients, the response to acetylcholine (from 2.8±0.5 to 16.5±3.6 mL · min-1 ·dL-1 [I/C, from 1.0±0.1 to 6.3±0.7]) was again potentiated by insulin (from 2.8±0.5 to 23.5±4.3 mL · min-1 · dL-1 [I/C, from 1.0±0.1 to 8.7±1.0], P<.001 versus saline). Ouabain infusion decreased basal FBF (from 3.0±0.5 to 2.1±0.3 mL · min-1 · dL-1 [I/C, from 1.0±0.1 to 0.7±0.4], P<.01), did not alter the response to acetylcholine (from 2.1±0.4 to 13.1±3.2 mL · min-1 · dL-1 [I/C, from 0.7±0.4 to 4.4±0.5], P=NS versus acetylcholine during saline infusion), but abolished the potentiating effect of insulin on acetylcholine-induced vasodilation (FBF, from 2.2±0.5 to 12.8±2.6 mL · min-1 · dL-1 [I/C, from 0.7±0.1 to 4.5±0.5], P=NS versus acetylcholine during saline and insulin infusion).
Protocol D
To rule out the possible interference caused by
L-NMMA–induced
vasoconstriction on the response to acetylcholine, in 4 additional
normotensive subjects norepinephrine was infused
intrabrachially at a rate of 0.05
µg · min-1 · dL-1. FBF
decreased
from 2.6±0.1 to 1.4±0.1
µg · min-1 · dL-1 (I/C,
from
0.96±0.1 to 0.52±0.3), a vasoconstrictor effect comparable to
L-NMMA
(50%), but neither vasodilation to acetylcholine nor the
facilitating effect of local hyperinsulinemia on
the latter was altered (Table 2, protocol 2). To further
exclude
any interference of ouabain-induced vasoconstriction on the
response to acetylcholine, in another 4 hypertensive subjects
norepinephrine (0.015
µg · min-1 · dL-1), while
causing
an FBF decrease comparable to that obtained with ouabain (35%)
(FBF, from 3.2±0.3 to 2.1±0.3
mL · min-1 · dL-1 [I/C,
from
1.1±0.1 to 0.7±0.4], failed to alter either vasodilation to
acetylcholine or the potentiating effect of local
hyperinsulinemia; Table 2, protocol 3).
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Although it is generally accepted that systemic hyperinsulinemia lowers peripheral vascular resistances, in vivo studies that evaluated the direct vascular action of the hormone (ie, the forearm vasodilatory response to intrabrachial insulin) gave contradictory results. A few reports showed a direct relaxant effect of insulin (however, in two of these studies, a different technique—dye dilution—was used),20 21 22 several other studies did not confirm this finding.7 8 9 10 Clearly, this discrepancy may be related to methodological problems or differences in experimental design. Interestingly, a recent report by Neahring et al23 confirmed the original finding of Andres et al20 that the vehicle habitually used to dissolve insulin (saline plus albumin) can cause vasodilation, an effect probably related to the presence of albumin. Thus, it is conceivable that at least part of the direct insulin-induced vasodilation observed by some authors may be aspecific. In the present study, after intrabrachial insulin infusion in a total of 18 normotensive subjects and 22 essential hypertensive patients, we did not find significant modifications in mean FBF (normotensive subjects, 3.3±0.4 versus 3.5±0.5 mL · min-1 · dL-1; essential hypertensive patients, 3.1±0.2 versus 3.2±0.3 mL · min-1 · dL-1), although in some patients (3 of 18 normotensive subjects and 4 of 22 essential hypertensive patients) FBF did increase modestly.
The aim of the current study was to evaluate the effect of insulin on
endothelium-dependent vasodilation in humans. We
chose essential hypertension because vascular6 and
metabolic1 actions of systemic
hyperinsulinemia appear to be different in this
condition. Indeed, in the present series, forearm glucose
extraction caused by local insulin was significantly lower in the
hypertensive patients than in control subjects despite the short
preinfusion time. We found that forearm vasodilation to acetylcholine,
an endothelium-dependent vasodilator, is
potentiated by forearm hyperinsulinemia in both
normotensive subjects and patients with essential hypertension. Because
the response to sodium nitroprusside, a direct SMC relaxant, was not
altered by insulin, a nonspecific enhancement of vascular SMC
responsiveness to vasodilators was excluded. Importantly, the
potentiating effect of insulin on the response to acetylcholine was
similar in the two groups of patients (Fig 3), indicating that
in
essential hypertensive patients the action of the hormone on
endothelial function is intact even in the presence of
metabolic insulin resistance.
With regard to the mechanism(s) involved in the insulin-mediated potentiation of the response to acetylcholine, in normotensive control subjects inhibition of nitric oxide production by L-NMMA blunted the response to acetylcholine itself and abolished the potentiating effect of insulin at low doses of the muscarinic agonist (and reduced it at the higher rates). This indicates that the facilitating action of the hormone on endothelium-dependent vasodilation is, at least in part, mediated by activation of the L-arginine nitric oxide pathway. That L-NMMA canceled the effect of insulin only at low doses of acetylcholine can be explained by the fact that the L-arginine analogue is a competitive inhibitor, its action being curtailed by increasing concentrations of the substrate. Thus, Steinberg et al12 and Scherrer et al24 were able to abolish the vasodilation induced by systemic insulin by using a higher dose of L-NMMA. Furthermore, the extent of nitric oxide activation may be different with local insulin plus acetylcholine versus systemic insulin administration.
In contrast to the healthy control subjects, in essential hypertensive patients L-NMMA did not alter the effect of insulin on acetylcholine-induced vasodilation. It is important to note that in the hypertensive patients the constrictor effect of L-NMMA infusion was blunted compared with that in normotensive control subjects. In addition, even the control subjects' acetylcholine dose-response curves were flatter than those in normotensive subjects and were not altered by L-NMMA administration tested at two different doses. These findings, although not universally confirmed,25 are in line with previous observations showing that both basal26 and receptor-activated27 28 29 release of nitric oxide is impaired in essential hypertension. Therefore, the facilitating effect of insulin on acetylcholine-mediated vasodilation must also be exerted through mechanisms other than from the L-arginine–nitric oxide pathway.
Further support to this hypothesis is offered by our studies with ouabain. In fact, in the patients with essential hypertension, the inhibitor of the Na+-K+ pump prevented the facilitating effect exerted by insulin, although it did not alter acetylcholine-induced vasodilation under control conditions. It is noteworthy that in normotensive subjects ouabain did not affect either the control response to acetylcholine or the enhancing effect of insulin. Taken together, these results suggest that insulin-induced potentiation of endothelium-dependent vasodilation acts partially through different mechanisms in normotensive subjects and essential hypertensive patients. Direct evidence bearing on the mechanism by which ouabain counters insulin potentiation of acetylcholine vasodilation is not available. Evidence from animal studies indicates that both acetylcholine30 and insulin20 31 hyperpolarize cell membranes, an effect mediated by the Na+-K+ pump and antagonized by ouabain.20 30 At least in certain tissues, muscarinic agonists and other endothelial stimulants can activate the endothelium to produce a diffusible substance, ie, EDHF, which hyperpolarizes the membrane of SMCs.30 32 33 Thus, it is possible to hypothesize that in essential hypertensive patients insulin-induced potentiation of acetylcholine-induced vasodilation is to be mediated by SMC hyperpolarization. In summary, the vasodilation induced by acetylcholine usually is predominantly mediated by nitric oxide and therefore is inhibited by L-NMMA. This pathway is defective in essential hypertension and is not antagonized by L-NMMA. Therefore, other pathways must exist, one of which, when acted on by insulin, involves cell hyperpolarization because it is blocked by ouabain. Insulin per se is not a vasodilator despite the presence of specific receptors on both endothelial cell34 and SMC35 membranes. However, at some intracellular level (perhaps calcium36 ) in endothelial cells, insulin synergizes the vasodilating action of acetylcholine. This response is not impaired in essential hypertension, but in contrast to the normal situation, it is dependent more heavily on hyperpolarization than on nitric oxide production. Thus, in hypertension the ouabain-inhibitable pathway is amplified by insulin, possibly because it is hypertrophic relative to the classic nitric oxide–dependent pathway. Whether this imbalance is a compensatory adjustment or a primary defect and whether it bears any relation to the metabolic insulin resistance associated with essential hypertension remain to be investigated.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
The authors thank Moreno Rocchi for artwork.
Received December 15, 1994; revision received June 9, 1995; accepted July 5, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350-357. [Abstract]
2. Bonora E, Zavaroni I, Alpi O, Pezzarossa A, Bruschi F, Dall'Aglio E, Guerra L, Coscelli C, Butturini U. Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects. Diabetologia. 1987;30:719-723. [Medline] [Order article via Infotrieve]
3.
Hall JE, Brands MW, Kivlighn SD, Mizelle HL,
Hildebrandt DA, Gaillard CA. Chronic
hyperinsulinemia and blood pressure: interaction
with catecholamines?
Hypertension. 1990;15:519-527.
4. Liang C-S, Doherty JU, Faillace R, Maekawa K, Arnold S, Gavras H, Hood WB. Insulin infusion in conscious dogs: effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines. J Clin Invest. 1982;69:1321-1336.
5. 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.
6.
Baron AD, Brechtel-Hook G, Johnson A, Hardin D.
Skeletal muscle blood flow: a possible link between insulin
resistance and blood pressure.
Hypertension. 1993;21:129-135.
7.
Ferrannini E, Taddei S, Santoro D, Natali A, Boni A,
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.
8. Natali A, Buzzigoli G, Taddei S, Santoro D, Cerri M, Pedrinelli R, Ferrannini E. Effects of insulin on hemodynamics and metabolism in human forearm. Diabetes. 1990;39:490-500. [Abstract]
9.
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.
10.
Sakai K, Imaizumi T, Masaki H, Takeshita A.
Intra-arterial infusion of insulin attenuates
vasoreactivity in human forearm.
Hypertension. 1993;22:67-73.
11. Luscher TF, Vanhoutte PM. The Endothelium: Modulator of Cardiovascular Function. Boca Raton, Fla: CRC Press; 1990:1-228.
12. 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 decrease nitric oxide release. J Clin Invest. 1994;94:1172-1179.
13. Schultz KD, Schultz K, Schultz G. Sodium nitroprusside and other smooth muscle relaxants increase cyclic GMP levels in rat ductus deferens. Nature. 1977;265:750-751. [Medline] [Order article via Infotrieve]
14. Vollenweider P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P, Scherrer U. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest. 1993;92:147-154.
15. Whitney RJ. The measurement of volume changes in human limbs. J Physiol (Lond). 1953;121:1-27.
16.
Pedrinelli R, Taddei S, Graziadei L, Salvetti A.
Vascular responses to ouabain and norepinephrine in
low and normal renin hypertension.
Hypertension. 1986;8:786-792.
17. Vallance P, Coller J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997-1000. [Medline] [Order article via Infotrieve]
18. Tonomura Y. (Na+,K+)ATPase in the plasma membrane. In: Energy-Transducing ATPase: Structure and Kinetics. Cambridge, UK: Cambridge University Press; 240-281.
19.
Iannaccone ST, Kai-Xun LI, Sperelakis N, Lathrop DA.
Insulin-induced hyperpolarization in
mammalian skeletal muscle. Am J Physiol. 1989;256:C368-C374.
20. 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. 1961;41:108-115.
21. Gelfand RA, Barrett EJ. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987;80:1-6.
22.
Creager MA, Liang CS, Coffman JD. Beta
adrenergic-mediated vasodilator response to insulin in the human
forearm. J Pharmacol Exp Ther. 1985;235:709-714.
23.
Neahring JM, Stepniakowski K, Greene AS, Egan BM.
Insulin does not reduce forearm 
-vasoreactivity in obese
hypertensive or lean normotensive men.
Hypertension. 1993;22:584-590.
24. 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.
25.
Cockcroft JR, Chowienczyk PJ, Benjamin N, Ritter JM.
Preserved endothelium-dependent vasodilation
in patients with essential hypertension. N Engl
J Med. 1994;330:1036-1040.
26. Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial NG-monomethyl-L-arginine in patients with essential hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens. 1992;10:1025-1031. [Medline] [Order article via Infotrieve]
27.
Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA.
Role of endothelium-derived nitric oxide in
the abnormal endothelium-dependent vascular
relaxation of patients with essential hypertension.
Circulation. 1993;87:1468-1474.
28.
Taddei S, Mattei P, Virdis A, Sudano I, Ghiadoni L,
Salvetti A. Effect of potassium on vasodilation to acetylcholine
in essential hypertension. Hypertension. 1994;23:485-490.
29.
Panza JA, Garcìa CE,
Kilcoyne CM, Quyyumi A,
Cannon RO III. Impaired
endothelium-dependent vasodilation in patients with
essential hypertension: evidence that nitric oxide abnormality is not
localized to a single signal transduction pathway.
Circulation. 1995;91:1732-1738.
30. Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol. 1988;93:515-524.[Medline] [Order article via Infotrieve]
31. Moore RD, Rabovsky JL. Mechanism of insulin action on resting membrane potential of frog skeletal muscle. Am J Physiol. 1978;235:C249-C254.
32.
Beny JL, Brunet PC.
Electrophysiological and mechanical
effects of substance P and acetylcholine on rabbit aorta.
J Physiol (Lond). 1988;398:277-289.
33. Nakashima M, Mombouli JV, Taylor AA, Vanhoutte PM. Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries. J Clin Invest. 1993;92:2867-2871.
34. King GL, Goodman AD, Buzney S, Moses A, Kahn CR. Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest. 1985;75:1028-1036.
35. Pfeiffe B, Ditschuneit H. Effect of insulin on growth of cultured human arterial smooth muscle cells. Diabetologia. 1981;20:155-158. [Medline] [Order article via Infotrieve]
36. Rasmussen H, Rasmussen JE. Calcium as intracellular messenger: from simplicity to complexity. Curr Top Cell Regul. 1990;31:1-109.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  D. Versari, E. Daghini, A. Virdis, L. Ghiadoni, and S. Taddei Endothelial Dysfunction as a Target for Prevention of Cardiovascular Disease Diabetes Care, November 1, 2009; 32(suppl_2): S314 - S321. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fleming Double Tribble: Two TRIB3 Variants, Insulin, Akt, and eNOS Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1216 - 1218. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Sudano, A. Virdis, S. Taddei, L. Spieker, R. Corti, G. Noll, A. Salvetti, and T. F. Luscher Chronic Treatment With Long-Acting Nifedipine Reduces Vasoconstriction to Endothelin-1 in Essential Hypertension Hypertension, February 1, 2007; 49(2): 285 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Schramm, T. Dinh, and A. Veves Microvascular Changes in the Diabetic Foot International Journal of Lower Extremity Wounds, September 1, 2006; 5(3): 149 - 159. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Taddei, D. Versari, A. Cipriano, L. Ghiadoni, F. Galetta, F. Franzoni, A. Magagna, A. Virdis, and A. Salvetti Identification of a Cytochrome P450 2C9-Derived Endothelium-Derived Hyperpolarizing Factor in Essential Hypertensive Patients J. Am. Coll. Cardiol., August 1, 2006; 48(3): 508 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Vincent, L. H. Clerk, J. R. Lindner, W. J. Price, L. A. Jahn, H. Leong-Poi, and E. J. Barrett Mixed meal and light exercise each recruit muscle capillaries in healthy humans Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1191 - E1197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Hermann, W. Li, H. Dominguez, N. Ihlemann, C. Rask-Madsen, A. Major-Pedersen, D. B. Nielsen, K. W. Hansen, M. Hawkins, L. Kober, et al. Quinapril Treatment Increases Insulin-Stimulated Endothelial Function and Adiponectin Gene Expression in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1001 - 1008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sydow, C. E Mondon, and J. P Cooke Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA Vascular Medicine, July 1, 2005; 10(1_suppl): S35 - S43. [Abstract] [PDF]
|
|
|
|
|
|
K. Sydow, C. E Mondon, and J. P Cooke Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA Vascular Medicine, May 1, 2005; 10(2_suppl): S35 - S43. [Abstract] [PDF]
|
|
|
|
 |
|
 M. A. Vincent, L. H. Clerk, J. R. Lindner, A. L. Klibanov, M. G. Clark, S. Rattigan, and E. J. Barrett Microvascular Recruitment Is an Early Insulin Effect That Regulates Skeletal Muscle Glucose Uptake In Vivo Diabetes, June 1, 2004; 53(6): 1418 - 1423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Randriamboavonjy, J. Schrader, R. Busse, and I. Fleming Insulin Induces the Release of Vasodilator Compounds From Platelets by a Nitric Oxide-G Kinase-VAMP-3-dependent Pathway J. Exp. Med., February 2, 2004; 199(3): 347 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, M. A. Vincent, S. M. Richards, L. H. Clerk, S. Rattigan, M. G. Clark, and E. J. Barrett Insulin Sensitivity of Muscle Capillary Recruitment In Vivo Diabetes, February 1, 2004; 53(2): 447 - 453. [Abstract] [Full Text]
|
|
|
|
|
|
J. Westerbacka, R. Bergholm, M. Tiikkainen, and H. Yki-Jarvinen Glargine and Regular Human Insulin Similarly Acutely Enhance Endothelium-Dependent Vasodilatation in Normal Subjects Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 320 - 324. [Abstract] [Full Text]
|
|
|
|
|
|
S. Vehkavaara and H. Yki-Jarvinen 3.5 Years of Insulin Therapy With Insulin Glargine Improves In Vivo Endothelial Function in Type 2 Diabetes Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 325 - 330. [Abstract] [Full Text]
|
|
|
|
|
|
T. S. Hermann, C. Rask-Madsen, N. Ihlemann, H. Dominguez, C. B. Jensen, H. Storgaard, A. A. Vaag, L. Kober, and C. Torp-Pedersen Normal Insulin-Stimulated Endothelial Function and Impaired Insulin-Stimulated Muscle Glucose Uptake in Young Adults with Low Birth Weight J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1252 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sundell and J. Knuuti Insulin and myocardial blood flow Cardiovasc Res, February 1, 2003; 57(2): 312 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tamminen, J. Westerbacka, S. Vehkavaara, and H. Yki-Jarvinen Insulin-Induced Decreases in Aortic Wave Reflection and Central Systolic Pressure Are Impaired in Type 2 Diabetes Diabetes Care, December 1, 2002; 25(12): 2314 - 2319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. H. Serne, R. G. IJzerman, R. O.B. Gans, R. Nijveldt, G. de Vries, R. Evertz, A. J.M. Donker, and C. D.A. Stehouwer Direct Evidence for Insulin-Induced Capillary Recruitment in Skin of Healthy Subjects During Physiological Hyperinsulinemia Diabetes, May 1, 2002; 51(5): 1515 - 1522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sundell, P. Nuutila, H. Laine, M. Luotolahti, K. Kalliokoski, O. Raitakari, and J. Knuuti Dose-Dependent Vasodilating Effects of Insulin on Adenosine-Stimulated Myocardial Blood Flow Diabetes, April 1, 2002; 51(4): 1125 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dawes, C. Sieniawska, T. Delves, R. Dwivedi, P. J. Chowienczyk, and J. M. Ritter Barium Reduces Resting Blood Flow and Inhibits Potassium-Induced Vasodilation in the Human Forearm Circulation, March 19, 2002; 105(11): 1323 - 1328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kimura, A.-M. Jefferis, H. Watanabe, and J. Chin-Dusting Insulin Inhibits Acetylcholine Responses in Rat Isolated Mesenteric Arteries via a Non-Nitric Oxide Nonprostanoid Pathway Hypertension, January 1, 2002; 39(1): 35 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Coggins, J. Lindner, S. Rattigan, L. Jahn, E. Fasy, S. Kaul, and E. Barrett Physiologic Hyperinsulinemia Enhances Human Skeletal Muscle Perfusion by Capillary Recruitment Diabetes, December 1, 2001; 50(12): 2682 - 2690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gaenzer, W. Sturm, G. Neumayr, R. Kirchmair, C. Ebenbichler, A. Ritsch, B. Foger, G. Weiss, and J. R Patsch Pronounced postprandial lipemia impairs endothelium-dependent dilation of the brachial artery in men Cardiovasc Res, December 1, 2001; 52(3): 509 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rask-Madsen, N. Ihlemann, T. Krarup, E. Christiansen, L. Kober, C. Nervil Kistorp, and C. Torp-Pedersen Insulin Therapy Improves Insulin-Stimulated Endothelial Function in Patients With Type 2 Diabetes and Ischemic Heart Disease Diabetes, November 1, 2001; 50(11): 2611 - 2618. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Z. Goldstein, B. E. Hurwitz, M. M. Llabre, N. Schneiderman, M. Gutt, J. S. Skyler, R. J. Prineas, and R. P. Donahue Modeling Preclinical Cardiovascular Risk for Use in Epidemiologic Studies: Miami Community Health Study Am. J. Epidemiol., October 15, 2001; 154(8): 765 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Virdis, L. Ghiadoni, H. Cardinal, S. Favilla, P. Duranti, R. Birindelli, A. Magagna, G. Bernini, G. Salvetti, S. Taddei, et al. Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1106 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Taddei, A. Virdis, L. Ghiadoni, A. Magagna, S. Favilla, A. Pompella, and A. Salvetti Restoration of Nitric Oxide Availability After Calcium Antagonist Treatment in Essential Hypertension Hypertension, March 1, 2001; 37(3): 943 - 948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vehkavaara, J. Westerbacka, T. Hakala-Ala-Pietilä, A. Virkamäki, O. Hovatta, and H. Yki-Järvinen Effect of Estrogen Replacement Therapy on Insulin Sensitivity of Glucose Metabolism and Preresistance and Resistance Vessel Function in Healthy Postmenopausal Women J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4663 - 4670. [Abstract] [Full Text]
|
|
|
|
|
|
S. Vehkavaara, S. Makimattila, A. Schlenzka, J. Vakkilainen, J. Westerbacka, and H. Yki-Jarvinen Insulin Therapy Improves Endothelial Function in Type 2 Diabetes Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 545 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ghiadoni, A. Virdis, A. Magagna, S. Taddei, and A. Salvetti Effect of the Angiotensin II Type 1 Receptor Blocker Candesartan on Endothelial Function in Patients With Essential Hypertension Hypertension, January 1, 2000; 35(1): 501 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Straznicky, C. J. O'Callaghan, V. E. Barrington, and W. J. Louis Hypotensive Effect of Low-Fat, High-Carbohydrate Diet Can Be Independent of Changes in Plasma Insulin Concentrations Hypertension, October 1, 1999; 34(4): 580 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Taddei, L. Ghiadoni, A. Virdis, S. Buralli, and A. Salvetti Vasodilation to Bradykinin Is Mediated by an Ouabain-Sensitive Pathway as a Compensatory Mechanism for Impaired Nitric Oxide Availability in Essential Hypertensive Patients Circulation, September 28, 1999; 100(13): 1400 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Jensen and E. J. Messina C-peptide induces a concentration-dependent dilation of skeletal muscle arterioles only in presence of insulin Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1223 - H1228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Hasdai, D. R. Holmes Jr., D. M. Richardson, U. Izhar, and A. Lerman Insulin and IGF-I attenuate the coronary vasoconstrictor effects of endothelin-1 but not of sarafotoxin 6c Cardiovasc Res, September 1, 1998; 39(3): 644 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Hasdai, R. A. Rizza, D. R. Holmes Jr, D. M. Richardson, P. Cohen, and A. Lerman Insulin and Insulin-like Growth Factor-I Cause Coronary Vasorelaxation In Vitro Hypertension, August 1, 1998; 32(2): 228 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Bonadonna, M. P. Saccomani, S. Del Prato, E. Bonora, R. A. DeFronzo, and C. Cobelli Role of Tissue-Specific Blood Flow and Tissue Recruitment in Insulin-Mediated Glucose Uptake of Human Skeletal Muscle Circulation, July 21, 1998; 98(3): 234 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Taddei, A. Virdis, L. Ghiadoni, A. Magagna, and A. Salvetti Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activity in Essential Hypertension Circulation, June 9, 1998; 97(22): 2222 - 2229. [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]
|
|
|
|
|
|
A. Natali, A. Q. Galvan, N. Pecori, G. Sanna, E. Toschi, and E. Ferrannini Vasodilation With Sodium Nitroprusside Does Not Improve Insulin Action in Essential Hypertension Hypertension, February 1, 1998; 31(2): 632 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Sobrevia, D L Yudilevich, and G E Mann Elevated D-glucose induces insulin insensitivity in human umbilical endothelial cells isolated from gestational diabetic pregnancies J. Physiol., January 1, 1998; 506(1): 219 - 230. [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]
|
|
|
|
|
|
S. Taddei, A. Virdis, L. Ghiadoni, S. Uleri, A. Magagna, and A. Salvetti Lacidipine Restores Endothelium-Dependent Vasodilation in Essential Hypertensive Patients Hypertension, December 1, 1997; 30(6): 1606 - 1612. [Abstract] [Full Text]
|
|
|
|
|
|
K. T. Stepniakowski, G. Lu, G. D. Miller, and B. M. Egan Fatty Acids, Not Insulin, Modulate {alpha}1-Adrenergic Reactivity in Dorsal Hand Veins Hypertension, November 1, 1997; 30(5): 1150 - 1155. [Abstract] [Full Text]
|
|
|
|
|
|
S. Taddei, A. Virdis, P. Mattei, L. Ghiadoni, C. B. Fasolo, I. Sudano, and A. Salvetti Hypertension Causes Premature Aging of Endothelial Function in Humans Hypertension, March 1, 1997; 29(3): 736 - 743. [Abstract] [Full Text]
|
|
|
|
|
|
S. Taddei, A. Virdis, L. Ghiadoni, A. Magagna, and A. Salvetti Cyclooxygenase Inhibition Restores Nitric Oxide Activity in Essential Hypertension Hypertension, January 1, 1997; 29(1): 274 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J.J. Tack, J. A. Lutterman, G. Vervoort, T. Thien, and P. Smits Activation of the Sodium-Potassium Pump Contributes to Insulin-Induced Vasodilation in Humans Hypertension, September 1, 1996; 28(3): 426 - 432. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||