Opposing Effects of Angiotensin II on Muscle and Renal Blood Flow under Euglycemic Conditions
DANILO FLISER,
RALF DIKOW,
SADRI DEMUKAJ and
EBERHARD RITZ
Department of Internal Medicine, Ruperto-Carola University,
Heidelberg, Germany.
Correspondence to Dr. Eberhard Ritz, Division of Nephrology, Department of
Internal Medicine, Ruperto-Carola University, Bergheimerstrasse 56 a, 69115
Heidelberg, Germany. Phone: 49-06221-911-20; Fax: 49-06221-16-24-76; E-mail:
prof.e.ritz{at}t-online.de
Abstract. Angiotensin II (Ang II) enhances insulin sensitivityin
humans, and this is associated with a paradoxical increasein skeletal muscle
blood flow. It is unclear whether these effectsare mediated via subtype 1
receptors of Ang II, because thesereceptors are thought to mediate
vasoconstriction. Insulin-stimulatedglucose uptake (euglycemic clamp
technique) and leg muscle bloodflow (plethysmography) were measured in nine
healthy male volunteers(mean age, 24 ± 2 yr) on three occasions using
a double-blind,placebo-controlled study design. The subjects were allocated
inrandom order to (1) placebo premedication per os plus placebo
infusion,(2) placebo premedication per os plus infusion of 5 ng Ang
II/kgper min, and (3) premedication with 300 mg of the angiotensin
II-1-receptorantagonist irbesartan per os plus infusion of 5 ng Ang II/kgper
min. In addition, GFR and effective renal plasma flow wereassessed using the
steady-state inulin- and paraaminohippurateclearance. Insulin sensitivity
(i.e., M value) and muscle bloodflow after infusion of Ang II (9.3
± 1.8 mg/kg per min;17.7 ± 2.1 ml/100 g per min) were
significantly higherthan after placebo infusion (7.2 ± 1.6 mg/kg per
min,P < 0.02; 13.5 ± 1.8 ml/100 g per min, P <
0.01).In contrast, after premedication with irbesartan, they werenot
significantly different (7.5 ± 1.7 mg/kg per min;14.3 ± 1.9
ml/100 g per min) as compared with placeboinfusion. Mean GFR and effective
renal plasma flow were significantlylower (P < 0.01), and renal
vascular resistance was significantlyhigher (P < 0.01) with Ang
II infusion as compared with theplacebo infusion study. Premedication with
irbesartan almostcompletely blocked the vasoconstrictive effect of Ang II on
renalvasculature. Under hyperinsulinemic euglycemic conditions, infusionof
Ang II has opposing effects on regional arterial blood flow,i.e., an
increase in skeletal muscle blood flow, but vasoconstrictionof renal
vasculature. Both effects are antagonized by blockadeof subtype 1 Ang II
receptors.
It has been documented recently that subpressor as well as pressordoses of
angiotensin II (Ang II) enhance insulin-stimulatedglucose uptake,
i.e., increase insulin sensitivity, in healthyvolunteers
(1,2,3,4,5).
The mechanism of this action has notbeen completely elucidated, but it seems
to be mediated viaincreased blood flow to insulin-sensitive tissues,
e.g., skeletalmuscles
(1,2,3,
6). It has been speculated that
Ang II increasesmuscle blood flow via "capillary recruitment" and
that the increasein muscle blood flow and insulin-stimulated glucose uptake
mayreflect a homeostatically useful action of Ang II to shunt bloodand
nutrients, e.g., glucose, away from less insulin-sensitive
(splanchnic)to more insulin-sensitive (skeletal muscles) tissues in the
presenceof hyperinsulinemia
(2).
It is unclear whether the effect of Ang II on muscle blood flowand on
insulin sensitivity is mediated via subtype 1 receptorsof Ang II, because the
usual response to stimulation of thesereceptors is vasoconstriction
(7). To clarify this issue, we
infusedAng II under euglycemic hyperinsulinemic conditions (euglycemicclamp)
in a group of healthy volunteers with and without preadministrationof
irbesartan, an Ang II subtype 1 receptor antagonist, usinga double-blind,
randomized, placebo-controlled study design.In parallel to muscle blood flow,
we assessed the effects ofAng II in a second vascular bed by measuring renal
hemodynamics,i.e., GFR and effective renal plasma flow (ERPF).
Subjects and Protocol
The protocol was approved by the Ethics Committee of the Universityof
Heidelberg; a double-blind, randomized, crossover protocolwas chosen. Written
informed consent was given by nine healthymale volunteers (mean age, 24
± 2 yr; mean body massindex, 22.5 ± 1.0 kg/m2). They
were normotensive nonsmokerswho took no medication. Their family histories
were negativefor hypertension or metabolic diseases. At entry into the study,
physicalexamination, routine chemistry, and urinalysis were performed.Normal
glucose tolerance was documented using a 100-g oral glucosetolerance test
with simultaneous determinations of insulin levels.
All subjects were allocated in random order to the three interventions:
euglycemicclamp with (1) placebo premedication per os plus placebo
infusion,(2) placebo per os plus infusion of 5 ng Ang II/kg per min
(HypertensinCiba®, Ciba-Geigy Co., Basel, Switzerland), and (3)
premedicationwith 300 mg of the Ang II-1-receptor antagonist irbesartan per
osplus infusion of 5 ng Ang II/kg per min. The interval betweenthese
interventions was 7 d. For 3 d before each clamp study,all participants
adhered to an isocaloric diet standardizedwith respect to sodium content. The
subjects had constant weight(± 0.5%) for at least 4 wk before and
during the study.Smoking and alcohol consumption were not allowed, and
physicalactivity was maintained at its usual level throughout.
All participants were admitted to the clinic at 9 p.m. on theday before
the clamp experiments. On the morning of the nextday, a euglycemic clamp
experiment was performed in a quietroom from 9 a.m. to 11 a.m. after an
overnight fast. At 8 a.m.,either placebo or 300 mg of the Ang II-1-receptor
blocker irbesartanwas administered in random order. After the clamp was
started,all participants were randomly assigned to receive either placebo
(salineinfusion) or 5 ng Ang II/kg per min dissolved in saline at identical
infusionrates. On all study days, GFR and effective renal plasma flowwere
examined using steady-state inulin (Cin) and paraaminohippurate
(CPAH)infusion techniques as described in detail elsewhere
(8). Inbrief, a priming dose
of 1500 mg of inulin/m2 (Inutest®,Laevosan, Linz, Austria) and
500 mg of paraaminohippurate acid/m2(Nephrotest®, BAG GmbH,
Lich, Germany) were given at 8 a.m.The bolus injection was followed by
continuous infusions ofinulin (10 mg/m2 per min) and PAH (8
mg/m2 per min) maintainedwith ultraprecise pumps (Perfusor
FT®, Braun Melsungen,Melsungen, Germany). After an equilibration period,
blood samplesfor measurements of GFR and ERPF were taken at regular
intervals.In parallel, mean arterial BP and heart rate were monitored
oscillometricallythroughout the clamp experiments (Dinamap®, Critikon
Co.,Tampa, FL). Blood samples for measurements of serum insulinand potassium
levels were taken at the start and thereafterat regular intervals until the
end of each clamp. Muscle perfusionwas measured using a standard strain-gauge
occlusion plethysmograph(Periquant 803®, Gutmann Medizin Elektronik GmbH,
Eurasburg,Germany) on the leg (calf) at the end of each clamp investigation
(9).To assess the
reproducibility of plethysmographic measurements,we measured leg muscle blood
flow in our volunteers at admissionto the metabolic ward, i.e., on
the evening before the clampexperiments. The mean coefficient of variation
for three repeatedmeasurements in nine volunteers was 12.7 ± 4.2%.
Measurements and Calculations
A standard protocol of the euglycemic hyperinsulinemic clamptechnique was
used as described in detail elsewhere
(10). Inbrief, a priming
bolus infusion of 100 mU of insulin/m2 permin (H-Insulin®,
Hoechst AG, Frankfurt-Hoechst, Germany)was given for 2 min. Thereafter,
insulin administration wasgradually decreased to a constant infusion rate of
40 mU/m2per min. Plasma insulin levels were raised by this mode of
administrationto approximately 750 to 800 pmol/L in healthy volunteers. To
preventadsorption of insulin to the infusion line, 2 ml of the subjects'own
blood was added to the insulin infusion. Four min afterthe start of the
insulin infusion, glucose infusion (Glucosteril20%®, Fresenius AG, Bad
Homburg, Germany) was started. Bloodsamples for measurements of plasma
glucose levels were takenfrom a retrograde dorsal hand vein cannula
throughout the clampat 5-min intervals. The hand was rested in a heated box
(approximately55°C) to arterialize the venous blood. Plasma glucose was
measuredwith the Glucoanalyzer II® (Beckmann Instruments, Munich,
Germany).The infusion rate was adapted so as to maintain a euglycemicblood
glucose concentration. The coefficient of variation ofthe infusion rate for
repeat clamp experiments in the same subjectwas 4.1%. The amount of glucose
infused to maintain euglycemiawas evaluated in the last 40 min of the clamp,
i.e., after steadystates of glucose infusion and plasma glucose
levels were achieved.The mean M values were calculated from the glucose
infusionrate and the plasma glucose concentrations for this period toassess
insulin sensitivity as described elsewhere
(10). Theinvestigator
performing the clamp studies was blinded with respectto the type of infusion,
i.e., placebo or Ang II, and with respectto the BP measurements.
Serum insulin concentrations were measured using a double-sandwich
radioimmunoassay(normal range, 40 to 150 pmol/L), and serum potassium levels
weremeasured with flame photometry (AFM 5051®, Eppendorf AG,Eppendorf,
Germany). Inulin was measured enzymatically usinginulinase as described by
Kühnle et al.
(11) and paraaminohippurate
photometricallyafter Bratton and Marshall
(12). Inulin and
paraaminohippurateclearances were calculated from the delivered dose: C = (Ir
xIc)/Sc, where C is the clearance, Ir is the infusion rate (ml/min),Ic
is the concentration of the analyte in the infusion fluid(mg/ml), and Sc is
the plasma concentration of the analyte (mg/ml).Filtration fraction was
calculated as the ratio Cin/CPAH, andrenal vascular
resistance was calculated using the followingequation:
Vascular resistance in the calf was calculated as mean arterialBP (mmHg)
divided by muscle blood flow (ml/100 ml per min) andexpressed in resistance
units.
Statistical Analyses
The primary study endpoints were (1) the M value from minute80 to
minute 120 of the clamp and (2) muscle blood flow. Normalityof data
distribution was assessed with the Shapiro-Wilk test.The intra-individual
data on all three study days were evaluatedwith a two-way ANOVA using the
SPSS statistical package (SPSS,Inc., Chicago, IL). A paired t test
was applied to compare meansbetween groups when the ANOVA gave significant
differences.Bonferroni correction was applied to correct for multiple
comparisonof data. The zero hypothesis was rejected when the P level
was> 0.05. All data are presented as mean ± SD.
With placebo infusion, the mean M value, i.e., insulin
sensitivity,in healthy volunteers was 7.2 ± 1.6 mg/kg per min. Itwas
significantly (P < 0.02) higher with infusion of 5 ng/kgper min
of Ang II (9.3 ± 1.8 mg/kg per min). In contrast,after administration
of the Ang II subtype 1 receptor blockerirbesartan, it was not significantly
different (7.5 ±1.7 mg/kg per min) from placebo infusion, but it was
significantly(P < 0.05) lower than with infusion of Ang II. The
individualresponses to infusion of Ang II with and without coadministration
ofirbesartan are shown in Figure
1. The infusion of Ang II consistentlyincreased insulin
sensitivity in all nine volunteers, and theAng II-induced increase in insulin
sensitivity (M value) wasblocked in part or completely in all volunteers
examined. Incontrast, mean serum glucose, insulin, and potassium levelsdid
not differ significantly between treatments
(Table 1).
Figure 1. Muscle blood flow (MBF) and insulin sensitivity (M value) in nine healthy
volunteers with (1) placebo premedication per os plus placebo
infusion, (2) placebo premedication per os plus infusion of 5 ng Ang
II/kg per min, and (3) premedication with 300 mg of the angiotensin
II-1 receptor antagonist irbesartan per os plus infusion of 5 ng Ang II/kg per
min. , individual values of muscle blood flow and individual M values
with different treatments, respectively; [UNK], mean muscle blood flow and
mean M values, respectively.
Table 1. Metabolic and hemodynamic variables at the start and at the end of the
clamp studies in nine healthy volunteersa
The average mean arterial BP during the euglycemic clamp wasunchanged
during sham infusion; it increased significantly withinfusion of Ang II
(Table 1). Again, the increase
was blockedwith irbesartan pretreatment. Mean leg muscle blood flow was
significantlyhigher with infusion of Ang II as compared with placebo
infusion,but the Ang II-induced increase in muscle blood flow was almost
completelyobliterated with irbesartan pretreatment
(Table 2 and
Figure 1).Mean calculated
vascular resistance in the calf decreasedslightly but significantly with
infusion of Ang II during euglycemichyper-insulinemia as compared with
placebo infusion, and thiseffect was blocked by pretreatment with irbesartan
as well.The difference between infusion of Ang II plus placebo per osand Ang
II infusion after irbesartan administration did notreach statistical
significance, however. Both mean GFR (Cin)and ERPF
(CPAH) were significantly lower with Ang II infusionas compared
with placebo infusion; filtration fraction and renalvascular resistance were
significantly higher (Table 2).
TheAng II-induced changes in renal hemodynamics were consistentin all nine
volunteers examined; they were abolished with administrationof irbesartan
(Figure 2).
Figure 2. GFR and effective renal plasma flow (ERPF) in nine healthy volunteers with
(1) placebo premedication per os plus placebo infusion, (2)
placebo premedication per os plus infusion of 5 ng Ang II/kg per min, and
(3) premedication with 300 mg of the angiotensin II-1 receptor
antagonist irbesartan per os plus infusion of 5 ng Ang II/kg per min. ,
individual values of GFR and effective renal plasma flow with different
treatments, respectively; [UNK], mean GFR and mean effective renal plasma
flow, respectively.
The results of the present study document that in healthy subjects,Ang II
caused an increase of muscle blood flow under euglycemichyperinsulinemic
conditions and in parallel, an increase ofinsulin sensitivity. Both effects
are mediated via the Ang IIsubtype 1 receptor. The Ang II subtype 1 receptor
blocker irbesartanalmost completely inhibited the effect of Ang II on both
insulinsensitivity and muscle blood flow. In contrast to its vasodilatory
effecton skeletal muscle, Ang II induced vasoconstriction in the renal
circulationand caused an increase of renal vascular resistance. The Ang
II-1-receptorantagonist irbesartan abrogated both actions of Ang II,
i.e.,vasodilation as well as vasoconstriction. These observations
pointto opposing actions of Ang II on the (micro)vasculature of different
vascularterritories that are mediated via the same receptor subtype,
i.e.,the Ang II receptor subtype 1.
The results of a recent experimental study in rats suggestedthat the
pressor action of Ang II, i.e., vasoconstriction, ismediated through
Ang II receptor subtype 1 but that Ang II receptorsubtype 2 mediates an
opposing vasodepressor effect, i.e., vasodilation
(13).This suggests a dual
hemodynamic action of Ang II mediated viatwo different receptors. Indeed,
some past experimental studieson isolated blood vessels showed a biphasic
arteriolar responseto Ang II, i.e., a brief increase in arteriolar
resistance (reductionin blood flow) followed by a sustained decrease below
baseline(increase in blood flow)
(14,15).
Both effects were blockedby saralasin, a nonspecific Ang II receptor
antagonist. SpecificAng II receptor antagonists were not available at that
time.Our observation in humans does not confirm the above hypothesisof a
dual action of Ang II mediated by two different receptorsubtypes. On the
contrary, our results clearly demonstrate thata pressor dose of Ang II has
opposing effects in different vascularterritories, i.e.,
vasoconstriction in the kidney and vasodilationin the skeletal muscle
vessels. Both effects were blocked byirbesartan, a highly specific Ang II
subtype 1 receptor antagonist.Our finding of opposing effects of Ang II in
different vascularbeds is in line with results of recent experimental studies
andstudies in humans. For example, Motwani and Struthers
(16) showedthat in healthy
subjects, infusion of Ang II caused a dose-dependentredistribution of cardiac
output and intravascular volume fromsplanchnic to leg vessels. Similar
observations were made byBuchanan et al.
(2), who found a dose-dependent
increase infemoral artery flow in healthy subjects during Ang II infusion.
Theauthors did not calculate femoral vascular resistance, but fromtheir data
one can calculate that it decreased despite an increasein arterial BP. These
findings suggest that Ang II induces pronouncedvasoconstriction in the renal
and splanchnic vascular beds,leading to an overall increase in total
peripheral resistanceand arterial BP. This view is corroborated by our
finding andby observations of others that infusion of Ang II nearly
obliteratesinsulin secretion via a marked reduction of blood flow to the
pancreas,whereas it fails to affect myocardial blood flow
(17,18,19,20).
Therole of specific Ang II receptors was not investigated in thesestudies,
however.
The results of the present study confirm that a pressor doseof Ang II
consistently increases insulin-stimulated glucosedisposal and muscle blood
flow in healthy subjects
(1,2,3,5).
Weand Buchanan et al.
(1,2)
showed that the Ang II-induced increaseof insulin sensitivity is
dose-dependent and is demonstrableeven after a maximal (plateau) blood
insulin concentration hasbeen achieved
(2). Further increasing the
rate of insulin infusiondid not increase insulin-stimulated glucose disposal.
Superimpositionof Ang II infusion under conditions of maximal
hyperinsulinemiafurther increased glucose disposal by approximately 20%,
however.The effect of Ang II is therefore not simply explained by a
potentiationof the action of insulin but is probably mediated via recruitment
ofadditional capillaries with an increase in (measurable) muscleblood flow
(2). This suggests that there
is interaction betweenthe effects of insulin and of Ang II on skeletal
muscles ondifferent levels: (1) Ang II augments the metabolic effect
ofinsulin, but (2) insulin in turn alters the hemodynamic actionof
Ang II. The latter proposal is based on the observation thatthe effect of Ang
II on muscle blood flow was detectable underbasal (fasting) insulinemia but
was markedly potentiated underhyperinsulinemic (euglycemic) conditions. In
contrast, the pressorresponse to Ang II was blunted during hyperinsulinemia
as comparedwith basal (fasting) insulinemia
(2). Taken together, Ang II
redistributescardiac output, i.e., blood flow, from less
insulin-sensitive(splanchnic) to more insulin-sensitive (skeletal muscle)
tissues,and this effect is augmented by insulin. This homeostaticallyuseful
action may be particularly important in the postprandialphase when glucose
must be cleared from blood. It is thereforeof interest that in patients with
type 2 diabetes mellitus,the effect of Ang II on muscle perfusion and on
insulin-stimulatedglucose uptake is blunted, i.e., the clearance of
glucose fromthe blood during hyperinsulinemia is markedly impaired
(3).In some of these patients,
infusion of Ang II under euglycemicconditions even decreased muscle perfusion
and insulin sensitivity.In parallel, renal vasoconstriction was more
pronounced (3).These
observations suggest that in patients with type 2 diabetes,the action of Ang
II on muscle and renal microvasculature isaltered, and this is reminiscent of
the finding that endothelialrelaxation is impaired in these patients
(21,22),
They furthersuggest that the interplay between the insulin and
renin-angiotensinsystems is abnormal in patients with type 2 diabetes
mellitusand potentially in subjects with the metabolic syndrome
(3).Indirect evidence
supporting this idea comes from the recentlypublished CAPPP trial
(23). Patients with essential
hypertensionand who were treated with the angiotensin-converting enzyme
inhibitorcaptopril developed significantly less type 2 diabetes mellitus
duringthe follow-up as compared with patients who were treated with
conventionalantihypertensive therapy.
In a recent experimental study, the effect of Ang II on theintracellular
action of insulin was explored in a rat aortasmooth muscle cell culture
(24). It is interesting that
AngII inhibited the insulin-stimulated insulin receptor
substrate-1-associatedphosphatidylinositol 3-kinase activity in a
dose-dependent manner,and this action resulted in the inhibition of normal
interactionsbetween the insulin signaling pathway components. Furthermore,
thefindings suggested that the effect of Ang II was not mediatedvia Ang II
subtype 1 or Ang II subtype 2 receptors but via anotherpathway
(24). The authors obtained
similar results in a ratheart model and concluded that overactivity of the
renin-angiotensinsystem is likely to impair insulin signaling and contribute
toinsulin resistance in essential hypertension
(25). These findingscontrast
with our results and observations of other authors
(1,2,3,4,5),
whichclearly document a stimulatory effect of Ang II on insulin sensitivity
inhumans, at least under hyperinsulinemic conditions. The divergentresults
are not necessarily contradictory, because the actionof Ang II on cell
cultures may be different from the effectin vivo. In line with this
argument are observations in patientswith renovascular hypertension and a
stimulated renin-angiotensinsystem, where insulin sensitivity is not impaired
(26,27).
Additionalstudies are therefore warranted to explore in more detail the
relationshipbetween the renin-angiotensin and insulin system in humans.
To interpret our results correctly, it is useful to considersome
methodologic points. The serum insulin levels achievedwith our euglycemic
clamp protocol were similar to those observedin most other studies where this
standard protocol was applied,i.e., approximately 800 pmol/L
(4,5,10,28).
This standardizedprotocol has been adopted to allow comparison of different
studies.The serum insulin concentrations achieved with this insulindose are
approximately 6 to 8 times higher than fasting seruminsulin concentrations in
healthy, nondiabetic subjects. Suchlevels are regularly observed, however, in
insulin-resistantsubjects after a glucose load, e.g., in patients
with type 2diabetes, in obese patients, and in patients with renal diseases
(28,29).
Insuch patients, postprandial serum insulin concentrations stayin this
(patho)physiologic range for prolonged periods of time.Furthermore, we chose
an infusion of 5 ng Ang II/kg per minto achieve a clear and definite effect
on renal and muscle perfusion,but we are well aware that this dose yields
pharmacologic AngII plasma concentrations
(1).
In the present study, we used 300 mg of the Ang II receptorantagonist
irbesartan per os. The drug was administered at least2 h before insulin
sensitivity, muscle blood flow, and renalhemodynamics were assessed.
Pharmacologic studies in healthysubjects have shown that this dose of
irbesartan is sufficientto cause nearly 100% blockade of the Ang II receptor
subtype1-mediated vasoconstriction 2 h after administration
(30). Thisobservation is
corroborated by our finding that the infusionof 5 ng Ang II/kg per min in
healthy volunteers did not affectBP after pretreatment with this dose of
irbesartan; similarresults were obtained in previous studies
(31).
We conclude that in humans, (1) the Ang II-induced increaseof
muscle blood flow and of insulin sensitivity is mediatedvia Ang II-1
receptors and that (2) in the presence of euglycemic
hyperinsulinemia,Ang II definitively has opposing effects on blood flow in
differentvascular territories, i.e., decrease of renal perfusion but
increaseof skeletal muscle blood flow. Both effects are mediated viathe Ang
II receptor subtype 1.
Acknowledgments
We thank Bristol-Myers Squibb Pharma (Munich, Germany) for financial
supportof the study.
Footnotes
Dr. Timothy Meyer served as guest editor and supervised thereview and
final disposition of this manuscript.
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Received for publication December 27, 1999.
Accepted for publication March 27, 2000.
Top
Abstract
Introduction
, individual values of muscle blood flow and individual M values
with different treatments, respectively; [UNK], mean muscle blood flow and
mean M values, respectively.