Download Renal blood flow in heart failure patients during exercise - AJP

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Blood type wikipedia , lookup

Men who have sex with men blood donor controversy wikipedia , lookup

Blood bank wikipedia , lookup

Hemorheology wikipedia , lookup

Hemolytic-uremic syndrome wikipedia , lookup

Transcript
Am J Physiol Heart Circ Physiol 287: H2834 –H2839, 2004.
First published August 19, 2004; doi:10.1152/ajpheart.00394.2004.
Renal blood flow in heart failure patients during exercise
Afsana Momen,1 Douglas Bower,1 John Boehmer,1 Allen R. Kunselman,2
Urs A. Leuenberger,1 and Lawrence I. Sinoway1,3
1
Division of Cardiology, Department of Medicine, and 2Department of Health Evaluation Sciences,
Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey 17033;
and 3Lebanon Veterans Administration Medical Center, Lebanon, Pennsylvania 17042
Submitted 27 April 2004; accepted in final form 16 August 2004
leads to increases in heart rate (HR), blood pressure
(BP), ventilation, and peripheral vasoconstriction. Renal vasoconstriction occurs during exercise in humans (16, 19) as a
result of increased sympathetic outflow. This reflex renal
vasoconstriction acts to maintain BP as well as to redistribute
blood flow toward metabolically active skeletal muscle. A
recent study from this laboratory observed reflex renal vasoconstriction during forearm exercise. Furthermore, these experiments suggested that the renal vasoconstriction was due
primarily to engagement of mechanically sensitive afferents in
the contracting skeletal muscle (19).
Reduced exercise capacity and sympathoexcitation are cardinal features of congestive heart failure (HF). Primary mechanisms responsible for early fatigability during exercise in HF
patients are thought to be due to diminished perfusion in active
skeletal muscle due to reduced blood flow and/or to abnormal
muscle metabolism in HF patients (12, 17, 30, 31). This
mismatch between metabolic demand and muscle perfusion
can engage the muscle reflex evoking sympathoexcitation (25).
Resting sympathetic activity is increased in HF patients (8).
Although a wealth of information has been obtained regarding
the sympathetic neural responses to exercise in HF, far fewer
studies have been designed to determine the mechanisms
responsible for sympathetically mediated vasoconstriction during exercise in this disease. Studies using a rhythmic handgrip
(HG) protocol demonstrated increased BP (21, 27) and muscle
sympathetic nerve activity (MSNA) in HF patients due to
increased metaboreflex activation. In contrast, Sterns et al.
(29), using a static exercise paradigm, found attenuated
metaboreflex-mediated increases in MSNA in HF. In the latter
study, it was speculated that the metaboreflex was desensitized
in HF. It was also suggested in this report that some other
neural mechanism was preferentially engaged during exercise
in HF so that the “overall” sympathetic response to exercise
was preserved. Later, in a study utilizing limb congestion to
preferentially engage mechanically sensitive muscle afferents,
McClain et al. (14) documented that enhanced MSNA during
static HG exercise could be caused by increased muscle mechanoreflex stimulation.
Two separate reports using different exercise paradigms
found that renal blood flow falls to a greater extent in HF
subjects than in controls (15, 23). Middlekauff et al. (15), using
the positron emission tomography (PET) scan method, found
that rhythmic HG led to a greater increase in renal vascular
resistance (RVR) in HF than in controls. Because of the limited
time resolution of this method, the investigators were unable to
determine the neural mechanisms responsible for the greater
vasoconstrictor response in HF. The lack of time resolution of
the PET method prevents a careful evaluation of the time
course of responses within the first few seconds after exercise
is initiated. This is particularly important because central
command and the muscle mechanoreflex become engaged
within a few seconds of the onset and initiation of contraction
(4, 9, 26). Middlekauff et al. (15) also found sustained increases in RVR in HF during a 2- to 3-min recovery period.
The explanation for this finding was not clear, although activation of humoral systems could not be excluded.
Accordingly, we designed a study in which renal blood flow
velocity (RBV) in HF subjects and controls was evaluated with
the Doppler ultrasound technique (Duplex ultrasound). We
reasoned that because of its excellent temporal resolution, this
technique would allow us to examine the role of these putative
neural mechanisms in controlling renal blood flow during
Address for reprint requests and other correspondence: L. I. Sinoway,
Cardiology, H047, Pennsylvania State College of Medicine, PO Box 850,
Hershey, PA 17033 (E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
kidney; nervous system; sympathetic; vasoconstriction
EXERCISE
H2834
http://www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.32.247 on June 18, 2017
Momen, Afsana, Douglas Bower, John Boehmer, Allen R.
Kunselman, Urs A. Leuenberger, and Lawrence I. Sinoway. Renal
blood flow in heart failure patients during exercise. Am J Physiol
Heart Circ Physiol 287: H2834 –H2839, 2004. First published August
19, 2004; doi:10.1152/ajpheart.00394.2004.—During exercise, reflex
renal vasoconstriction maintains blood pressure and helps in redistributing blood flow to the contracting muscle. Exercise intolerance in
heart failure (HF) is thought to involve diminished perfusion in active
muscle. We studied the temporal relationship between static handgrip
(HG) and renal blood flow velocity (RBV; duplex ultrasound) in 10
HF and in 9 matched controls during 3 muscle contraction paradigms.
Fatiguing HG (protocol 1) at 40% of maximum voluntary contraction
led to a greater reduction in RBV in HF compared with controls
(group main effect: P ⬍ 0.05). The reduction in RBV early in HG
tended to be more prominent during the early phases of protocol 1.
Similar RBV was observed in the two groups during post-HG circulatory arrest (isolating muscle metaboreflex). Short bouts (15 s) of HG
at graded intensities (protocol 2; engages muscle mechanoreflex
and/or central command) led to greater reductions in RBV in HF than
controls (P ⬍ 0.03). Protocol 3, voluntary and involuntary biceps
contraction (eliminates central command), led to similar increases in
renal vasoconstriction in HF (n ⫽ 4). Greater reductions in RBV were
found in HF than in controls during the early phases of exercise. This
effect was not likely due to a metaboreflex or central command. Thus
our data suggest that muscle mechanoreflex activity is enhanced in HF
and serves to vigorously vasoconstrict the kidney. We believe this
compensatory mechanism helps preserve blood flow to exercising
muscle in HF.
H2835
HEART FAILURE, RENAL BLOOD FLOW, AND HANDGRIP
Table 1. Resting data in HF and control groups
Protocol 1
MVC, kg
HR, beats/min
MAP, mmHg
Renal blood flow velocity, cm/s
RVR, units
Protocol 2
HF
Control
P value
HF
Control
P value
27⫾3
73⫾5
87⫾4
42.9⫾4.3
2.2⫾0.3
36⫾3
57⫾3
94⫾2
47.4⫾2.9
2.0⫾0.1
⬍0.036
⬍0.010
NS
NS
NS
27⫾3
74⫾5
85⫾4
46.3⫾5.0
2.0⫾0.2
36⫾3
57⫾3
87⫾3
52.4⫾4.4
1.8⫾0.2
⬍0.036
⬍0.011
NS
NS
NS
Data are expressed as means ⫾ SE. HF, heart failure; MVC, maximum voluntary contraction; HR, heart rate; MAP, mean arterial pressure; RVR, renal vascular
resistance; NS, not significant. Protocol 1 is from 40% static to fatigue; protocol 2 is graded handgrip. Statistics reflect unpaired t-test comparing between HF
and control groups.
METHODS
Study Population
A group of 10 HF patients (7 men and 3 women, age 56 ⫾ 4 yr,
mean body mass index 27 ⫾ 1 kg/m2) and 9 healthy volunteers (7 men
and 2 women, age 56 ⫾ 5 yr, mean body mass index 24 ⫾ 1 kg/m2)
were studied. Each subject signed an informed written consent, and a
physical examination was performed. The study protocols were approved by the Institutional Review Board of the Milton S. Hershey
Medical Center. The healthy volunteers previously studied in this
laboratory were age and sex matched to the HF patients. The healthy
control volunteers were normotensive nonsmokers who were not
receiving medications (18).
HF patients were recruited from the Cardiovascular Clinic at The
Hershey Medical Center. Five were New York Heart Association
class II, 4 were class III, and 1 was class IV. The causes of HF were
either ischemic (n ⫽ 3) or idiopathic cardiomyopathy (n ⫽ 7). All HF
patients were clinically stable. Medications include the following:
␤-blockers (n ⫽ 9), digoxin (n ⫽ 7), angiotensin-converting enzyme
inhibitors (n ⫽ 8), diuretics (n ⫽ 7), and nitrates (n ⫽ 3). Two of the
HF patients had insulin-dependent diabetes. Medications were withheld on the morning of the study.
Renal Blood Flow Velocity
All subjects were studied in the post absorptive state. Duplex
ultrasound (HDI 5000, ATL Ultrasound; Bothell, WA) was used to
determine renal blood flow dynamics. The renal artery was scanned
using the anterior abdominal approach while the subject was supine.
A curved-array transducer (2–5 MHz) with a 2.5-MHz pulsed Doppler
frequency was used. The probe insonation angle to the renal artery
was ⬍60° with the focal zone set at the renal artery depth. To obtain
optimum velocity tracings, the transducer was held in a constant
position, and the data were obtained in the same phase of the
respiratory cycle of the respective subject. Care was taken to ensure
that the subject did not perform Valsalva maneuvers during HG. The
Doppler tracings were analyzed using ATL software (HDI 5000) to
obtain mean velocity. Each velocity measurement was normalized to
a time constant of 1 s. Subsequently, the RVR index was calculated by
dividing mean arterial pressure by RBV (in cm/s). RVR is expressed
in arbitrary units.
HR (electrocardiogram) and BP (Finapres, Ohmeda; Madison, WI)
were also obtained continuously throughout the protocols. Resting BP
was determined with an automated sphygmomanometer (Dinamap,
Critikon; Tampa, FL).
Study Protocols
Protocol 1: fatiguing static exercise followed by post-HG circulatory arrest. The maximum voluntary contraction (MVC) of the nondominant arm was determined in each subject. Baseline HR, mean
arterial pressure (MAP), and RBV were obtained over 5 min before
each protocol. HG was performed at 40% MVC until fatigue. Immediately before the subject’s point of fatigue, a forearm cuff was
inflated to 250 mmHg for 2 min [post-HG circulatory arrest (PHGCA)]. At the end of exercise, each subject rated their effort level as 20
(Borg scale) (1).
Protocol 2: static HG exercise at graded intensity. Five minutes of
baseline HR, MAP, and RBV were collected. Each subject then
Fig. 1. A: percent change data in renal blood flow velocity (y-axis) as a function of percent time to fatigue
(x-axis) during static handgrip at 40% maximum voluntary contraction. Data are presented as means ⫾ SE. B:
comparison between baseline and posthandgrip circulatory arrest (PHG-CA) renal blood flow velocity in heart
failure (HF) and control groups. P values reflect statistical
analysis using two-way ANOVA comparing between HF
(F, n ⫽ 10) and control subjects (E, n ⫽ 9). Note the
significant greater reduction in renal blood flow velocity
in HF than in controls during fatiguing handgrip exercise.
AJP-Heart Circ Physiol • VOL
287 • DECEMBER 2004 •
www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.32.247 on June 18, 2017
exercise. This method allows subjects to perform multiple
exercise paradigms on the same day (19). Because technically
it is presently impossible to obtain direct measurements of
renal sympathetic nerve activity in humans during exercise,
RBV and RVR index (calculated) are used as surrogate for
renal sympathetic nerve activity. The results of these studies
suggest that renal blood flow falls to a greater degree during
exercise in HF than in controls. Moreover, this effect is seen
within the first few seconds of exercise. The results of these
studies indicate that muscle mechanoreflex activity is augmented in congestive HF.
H2836
HEART FAILURE, RENAL BLOOD FLOW, AND HANDGRIP
Table 2. Protocol 1 data for HR, MAP, and resistance
10%
20%
40%
60%
80%
100%
HF
Control
HF
Control
HF
Control
HF
Control
HF
Control
HF
Control
Statistics
P
⌬%HR
6.9⫾2.0
8.3⫾1.3
7.6⫾2.5
8.5⫾1.7
9.4⫾2.8
15.3⫾1.4
14.3⫾3.1
18.9⫾2.1
14.2⫾4.1
21.2⫾2.5
14.7⫾3.7
24.8⫾3.1
⌬%MAP
7.9⫾3.1
5.2⫾1.8
6.7⫾2.6
11.4⫾2.4
9.4⫾2.8
17.6⫾2.5
14.2⫾3.5
25.1⫾3.4
15.4⫾3.9
33.7⫾4.6*
20.3⫾4.3
34.9⫾4.5*
⌬%RVR
34.7⫾9.1
13.6⫾5.3
33.7⫾5.2
25.2⫾5.0
35.6⫾6.1
29.0⫾7.3
48.5⫾5.7
46.4⫾10.1
50.2⫾6.7
60.7⫾15.6
65.1⫾9.4
77.3 ⫾14.8
Group
Paradigm
Interaction
Group
Paradigm
Interaction
Group
Paradigm
Interaction
NS
⬍0.001
NS
⬍0.091
⬍0.001
⬍0.005
NS
⬍0.001
NS
Data are expressed as means ⫾ SE. Data (%change from respective baseline) from fatiguing static handgrip protocol for HR, MAP, and RVR are shown.
Statistics reflect two-way ANOVA comparing between HF (n ⫽ 10) and control groups (n ⫽ 9). *P ⬍ 0.05.
Data Analysis and Statistics
Values were averaged over a 5-min rest period before each paradigm.
In the fatiguing static HG protocol, variables were measured at
10%, 20%, 40%, 60%, 80%, and 100% (peak) of the respective
subject’s time to exhaustion. Data from the last 15 s of PHG-CA was
used in the statistical analyses.
In the second protocol, data were analyzed in 5-s time periods.
Statistical analyses were performed separately on each 5-s period (i.e.,
1–5, 6 –10, and 11–15 s).
Data are presented as mean ⫾ SE. Resting values in HF and
controls were compared with unpaired t-tests. For the voluntary and
involuntary biceps contraction protocol, repeated-measures one-way
ANOVA models, having a first-order autoregressive variance-covariance structure to account for the within-subject correlation, were fit to
the data to compare response variables to baseline in the HF group
using Dunnett’s test in the post hoc analysis to control type I error.
Repeated-measures two-way ANOVA models, having a first-order
autoregressive variance-covariance structure to account for the with-
in-subject correlation, were fit to the data for each response variable
to assess the two main effects of group (between HF and healthy
subjects) and HG paradigm and the possible interaction of these two
effects. A Bonferroni correction to control type I error for multiple
comparisons was applied to the tests of simple effects at respective
time periods during the contraction paradigms when HF was compared with healthy controls. P ⬍ 0.05 was considered significant. All
analyses were performed with the SAS statistical software package
(SAS Institute; Cary, NC).
RESULTS
At rest, HR was greater in HF than controls (P ⬍ 0.05; Table
1). MVC was lower in HF than in controls (P ⬍ 0.05; Table 2).
However, no significant differences were found with regards to
age, sex, and body mass index [P ⫽ not significant (NS)].
Protocol 1: Fatiguing Static HG Followed by PHG-CA
The time to fatigue was not different in the two groups (HF,
103 ⫾ 3 s, n ⫽ 10, vs. controls, 134 ⫾ 12 s, n ⫽ 9; P ⫽ (NS).
RBV fell more during fatiguing HG in the HF group than in the
controls (group main effect, 0.037; Fig. 1A). The magnitude of
increases in MAP tended to be smaller in HF than in controls.
This effect seemed most pronounced toward the end of exercise (Table 2). Thus, despite a greater fall in RBV in HF, RVR
was similar in the two groups (Table 2). During PHG-CA,
resistances (paradigm effect, P ⬍ 0.002) and RBV responses
were similar in the two groups (Table 3 and Fig. 1B).
Table 3. Minute 2 of PHG-CA during protocol 1
HF
Control
Baseline
PHG-CA
Baseline
PHG-CA
Statistics
P
HR, beats/min
72.9⫾4.7
77.0⫾5.3
56.9⫾2.7*
58.7⫾2.9*
MAP, mmHg
87.0⫾4.0
99.4⫾3.3
93.6⫾1.9
115.7⫾3.7*
2.2⫾0.3
3.0⫾0.5
2.0⫾0.1
2.9⫾0.4
Group
Paradigm
Interaction
Group
Paradigm
Interaction
Group
Paradigm
Interaction
⬍0.009
⬍0.065
NS
⬍0.017
⬍0.001
⬍0.033
NS
⬍0.002
NS
RVR, mmHg䡠cm⫺1䡠s⫺1
Data are expressed as means ⫾ SE. Posthandgrip circulatory arrest (PHG-CA) data (the last 15 s) for HR, MAP, and RVR responses are shown. Statistics
reflect two-way ANOVA comparing between HF and control groups. *P ⬍ 0.05, comparison between HF and control groups using two-way ANOVA on
corresponding HR, MAP, and RVR values.
AJP-Heart Circ Physiol • VOL
287 • DECEMBER 2004 •
www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.32.247 on June 18, 2017
performed 15 s bouts of static HG at 10%, 30%, 50%, and 70% MVC.
The same sequence was maintained in all subjects with a 1-min period
of rest between bouts.
Protocol 3: involuntary and voluntary biceps contraction. Percutaneous electrical stimulation was utilized to induce involuntary
biceps contraction. Electrical pads (5 ⫻ 5 cm2) were placed ⬃3 cm
apart, and the biceps muscle was electrically stimulated (200 V; phase
duration, 0.3 ms; phase interval, 0.1 ms). Electrical biceps contraction
evoked ⬃15–30% of MVC and was sustained for ⬃15 s without
eliciting pain. The subjects then performed 15 s of voluntary biceps
contractions at the same tension that had been generated during
involuntary contraction.
H2837
HEART FAILURE, RENAL BLOOD FLOW, AND HANDGRIP
Table 4. Data from Protocol 2
Graded Protocol in HF Group
10%
Graded Protocol in Control Group
50%
70%
10%
30%
50%
70%
1.2⫾1.1
4.5⫾1.7
3.3⫾1.3
6.5⫾3.6
1.0⫾1.8
2.9⫾1.5
4.9⫾2.0
7.4⫾2.2
MAP
4.8⫾1.3
4.8⫾1.9
7.7⫾2.1
6.1⫾3.1
4.4⫾1.4
8.5⫾1.7
10.0⫾2.1
14.0⫾2.0*
RVR
13.7⫾4.1
22.2⫾6.1
24.8⫾6.7
25.2⫾6.7
4.6⫾2.4
4.8⫾3.8
11.3⫾4.0
14.3⫾6.0
1.7⫾1.0
3.0⫾2.5
3.2⫾3.3
9.6⫾4.0
1.2⫾1.5
1.3⫾1.4
8.0⫾2.7
11.5⫾3.7
MAP
5.3⫾1.3
8.2⫾2.4
8.6⫾2.4
10.9⫾3.0
2.5⫾1.5
8.2⫾1.6
16.1⫾2.3
19.1⫾3.9
RVR
13.5⫾2.9
22.0⫾5.6
27.6⫾5.0
40.1⫾12.0
2.8⫾2.9
10.5⫾5.5
22.1⫾4.1
29.8⫾9.5
11–15 s
HR
⫺1.2⫾2.8
4.7⫾2.0
1.0⫾4.3
10.3⫾4.2
2.4⫾1.7
3.1⫾1.9
12.1⫾3.2
15.4⫾3.9
MAP
3.9⫾1.1
7.6⫾2.1
6.8⫾2.8
10.6⫾2.7
2.0⫾1.7
7.9⫾1.4
15.8⫾2.5*
21.1⫾4.3*
RVR
14.4⫾2.2
21.5⫾5.7
26.6⫾5.2
43.7⫾7.5
4.7⫾2.7
9.5⫾4.6
26.4⫾6.7
34.1⫾13.9
0–5 s
HR
6–10 s
HR
P Value
(2-way ANOVA)
Group
Paradigm
Interaction
Group
Paradigm
Interaction
Group
Paradigm
Interaction
NS
⬍0.020
NS
NS
⬍0.039
⬍0.064
⬍0.015
NS
NS
Group
Paradigm
Interaction
Group
Paradigm
Interaction
Group
Paradigm
Interaction
NS
⬍0.002
NS
NS
⬍0.001
⬍0.015
NS
⬍0.003
NS
Group
Paradigm
Interaction
Group
Paradigm
Interaction
Group
Paradigm
Interaction
NS
⬍0.002
⬍0.043
NS
⬍0.001
⬍0.012
NS
⬍0.001
NS
Data are expressed as mean ⫾ SE. Graded handgrip protocol data (%change from respective baseline value) for HR, MAP and RVR are shown. *P ⬍ 0.05,
comparison between HF (n ⫽ 10) and control groups (n ⫽ 9) using two-way ANOVA on HR, MAP, and RVR responses to handgrip.
Protocol 2: Static HG Exercise at Graded Intensities
The data for RVR, HR, and MAP are shown in Table 4.
Increases in RVR were found in both HF (n ⫽ 10) and
control (n ⫽ 9) groups during short bouts of hardgrip (Table
4). Larger RBV reductions were found in HF than in
controls (Fig. 2). Although no group difference was observed in MAP responses, smaller MAP responses in HF
were seen at the higher workloads during 0 –5 and 11–15 s
of HG exercise (P ⬍ 0.05; Table 4).
Protocol 3: Involuntary Versus Voluntary
Biceps Contraction
Involuntary and voluntary biceps contraction evoked RVR
responses in HF (n ⫽ 4, one-way ANOVA, P ⫽ 0.036).
Increases in RVR were similar, 19 ⫾ 5% and 25 ⫾ 6% (P ⫽
NS), during involuntary and voluntary biceps contraction,
respectively.
DISCUSSION
The major finding in this report was that HF patients compared with healthy controls had greater renal blood flow
reductions during the early phase of static exercise. These
studies provide evidence that the muscle mechanoreflex plays
a crucial role in regulating renal blood flow during exercise
in HF.
Resting RBV, RVR, and MAP were not different in the HF
patients and control subjects. A prior report also suggests that
baseline renal norepinephrine (NE) spillover is similar in HF
Fig. 2. Percent change data in renal blood
flow velocity (y-axis) during 15-s bouts of
static handgrip at 10, 30, 50, and 70% maximum voluntary contraction (x-axis) in HF (F,
n ⫽ 10) and control (E, n ⫽ 9) groups. Data
are presented as means ⫾ SE. Data were
examined separately for 0 –5 (A), 6 –10 (B),
and 11–15 (C) s. P values reflect statistical
analysis using two-way ANOVA (Bonferroni
corrected) comparing between HF and control
subjects. *Significant differences between HF
and control subjects at a respective point.
Note the significant greater reduction in renal
blood flow velocity in HF than in controls in
each 5-s time period of exercise.
AJP-Heart Circ Physiol • VOL
287 • DECEMBER 2004 •
www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.32.247 on June 18, 2017
30%
H2838
HEART FAILURE, RENAL BLOOD FLOW, AND HANDGRIP
AJP-Heart Circ Physiol • VOL
in renal blood flow were seen at lower stimulus frequency in
HF than were observed in normal control rats. These results
suggest that vascular sensitivity may be heightened in HF. We
doubt that this explains our results because if this were the
explanation, we would have expected to see a greater reduction
in renal blood flow during PHG-CA in HF.
Clinical Implications
We speculate that exaggerated renal blood flow reduction
observed in HF patients in the present study represents a
compensatory mechanism that maintains blood flow to exercising muscle in the face of diminished levels of cardiac
output. Our data further suggest that this renal blood flow
response was predominantly due to local factors within contracting muscles and not to local renal factors (20). Prior
animal studies have documented that the muscle mechanoreflex can be sensitized by metabolic byproducts of muscle
contraction such as ATP (10) and lactic acid (22, 28), etc.
Enhanced lactate production due to abnormal skeletal muscle
metabolism is found in HF patients during exercise (13, 25).
Furthermore, in this laboratory, pilot studies using an animal
model of HF have observed increased ATP production in HF
rats during muscle stretch (unpublished observation). Because
the response was seen early in the present study, and central
command did not appear to be a major factor, we conclude that
the early large reduction in renal blood flow in HF was due to
an accentuated muscle mechanoreflex response in HF patients.
ACKNOWLEDGMENTS
The authors are grateful to Jennifer Stoner for expert manuscript preparation, Brian Handly, Shelly Silber, and Kristen Gray for technical support, and
the staff of the General Clinical Research Center.
GRANTS
The study was supported by National Institutes of Health Grants R01
AG-012227 (to L. I. Sinoway), R01 HL-070222 (to L. I. Sinoway), K24
HL-004011 (to L. I. Sinoway), P01 HL-077670 (to L. I. Sinoway), R01
HL-068699 (to U. A. Leuenberger), M01 RR-010732, and C06 RR-016499.
REFERENCES
1. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports
Exerc 14: 377–381, 1982.
2. DiBona GF and Sawin LL. Frequency response of the renal vasculature
in congestive heart failure. Circulation 107: 2159 –2164, 2003.
3. Gullestad L, Manhenke C, Aarsland T, Skardal R, Fagertun H,
Wikstrand J, and Kjekshus J. Effect of metoprolol CR/XL on exercise
tolerance in chronic heart failure - a substudy to the MERIT-HF trial. Eur
J Heart Fail 3: 463– 468, 2001.
4. Herr MD, Imadojemu V, Kunselman AR, and Sinoway LI. Characteristics of the muscle mechanoreflex during quadriceps contractions in
humans. J Appl Physiol 86: 767–772, 1999.
5. Kukin ML, Kalman J, Charney RH, Levy DK, Buchholz-Varley C,
Ocampo ON, and Eng C. Prospective, randomized comparison of effect
of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 99:
2645–2651, 1999.
6. Langton D, Way D, Trigg L, Blake D, and McGrath B. Vasoconstriction in the renal vascular bed during exercise: studies in control and heart
failure rabbits. Clin Exp Pharmacol Physiol 17: 219 –223, 1990.
7. Laughlin MH, Korthuis RJ, Duncker DJ, and Bache RJ. Control of
blood flow to cardiac and skeletal muscle during exercise. In: Handbook
of Physiology. Exercise: Regulation and Integration of Multiple Systems.
Bethesda, MD: Am. Physiol. Soc., 1996, sect. 12, chapt. 16, p. 705–769.
8. Leimbach WN Jr, Wallin BG, Victor RG, Aylward PE, Sundlöf G,
and Mark AL. Direct evidence from intraneural recordings for increased
287 • DECEMBER 2004 •
www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.32.247 on June 18, 2017
and in control subjects (23). These findings are at odds with
those of Middlekauff et al. (15), who found lower baseline
renal blood flows in HF than in controls. Whether this reduced
resting renal blood flow was related to the severity of HF in the
patients studied is not clear. It must be emphasized that with
the methods used in the present report, we were unable to
measure renal artery diameter and therefore were unable to
compare resting levels of flow in the two groups. Thus comparisons of resting flow and vascular resistance reported in this
study must be viewed with some caution. However, because
renal diameter does not change during renal vasoconstriction
with pharmacological compounds (11), we believe statements
regarding flow velocity changes from resting velocity are valid.
During short bouts of HG, renal blood flow fell more in HF
patients than in controls. During fatiguing HG, we observed a
group main effect (P ⬍ 0.04). Review of the data (Fig. 1)
suggests that this effect was more prominent early in exercise
than late in exercise, although a significant interaction was not
noted. Similar observations were made by Langton et al. (6)
using a doxorubicine-induced rabbit HF model. Compared
with controls, HF rabbits had markedly reduced renal blood
flows during submaximal exercise, whereas blood flow responses were similar in the two groups at the end of fatiguing
exercise (6). In this report, the duration of HG to fatigue was
not significantly different between groups. Because 9 of 10 HF
subjects were receiving ␤-blocker treatment, the question may
arise regarding the effects of ␤-blockers on exercise capacity in
HF. Although ␤-blockers generally cause a reduction in exercise capacity in healthy subjects, their effects in HF are not
consistent. Studies in HF patients have reported either no effect
(3) or little improvement (5, 24) in exercise capacity with
␤-blocker treatment. Another important issue is the mode of
exercise. In our report, all subjects performed isometric HG.
Unlike dynamic exercise, blood flow to the contracting muscle
becomes limited (7) during isometric exercise because muscle
contraction itself occludes blood vessels. Thus we believe that
the effects of ␤-blocker treatment on skeletal muscle blood
flow would be far less important than if we had examined renal
blood flow during rhythmic exercise in HF.
In the present study, it is unlikely that the muscle metaboreflex played an important role in eliciting the exaggerated renal
vasoconstrictor response to exercise in HF. This is because the
effect was seen early in exercise and the PHG-CA values for
RBV reduction were not greater in HF patients than in controls.
An argument can be made for greater central command in HF.
However, if this had been the case, we would have expected a
bigger HR response in HF patients than in controls. Moreover,
voluntary and involuntary biceps contractions evoked similar
increases in RVR in the HF patients and controls. If central
command were an important mechanism responsible for renal
vasoconstriction in humans, we would have expected no constrictor response during involuntary contraction. Thus these
data suggest that the majority of the reduction in RBV during
the initial periods of HG is due to augmented engagement of
the muscle mechanoreflex in the HF patients.
It should be noted that Rundqvist and colleagues (23) demonstrated similar relative changes in renal NE spillover during
supine bicycle exercise in HF and in controls even though renal
blood flow fell to a greater degree in HF patients than in
controls. Moreover, DiBona et al. (2), using graded renal nerve
stimulation in a rat model of HF, demonstrated that reductions
HEART FAILURE, RENAL BLOOD FLOW, AND HANDGRIP
9.
10.
11.
12.
13.
15.
16.
17.
18.
19.
AJP-Heart Circ Physiol • VOL
20. Muller AF, Batin P, Evans S, Hawkins M, and Cowley AJ. Regional
blood flow in chronic heart failure: the reason for the lack of correlation
between patients’ exercise tolerance and cardiac output? Br Heart J 67:
478 – 481, 1992.
21. Piepoli M, Clark AL, Volterrani M, Adamopoulos S, Sleight P, and
Coats AJS. Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart
failure. Effects of physical training. Circulation 93: 940 –952, 1996.
22. Rotto DM and Kaufman MP. Effect of metabolic products of muscular
contraction on discharge of group III and IV afferents. J Appl Physiol 64:
2306 –2313, 1988.
23. Rundqvist B, Eisenhofer G, Elam M, and Friberg P. Attenuated cardiac
sympathetic responsiveness during dynamic exercise in patients with heart
failure. Circulation 95: 940 –945, 1997.
24. Sanderson JE, Chan SK, Yip G, Yeung LY, Chan KW, Raymond K,
and Woo KS. Beta-blockade in heart failure: a comparison of carvedilol
with metoprolol. J Am Coll Cardiol 34: 1522–1528, 1999.
25. Shoemaker JK, Naylor HL, Hogeman CS, and Sinoway LI. Blood flow
dynamics in heart failure. Circulation 99: 3002–3008, 1999.
26. Silber DH, Sinoway LI, Leuenberger UA, and Amassian VE. Magnetic
stimulation of the human motor cortex evokes skin sympathetic nerve
activity. J Appl Physiol 88: 126 –134, 2000.
27. Silber DH, Sutliff G, Yang QX, Smith MB, Sinoway LI, and Leuenberger UA. Altered mechanisms of sympathetic activation during rhythmic forearm exercise in heart failure. J Appl Physiol 84: 1551–1559, 1998.
28. Sinoway LI, Hill JM, Pickar JG, and Kaufman MP. Effects of contraction and lactic acid on the discharge of group III muscle afferents in
cats. J Neurophysiol 69: 1053–1059, 1993.
29. Sterns DA, Ettinger SM, Gray KS, Whisler SK, Mosher TJ, Smith
MB, and Sinoway LI. Skeletal muscle metaboreceptor exercise responses
are attenuated in heart failure. Circulation 84: 2034 –2039, 1991.
30. Wilson JR, Martin JL, Schwartz D, and Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow
to skeletal muscle. Circulation 69: 1079 –1087, 1984.
31. Zelis R, Longhurst J, Capone RJ, and Mason DT. A comparison of
regional blood flow and oxygen utilization during dynamic forearm
exercise in normal subjects and patients with congestive heart failure.
Circulation 50: 137–143, 1974.
287 • DECEMBER 2004 •
www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.32.247 on June 18, 2017
14.
central sympathetic outflow in patients with heart failure. Circulation 73:
913–919, 1986.
Leuenberger UA, Mostoufi-Moab S, Herr M, Gray K, Kunselman A,
and Sinoway LI. Control of skin sympathetic nerve activity during
intermittent static handgrip exercise. Circulation 108: 2329 –2335, 2003.
Li J and Sinoway LI. ATP stimulates chemically sensitive and sensitizes
mechanically sensitive afferents. Am J Physiol Heart Circ Physiol 283:
H2636 –H2643, 2002.
Marraccini P, Fedele S, Marzilli M, Orsini E, Dukic G, Serasini L, and
L’Abbate A. Adenosine-induced renal vasoconstriction in man. Cardiovasc Res 32: 949 –953, 1996.
Massie B, Conway M, Yonge R, Frostick S, Ledingham J, Sleight P,
Radda G, and Rajagopalan B. Skeletal muscle metabolism in patients
with congestive heart failure: relation to clinical severity and blood flow.
Circulation 76: 1009 –1019, 1987.
Massie BM, Conway M, Rajagopalan B, Yonge R, Frostick S, Ledingham J, Sleight P, and Radda G. Skeletal muscle metabolism during
exercise under ischemic conditions in congestive heart failure. Evidence
for abnormalities unrelated to blood flow. Circulation 78: 320 –326, 1988.
McClain J, Hardy C, Enders B, Smith M, and Sinoway L. Limb
congestion and sympathoexcitation during exercise: implications for congestive heart failure. J Clin Invest 92: 2353–2359, 1993.
Middlekauff HR, Nitzsche EU, Hoh CK, Hamilton MA, Fonarow GC,
Hage A, and Moriguchi JD. Exaggerated muscle mechanoreflex control
of reflex renal vasoconstriction in heart failure. J Appl Physiol 90:
1714 –1719, 2001.
Middlekauff HR, Nitzsche EU, Nguyen AH, Hoh CK, and Gibbs GG.
Modulation of renal cortical blood flow during static exercise in humans.
Circ Res 80: 62– 68, 1997.
Minotti JR, Christoph I, and Massie BM. Skeletal muscle function,
morphology, and metabolism in patients with congestive heart failure.
Chest 101: 333S–339S, 1992.
Momen A, Leuenberger UA, Handly B, and Sinoway LI. Effect of
aging on renal blood flow velocity during static exercise. Am J Physiol
Heart Circ Physiol 287: H735–H740, 2004.
Momen A, Leuenberger UA, Ray CA, Cha S, and Sinoway LI. Renal
vascular responses to static handgrip: role of the muscle mechanoreflex.
Am J Physiol Heart Circ Physiol 285: H1247–H1253, 2003.
H2839