(Circulation. 1998;98:1666-1674.)
© 1998 American Heart Association, Inc.
Chronic Amlodipine Treatment During the Development of Heart Failure
Francis G. Spinale, MD, PhD;
Rupak Mukherjee, PhD;
R. Stephen Krombach, BA;
Mark J. Clair, BS;
Jennifer W. Hendrick, BS;
Ward V. Houck, MD;
Latha Hebbar, MD;
Scott B. Kribbs, BS;
James L. Zellner, MD;
; Michael G. Dodd, PhD
From the Division of Cardiothoracic Surgery, Medical University of South
Carolina, Charleston, and Pfizer Central Research, Sandwich, UK (M.G.D.).
Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 418 CSB, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425.
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Abstract
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Background—This study examined
the effects of chronic amlodipine treatment on left
ventricular (LV) pump function, systemic
hemodynamics, neurohormonal status, and regional blood
flow distribution in an animal model of congestive heart failure (CHF)
both at rest and with treadmill exercise. In an additional series of in
vitro studies, LV myocyte contractile function was examined.
Methods and Results—Sixteen pigs were studied under normal
control conditions and after the development of chronic pacing–induced
CHF (240 bpm, 3 weeks, n=8) or chronic pacing and amlodipine (1.5
mg · kg-1 · d-1, n=8). Under
ambient resting conditions, LV stroke volume (mL) was reduced with CHF
compared with the normal control state (16±2 versus 31±2,
P<0.05) and increased with concomitant amlodipine
treatment (29±2, P<0.05). At rest, systemic and
pulmonary vascular resistance (dyne ·
s-1 · cm-5) increased with CHF
compared with the normal control state (3102±251 versus 2156±66 and
1066±140 versus 253±24, respectively, both P<0.05)
and were reduced with amlodipine treatment (2108±199 and 480±74,
respectively, P<0.05). With CHF, LV stroke volume
remained reduced and was associated with a 40% reduction in myocardial
blood flow during treadmill exercise, whereas chronic amlodipine
treatment normalized LV stroke volume and improved myocardial blood
flow. Resting and exercise-induced plasma norepinephrine
levels were increased by >5-fold in the CHF group and were reduced by
50% from CHF values with chronic amlodipine treatment. Resting plasma
endothelin (fmol/mL) increased with CHF compared with the normal state
(10.4±0.9 versus 3.1±0.3, P<0.05) and was reduced
with amlodipine treatment (6.6±1.1, P<0.5). With CHF,
LV myocyte velocity of shortening (µm/s) was reduced compared with
normal controls (39±1 versus 64±1, P<0.05) and was
increased with chronic amlodipine treatment (52±1,
P<0.05).
Conclusions—Chronic amlodipine treatment in this model of
developing CHF produced favorable hemodynamic,
neurohormonal, and contractile effects in the setting of developing
CHF.
Key Words: calcium channel blockers • heart failure • blood flow • hormones
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Introduction
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Therapeutic modalities for the syndrome of congestive
heart failure (CHF) have included a reduction in left
ventricular (LV) afterload by vasodilation and/or
neurohormonal modulation. However, previously performed clinical trials
with calcium (Ca2+) channel
antagonists, which effectively reduce systemic vascular
resistance and thereby LV afterload, have reported deleterious effects
in patients with CHF.1 2 3 4 However, newer
compounds of the dihydropyridine subclass of
Ca2+ channel antagonists, such as
amlodipine, have been shown to significantly reduce vascular resistance
properties without significant effects on myocardial
contractility.5 6 7 In a recent
clinical trial, amlodipine therapy was associated with no adverse
effects on morbidity or mortality in patients with severe
CHF.8 The fundamental mechanisms by which
amplodipine treatment may influence LV function and
hemodynamics during the development of CHF warrant
investigation. The overall goal of the present study was to examine
LV pump function, systemic hemodynamics, regional blood
flow, neurohormonal activity, and myocyte contractility
after chronic amlodipine treatment with developing CHF.
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Methods
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Sixteen pigs (25 kg, male, Hambone Farms, SC) were
chronically instrumented with aortic, pulmonary, and left
atrial catheters (model GPV, 9F, Access Technologies), a
pulmonary artery flow probe (20 mm, Transonics), and a
modified atrial pacemaker (model 8329, Medtronic, Inc) as described
previously.9 10 11 After a 10-day recovery from
surgery, baseline studies were performed at rest and with exercise, and
the pigs were then assigned to the following treatments: (1) rapid
pacing at 240 bpm for 21 days or (2) treatment with amlodipine (1.5
mg · kg-1 ·
d-1) for the entire pacing period (n=8). This
laboratory has demonstrated previously that this rate and duration of
rapid atrial pacing reliably causes LV dilation and pump
dysfunction.9 10 11 The amlodipine treatment was
given every morning in an oral formulation that has been shown
previously to maintain steady-state blood levels for this compound and
to have pharmacological activity against the vascular smooth muscle
L-type Ca2+ channel.6 12 At
the completion of the pacing protocol, the animals were returned to the
laboratory, and the pacemaker was deactivated. After a 1-hour
stabilization period, resting and treadmill data were
collected.
On the day of the study, the animals were placed in a custom-designed
sling, and LV echocardiographic measurements were
performed (ATL Ultramark VI, 2.25-MHz transducer). Pressures from the
access ports were obtained with calibrated transducers (Statham P23ID,
Gould) and digitized to the computer at a sampling frequency of 250 Hz
(80486 processor, Zenith Data Systems). The flow probe was connected to
a digital flowmeter (T106, Transonics) as well as being digitized. From
the arterial catheter, 30 mL of blood was drawn into
chilled tubes containing EDTA (1.5 mg/mL) and centrifuged
(2000g, 10 minutes, 4°C). Pulmonary artery and
left atrial samples were measured for oxygen saturation and hemoglobin
content (CO-Oximeter, Instruments Laboratory), and oxygen consumption
was computed.13 Fluorescent
microspheres (3x106, Molecular Probes)
were injected into the left atrium, and aortic samples were collected
for blood flow measurements. The pigs were then exercised at a
treadmill workload of 3 miles/h at a 15° incline for a 10-minute
interval, and measurements were repeated. After the final set of
measurements, the animals were euthanized with an overdose of
pentobarbital (1000 mg), and tissue was harvested. All animals were
treated and cared for in accordance with the National Institutes of
Health Guide for the Care and Use of Laboratory Animals
(National Research Council, Washington, DC, 1996).
The plasma samples were assayed for renin activity, endothelin
concentration, and catecholamine levels by methods
described previously.9 13 Blood flow was
determined in the LV free wall endocardium and epicardium, lung,
kidney, diaphragmatic muscle, latissimus dorsi, and gluteus maximus by
spectrofluorimetry (Gilford Fluoro IV).14
Coronary vascular resistance was determined as the mean aortic
pressure divided by LV myocardial blood flow and expressed as
mm Hg · min-1 ·
mL-1 · g-1.
LV Myocyte Contractile Function
For these studies, LV myocytes were harvested from 3 pigs that
underwent concomitant amlodipine treatment and rapid pacing, 3 pigs
with rapid pacing only, and 4 control pigs by methods described
previously.10 11 Isolated LV myocyte
contractility was then examined by computer-assisted
videomicroscopy.10 11 After baseline
measurements, contractile function was examined after a specific
inotropic stimulus in each myocyte in 1 of 3 ways: (1) after
ß-adrenergic receptor stimulation with 25 nmol/L isoproterenol
(-isoproterenol, Sigma Chemical Co), (2) after direct stimulation of
the L-type Ca2+ channel with 10 nmol/L of the
Ca2+ channel agonist -BayK 8644 (Research
Biochemicals International), or (3) in the presence of 8 mmol/L
extracellular Ca2+.
Data Analysis
Indices of LV function, systemic hemodynamics,
neurohormonal profiles, and regional blood flow were compared among the
treatment groups by ANOVA for repeated measures. For the myocyte
function studies, an ANOVA with a randomized-block split-plot design
was used. If the ANOVA revealed significant differences, pairwise tests
of individual group means were compared by use of Bonferroni
probabilities. All statistical procedures were performed with the BMDP
statistical software package (BMDP Statistical Software Inc). Results
are presented as mean±SEM. Values of P<0.05 were
considered to be statistically significant.
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Results
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In the CHF plus amlodipine group, plasma levels of amlodipine
obtained at the terminal study were 22±2 ng/mL (range, 15 to 28
ng/mL). In the CHF-only group, LV end-diastolic dimension
increased by 60% and fractional shortening decreased by 65% from
normal control values (Figure 1
). In the
CHF plus amlodipine group, LV end-diastolic dimension was
reduced from untreated CHF values, and LV fractional shortening
increased by 76%.
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Figure 1. LV end-diastolic dimension increased
with pacing CHF and was reduced from CHF values in which amlodipine was
given throughout the pacing protocol. LV fractional shortening fell in
CHF group and was increased in chronic amlodipine group.
*P<0.05 vs control state, +P<0.05 vs
CHF-only group.
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LV Function and Hemodynamics
Resting State
In the untreated CHF group, stroke volume and cardiac output were
reduced compared with the normal control state (Table 1). In the CHF plus amlodipine group,
stroke volume and cardiac output were not different from normal
control-state values. In the untreated CHF group, mean aortic pressure
was reduced and pulmonary artery and left atrial pressures were
increased compared with the normal control state. Systemic and
pulmonary vascular resistances were increased in the untreated
CHF group. Systemic vascular resistance was normalized and
pulmonary vascular resistance reduced in the CHF plus
amlodipine group compared with untreated CHF values. Left atrial oxygen
saturation levels were lower in the CHF plus amlodipine group compared
with the normal control state. In both CHF groups, pulmonary
artery oxygen saturation levels were lower than in the normal control
state. Basal, resting systemic oxygen consumption
(
O2) was 6.8±0.6 mL
O2 · min-1 ·
kg-1 in the normal control state and was
unchanged in either CHF group.
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Table 1. Systemic Hemodynamics and LV Pump Function With
Pacing-Induced CHF: Effects of Chronic Amlodipine
Treatment
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Treadmill Exercise
In both CHF groups, heart rate increased significantly from
resting values with exercise but remained lower than that achieved in
the normal control state. In the normal control state, cardiac output
increased 2-fold with treadmill exercise (Table 1
). In the untreated
CHF group, cardiac output increased from resting values but remained
reduced from normal control values. In the CHF-plus-amlodipine group,
cardiac output was similar to normal control values. Systemic and
pulmonary vascular resistance fell significantly with treadmill
exercise in the normal control state and in both CHF groups. In the
CHF-plus-amlodipine group, left atrial oxygen saturation values were
reduced from resting values as well as from normal control values.
Systemic O2 increased
significantly in the normal control state with exercise (6.8±0.6 to
34.2±2.5 mL O2 ·
min-1 · kg-1,
P<0.05). In the untreated CHF group, systemic
O2 increased from resting
values with exercise (5.7±0.5 to 19.7±1.1 mL
O2 · min-1 ·
kg-1, P<0.05) but was significantly
reduced from that achieved in the normal state (P<0.05). In
the CHF-plus-amlodipine group, systemic
O2 was similar to untreated
CHF values at rest (5.9±0.3 mL O2 ·
min-1 · kg-1) and
with exercise (23.9±3.0 mL O2 ·
min-1 · kg-1,
P<0.05).
Neurohormonal System Activity
Resting State
In both CHF groups, plasma norepinephrine and
epinephrine values were significantly increased from normal
control state levels (Table 2). In the
resting state, chronic amlodipine treatment with the development of
pacing CHF significantly reduced plasma norepinephrine
levels compared with untreated CHF values. Plasma renin activity
increased by 4-fold in the untreated CHF group compared with normal
control values and was significantly reduced in the CHF-plus-amlodipine
group. Plasma endothelin levels increased by 4-fold in the untreated
CHF group compared with normal control values. In the
CHF-plus-amlodipine group, plasma endothelin levels were reduced by
>40% from untreated CHF values. Plasma lactate levels were increased
by 3-fold in the untreated CHF group and were similar to control values
in the CHF-plus-amlodipine group.
Treadmill Exercise
Plasma catecholamines increased significantly in all 3
groups with treadmill exercise (Table 2). Chronic amlodipine treatment
during developing CHF significantly blunted the rise in both plasma
norepinephrine and epinephrine after
treadmill-induced exercise. Plasma endothelin values were lower in the
CHF-plus-amlodipine group compared with untreated CHF values.
Regional Blood Flow
Resting State
LV myocardial blood flow was reduced in the untreated CHF group
compared with normal control values (Table 3). In the CHF-plus-amlodipine group,
resting ambient LV myocardial blood flow was normalized.
Coronary vascular resistance was increased in the untreated CHF
group but was normalized in the CHF-plus-amlodipine group.
Pulmonary parenchymal flow was reduced by >65% from normal
control values in the untreated CHF group. Pulmonary
parenchymal flow increased by >50% in the CHF-plus-amlodipine group
compared with CHF-only values. Renal blood flow was reduced in both CHF
groups compared with normal control values.
Representative resting skeletal muscle blood flow, as
determined by blood flow to the latissimus dorsi and gluteus maximus
muscles, was similar between the normal control and CHF groups.
Treadmill Exercise
LV myocardial blood flow increased by 
4-fold in the normal
control state with treadmill exercise but was reduced in the pacing CHF
group (Table 3). With pacing CHF and chronic amlodipine treatment, LV
myocardial blood flow was increased from untreated CHF values but
remained lower than normal control values. Coronary vascular
resistance fell by 4-fold in the normal control state with
treadmill-induced exercise. In the untreated CHF group,
coronary vascular resistance was reduced from the resting state
but remained increased from normal control values. In the
CHF-plus-amlodipine group, coronary vascular resistance was
similar to normal control values. Pulmonary parenchymal flow
increased by 4-fold in the normal control state with treadmill exercise
and was significantly blunted in the untreated CHF group. In the
CHF-plus-amlodipine group, pulmonary flow was not significantly
different from the normal control values (P=0.12). Renal
blood flow increased by 50% in the normal control state with exercise
but was reduced by 40% in the untreated CHF group. Renal blood flow in
the CHF-plus-amlodipine group was similar to untreated CHF values.
Skeletal muscle blood flow increased by >5-fold in the control state
and was significantly reduced in both CHF groups; this was not affected
by chronic amlodipine treatment.
Myocyte Contractility
Myocyte contractile function was examined in >500 LV myocytes
from the normal control state, with the development of pacing CHF, and
with pacing CHF plus concomitant amlodipine treatment. LV myocyte
resting length was increased in the untreated CHF group (176±1 versus
126±1 µm, P<0.05). In the CHF-plus-amlodipine
group, resting myocyte length remained significantly increased from
control values (168±1 µm, P<0.05). Steady-state
myocyte contractile function was significantly reduced in the untreated
CHF group compared with normal control values (Table 4). In the CHF-plus-amlodipine group,
steady-state myocyte contractile function was improved from untreated
CHF values. However, steady-state myocyte function in the
CHF-plus-amlodipine group remained reduced from normal control values.
Although indices of myocyte shortening were improved in the
CHF-plus-amlodipine group, certain indices of myocyte relaxation were
not improved from untreated CHF values. For example, the time to 50%
relaxation was prolonged in both CHF groups compared with normal
control values, and this prolongation was not influenced by chronic
amlodipine treatment.
In the presence of isoproterenol, myocyte contractile function was
significantly blunted in the untreated CHF group (Table 4). In the
CHF-plus-amlodipine group, myocyte contractile function with
isoproterenol was improved from untreated CHF values. With increased
extracellular Ca2+, myocyte contractile function
was significantly reduced in the untreated CHF group. In the
CHF-plus-amlodipine group, myocyte function was significantly improved
from untreated CHF values in the presence of increased extracellular
Ca2+. Isolated myocyte contractile function
increased in all 3 groups in the presence of the L-type
Ca2+ channel agonist -BayK 8644. In the
untreated CHF group, myocyte function after -BayK 8644 administration
was reduced from normal control values. In the CHF-plus-amlodipine
group, indices of myocyte shortening were significantly improved after
the addition of -BayK 8644 compared with untreated CHF values.
However, indices of active myocyte relaxation, such as time to 50%
relaxation, remained significantly prolonged in the CHF-plus-amlodipine
group and were similar to untreated CHF values. The absolute change in
myocyte velocity of shortening after the addition of isoproterenol,
extracellular Ca2+, or -BayK 8644 was computed
for each individual myocyte and is shown in Figure 2.
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Figure 2. After ß-receptor stimulation, absolute change in
myocyte velocity of shortening was reduced in untreated CHF group. In
CHF-plus-amlodipine group, absolute change in velocity of shortening
was higher than untreated CHF values but remained reduced from normal
control values. With increased extracellular Ca2+, myocyte
velocity of shortening was reduced in untreated CHF group and
normalized in CHF-plus-amlodipine group. Direct stimulation of L-type
Ca2+ channel with -BayK 8644 increased myocyte velocity of
shortening in all 3 groups. However, absolute change in myocyte
velocity of shortening was reduced in untreated CHF group and was
normalized in CHF-plus-amlodipine group. *P<0.05 vs
control, +P<0.05 vs CHF-only values.
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Discussion
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Treatment with Ca2+ channel
antagonists has been historically associated with a
deterioration in hemodynamic status and symptoms in
patients with chronic LV dysfunction and CHF.1 2 3 4
There are significant differences, however, between subclasses of
Ca2+ channel antagonists with respect
to potency and duration of action, effects on myocardial
electrophysiology and contractility, and vascular
selectivity.5 6 7 12 One of the novel
Ca2+ channel antagonists with respect
to pharmacological profile and vascular selectivity is
amlodipine.5 7 12 A recent clinical trial
demonstrated that chronic amlodipine treatment in patients with CHF was
not associated with adverse effects on symptoms or
survival.8 More importantly, and in contrast to
past studies, this clinical study provided results suggesting that
amlodipine treatment in patients with CHF due to nonischemic
causes was associated with improved survival. In light of these
clinical observations, the present study was designed to examine
the effects of chronic amlodipine treatment on LV pump function,
systemic hemodynamics and neurohormonal status,
regional blood flow distribution, and myocyte
contractility in a porcine model of developing CHF due
to chronic rapid pacing. The unique and important findings of the
present study were 3-fold. First, concomitant amlodipine treatment
during the progression of pacing-induced CHF improved LV pump function,
increased myocardial blood flow, and reduced systemic and
pulmonary vascular resistance compared with untreated CHF
animals. Second, under resting conditions and with treadmill-induced
exercise, chronic amlodipine treatment during the development of pacing
CHF reduced plasma catecholamine and endothelin levels.
Third, chronic amlodipine treatment with developing CHF was associated
with improved steady-state isolated LV myocyte
contractility and improved inotropic capacity compared
with untreated CHF values. Thus, in contrast to conventional
Ca2+ channel antagonists, the
findings of the present study suggest that chronic amlodipine
treatment during developing CHF results in favorable effects on LV pump
function, hemodynamic and neurohormonal systems, and
myocyte contractile processes.
Contributory mechanisms for the improvement in LV pump function
observed with chronic amlodipine treatment most likely include reduced
LV afterload (reduced systemic vascular resistance), improved
myocardial blood flow, and a protective effect on myocyte
contractility. Chronic amlodipine treatment during the
development of pacing CHF also resulted in reduced LV
end-diastolic volume and left atrial pressures compared
with untreated CHF values. The progressive LV dilation that occurs with
chronic rapid pacing results in recruitment of the Frank-Starling
mechanism, but this mechanism is exhausted and results in diminished LV
stroke volume with prolonged periods of pacing.15
In the present study, the favorable LV loading conditions and
improved contractility that occurred with chronic
amlodipine and rapid pacing most likely attenuated the recruitment of
the Frank-Starling mechanism and thereby reduced the degree of LV
dilation. With treadmill-induced exercise, chronic amlodipine treatment
with pacing CHF improved LV pump function. Likely contributory factors
for this observation include reduced systemic vascular resistance,
improved myocardial blood flow, and increased capacity of LV myocytes
to respond to an inotropic stimulus compared with untreated CHF
values.
In the present study, ambient resting heart rate was increased and
the maximal heart rate achieved with treadmill-induced exercise reduced
with the development of pacing CHF. This observation is
consistent with clinical forms of CHF in which maximal heart
rates are reduced from normal target levels with exercise. In the
normal control state, the basic mechanism by which cardiac output was
increased with exercise was through increased heart rate, because LV
stroke volume remained unchanged. Interestingly, with pacing CHF,
contributory factors for the increased cardiac output with exercise
included a combination of increased LV stroke volume and heart rate.
Concomitant amlodipine treatment during the development of pacing CHF
reduced ambient resting heart rate but did not influence the maximal
heart rate achieved with treadmill exercise. The observation that
chronic amlodipine with pacing CHF did not diminish the maximal heart
rate achieved with treadmill exercise is similar to a past report that
demonstrated that Ca2+ channel
antagonist therapy in patients did not reduce maximal heart
rates achieved with exercise.16
In past clinical reports of CHF, the administration of
Ca2+ channel antagonists caused a
significant increase in plasma catecholamine
levels.3 4 The present study demonstrated
that chronic amlodipine treatment during the development of CHF
significantly reduced plasma catecholamine levels both at
rest and with treadmill-induced exercise. Voltage-dependent
Ca2+ channels have been identified in sympathetic
neurons and the adrenal medulla.17 The reduced
plasma catecholamine levels observed with chronic
amlodipine treatment during chronic rapid pacing could be attributed to
direct inhibitory effects on sympathetic neuroendocrine
activity. Chronic amlodipine treatment with developing CHF improved LV
stroke volume and cardiac output and was associated with a reduction in
resting ambient heart rate. Thus, a second contributory factor for the
reduction in plasma catecholamines that occurred with
chronic amlodipine treatment may have been decreased
baroreceptor-mediated sympathetic activity.
Endothelin is a potent bioactive peptide that modulates systemic,
pulmonary, and coronary vascular tone as well as
influencing neurohormonal system activity.18 19 20 21
For example, Kiowski et al20 reported that acute
administration of the nonselective endothelin receptor
antagonist bosentan significantly reduced systemic and
pulmonary vascular resistance in patients with CHF. In a model
of CHF induced by chronic caval occlusion, Cannan and
colleagues18 demonstrated that the
coronary vasoconstrictor effects of endothelin were increased.
Thus, in the present study, the decreased plasma endothelin levels
that occurred with chronic amlodipine treatment during developing
pacing CHF probably contributed to the concomitant reduction in
systemic, pulmonary, and coronary vascular resistance.
Plasma endothelin levels have been demonstrated to parallel the
severity of symptoms and degree of hemodynamic
instability in patients with CHF.19 Thus, likely
contributory factors for the diminished plasma endothelin levels that
occurred with chronic amlodipine treatment were improved LV
performance and diminished sympathetic activity. However,
chronic amlodipine treatment with developing CHF may have selectively
modulated endothelin synthesis and/or release. In a study by Nayler et
al,21 amlodipine significantly reduced the
expression of endothelin receptor binding sites in ischemic rat
hearts.
In past reports, treatment with Ca2+ channel
antagonists in patients with CHF has been associated with
increased plasma renin activity.1 In the
present study, chronic amlodipine treatment reduced resting plasma
renin activity from untreated CHF values. This reduction in resting
plasma renin activity was probably due to the improved LV pump function
and systemic hemodynamics that occurred with chronic
amlodipine treatment. Interestingly, with treadmill-induced exercise,
plasma renin activity increased in the chronic amlodipine–treated
group and was similar to that observed in the untreated CHF group. With
treadmill-induced exercise in the chronic amlodipine–treated group,
mean arterial pressure fell from resting values and was
associated with a persistent reduction in renal blood flow. Thus, the
increased plasma renin activity that occurred in the chronic amlodipine
group with exercise was probably due to a reflex response from the
juxtaglomerular apparatus of the kidney.
However, the mechanisms by which amlodipine influenced resting and
exercise plasma renin activity with developing CHF warrants further
study.
Although active ischemia and/or infarction is not a feature of
the pacing model of CHF, coronary vascular resistance and
endothelial control of myocardial blood flow are
significantly affected.9 15 Amlodipine has been
demonstrated to have a potent vasodilatory effect on coronary
vascular smooth muscle.5 6 12 In the present
study, chronic amlodipine treatment with developing pacing CHF
normalized resting LV myocardial blood flow at rest and improved
myocardial blood flow with exercise. Likely contributory mechanisms for
the improved LV myocardial blood flow with pacing CHF-plus-amlodipine
treatment was a direct effect on Ca2+ channel–
mediated smooth muscle tone and the reduction in circulating levels of
endothelin, both of which would reduce coronary vascular
resistance. It has been reported previously that in patients with
nonischemic cardiomyopathy, abnormalities
in myocardial oxygen delivery/demand exist.22
Thus, amlodipine treatment may provide significant coronary
vasodilatory effects in the setting of CHF, which may be of particular
benefit with respect to myocardial blood flow in patients with
relatively normal coronary arteries (no physical obstruction to
flow). Although this issue remains speculative, the finding that
amlodipine treatment was of particular benefit in CHF patients with
apparent nonischemic causes8 supports
this hypothesis.
With chronic amlodipine treatment and pacing CHF, pulmonary
vascular resistance remained increased and pulmonary
parenchymal flow was reduced from normal control values. In addition,
chronic amlodipine treatment during the development of pacing CHF
reduced left atrial oxygen saturation levels compared with either
normal control values or untreated CHF values. These observations
suggest that although chronic amlodipine treatment may have provided
favorable effects on pulmonary hemodynamics,
defects in transcapillary exchange and
oxygenation may have occurred. In a past clinical
report,8 an increased incidence of
pulmonary edema was noted in CHF patients after amlodipine
treatment.
The development of pacing CHF was associated with diminished indices of
steady-state LV myocyte contractile function. Concomitant amlodipine
treatment during the progression of pacing CHF improved myocyte
contractility. Thus, a contributory factor for the
improved LV pump function that was observed with chronic amlodipine
treatment in this model of CHF is a protective effect on intrinsic
contractile performance. With the development of pacing-induced
CHF, myocyte contractile response after ß-receptor stimulation was
attenuated. Likely contributory factors for the diminished myocyte
ß-adrenergic response with pacing-induced CHF are downregulation of
ß-receptors, alterations in the ß-receptor transduction pathway,
and diminished cAMP production.10 A
likely mechanism for the improved myocyte ß-adrenergic response with
chronic amlodipine treatment is the reduction in plasma
catecholamines, which in turn provided protective effects
on the ß-adrenergic transduction system. A second contributory factor
for the improved ß-adrenergic response with chronic amlodipine
treatment was a fundamental improvement in the capacity of the myocyte
to respond to an inotropic stimulus. This is evidenced by the fact that
myocyte responsiveness with extracellular Ca2+ or
activation of the L-type Ca2+ channel was
improved with amlodipine treatment compared with untreated CHF
values.
It was reported previously that a reduction in L-type
Ca2+ channel abundance and function occurs with
the development of severe CHF.23 With concomitant
amlodipine treatment during chronic rapid pacing, the inotropic
response after L-type Ca2+ channel activation was
significantly improved from untreated CHF values. In a past report,
Chapados and colleagues24 reported that chronic
treatment with the Ca2+ channel
antagonist nifedipine increased L-type
Ca2+ channel abundance and myocardial inotropic
responsiveness to Ca2+. Thus, contributory
mechanisms for the improved inotropic response to L-type
Ca2+ channel activation after chronic amlodipine
treatment observed in the present study include increased myocyte
L-type Ca2+ channel density as well as improved
contractile response to Ca2+.
This laboratory has reported increased resting intracellular
Ca2+ levels within pacing CHF myocytes, and these
alterations in Ca2+ homeostasis were associated
with a negative velocity of shortening–frequency
response.25 In the present study, the
diminished myocyte inotropic response to increased extracellular
Ca2+ with pacing CHF was most likely due to an
exacerbation of existing defects in Ca2+
homeostatic processes. With concomitant amlodipine treatment during
chronic pacing, myocyte inotropic response to extracellular
Ca2+ was improved from untreated CHF values.
Either with L-type Ca2+ channel activation or in
the presence of increased Ca2+, however, indices
of active relaxation remained prolonged with chronic amlodipine
treatment. Specifically, the time to 50% relaxation and total
contraction duration were unchanged with chronic amlodipine treatment
compared with untreated CHF values. The time to 50% relaxation
reflects the period of cross-bridge release and
Ca2+ resequestration by the sarcoplasmic
reticulum (SR). Past studies have reported a reduction in the
expression and abundance of SR Ca2+-ATPase with
the development of severe CHF.26 Thus, although
this remains speculative, the abnormalities in myocyte active
relaxation processes that occurred with the development of CHF may be
due to abnormalities in SR Ca2+-ATPase expression
and/or function. Furthermore, whether the lusitropic changes observed
at the level of the myocyte with the development of pacing CHF, which
persisted with amlodipine treatment, are translated to alterations in
LV myocardial diastolic properties warrants further
study.
The present study did not address whether the
hemodynamic effects of amlodipine were dose-dependent
or would produce additive effects with other interventions such as ACE
inhibition. Furthermore, the direct and potentially novel mechanisms by
which amlodipine influenced LV function and
contractility with developing CHF remain to be fully
established. For example, a recent study by Zhang and
Hintze27 reported that amlodipine potentiates
nitric oxide levels, similar to those observed with ACE inhibition.
Nevertheless, amlodipine treatment in this pacing model of developing
CHF improved LV loading conditions and pump function, reduced plasma
catecholamine and endothelin levels, and improved LV
myocardial blood flow both at rest and with treadmill exercise.
Finally, chronic amlodipine treatment with pacing CHF improved
contractility and inotropic response at the level of
the LV myocyte. These findings suggest that amlodipine may produce
favorable hemodynamic, neurohormonal, and contractile
effects in the setting of developing CHF.
|
Acknowledgments
|
|---|
This study was supported by NIH grant HL-45024, an AHA
Grant-in-Aid, and a Basic Research Grant from Pfizer Inc. Scott B.
Kribbs is a Medical Student Research Fellow of the AHA. Dr Spinale is
an Established Investigator of the AHA. The authors wish to express
their appreciation to Gloria Rios, Jignesh Joshi, and Rodney Yates for
their excellent technical assistance in this project.
|
Footnotes
|
|---|
Dr Dodd is employed by Pfizer.
Received December 10, 1997;
revision received May 12, 1998;
accepted May 20, 1998.
|
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Top
Abstract
Introduction
