(Circulation. 1995;92:1793-1800.)
© 1995 American Heart Association, Inc.
Articles |
Functional Significance of Presynaptic 
-Adrenergic Receptors in Failing and Nonfailing Human Left Ventricle
From the Cardiovascular Division (J.D.P., G.E.N., J.S.F.), Departments of Medicine, Mount Sinai Hospital and the Toronto Hospital, University of Toronto, Toronto, Ontario, Canada; and the Cardiovascular Division (J.S.L., W.S.C.), Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
Correspondence to John D. Parker, MD, Cardiovascular Division, Rm 1609, Mount Sinai Hospital, 600 University Ave, Toronto, Ontario, Canada M5G 1X5.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background There are
-adrenergic receptors on human
myocardium that exert positive inotropic effects. The
effect of -adrenergic receptor blockade on human left
ventricular (LV) performance has not been fully
explored. Although -adrenergic receptor blockade might have effects
on LV function that are mediated via blockade of postsynaptic
myocardial -adrenergic receptors, it is also possible that blockade
of presynaptic 2-adrenergic receptors and subsequent
increased release of norepinephrine would have effects on
LV performance. In the present study, we explored the
effects of nonselective -adrenergic receptor blockade on LV
performance and transcardiac
norepinephrine concentrations in a group of patients with
normal LV function and in a group of patients with congestive heart
failure secondary to dilated cardiomyopathy.
Methods and Results Using an intracoronary drug
infusion technique, we administered the nonselective -adrenergic
antagonist phentolamine to 13 patients with normal
LV function and 19 patients with congestive heart failure secondary to
dilated cardiomyopathy. With a high-fidelity LV
catheter, the systolic (+dP/dt) and diastolic (-dP/dt and
Tau) LV function responses to intracoronary infusion of
phentolamine (0.2 mg/minx5 minutes) were assessed. In 8
patients with normal ventricular function and 10 patients
with congestive heart failure, arterial and
coronary sinus blood samples were drawn to determine the
effects of phentolamine on catecholamine
concentrations. Phentolamine had no measurable effect on LV
performance or catecholamine concentrations in the
normal ventricular function group. In patients with
congestive heart failure, intracoronary
phentolamine caused a significant increase in +dP/dt and the
rate of isovolumic LV relaxation (-dP/dt and Tau). These
hemodynamic effects were accompanied by a significant
increase in coronary sinus norepinephrine
concentration but no change in arterial
norepinephrine concentration.
Conclusions Myocardial -adrenergic receptor blockade causes
significant inotropic and lusitropic effects in the failing but not the
nonfailing human LV. These effects appear to be mediated by increased
release of norepinephrine from cardiac nerves secondary to
blockade of presynaptic 2-adrenergic receptors.
Differences in the responses of the failing and nonfailing human LV
appear to reflect the higher level of sympathetic activation that is
seen in the group with congestive heart failure. This suggests that the
presynaptic 2-adrenergic receptor exerts a tonic
inhibitory effect on the release of
norepinephrine from cardiac nerves in patients with
congestive heart failure.
Key Words: receptors • adrenergic • alpha • diastole • cardiomyopathy
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Although the ß-adrenergic receptor exerts important effects on left ventricular inotropic and lusitropic function in humans, the role of the
-adrenergic receptor
pathway is less clear.1 In several animal species,
-adrenergic receptor stimulation causes an increase in myocardial
contractile state (reviewed in Benfey2 ). In humans,
myocardial -adrenergic receptors have been identified by
radioligand binding,3 4 5 and stimulation
of
myocardial -adrenergic receptors exerts a positive inotropic
response in situ.6 In vitro, -adrenergic receptor
stimulation prolongs the time course of myocardial contraction, and
some studies have suggested that the period of relaxation is
prolonged.7 8 9 Systemic infusion of
-adrenergic agonists may also be
associated with a slowing of the rate of isovolumic left
ventricular relaxation in intact animals10 ;
however, one study in humans found no effect of the -adrenergic
agonist methoxamine on left ventricular
relaxation.11
These investigations have focused on the postsynaptic effects of
-adrenergic stimulation on myocardial function. It is of importance
that the response to adrenergic receptor agonists and
antagonists may also reflect presynaptic modulation of
neurotransmitter release.12 Using an
intracoronary drug infusion technique (to avoid systemic
hemodynamic effects), we have previously reported that
myocardial -adrenergic receptor stimulation with
phenylephrine causes a positive inotropic effect in both
the normal and failing human left ventricle.6
Surprisingly, in that investigation, the intracoronary
administration of the nonselective -adrenergic receptor
antagonist phentolamine was also associated with an
increase in left ventricular peak +dP/dt in patients with
congestive heart failure that was of borderline statistical
significance; this effect was not observed in patients with normal
ventricular function. Subsequent analysis of left
ventricular responses to phentolamine revealed a
significant increase in the rate of left ventricular
relaxation during acute intracoronary -adrenergic
receptor blockade in patients with congestive heart
failure13 ; again, this effect was not observed in
those with normal left ventricular function. In the
present study, we extended our initial hemodynamic
observations to a larger number of subjects and attempted to elucidate
the mechanism by which -adrenergic receptor blockade might exert a
positive inotropic and lusitropic effect in the failing human left
ventricle. We hypothesized that these responses to phentolamine
were mediated by blockade of presynaptic 2-adrenergic
receptors with subsequent increased neuronal release of
norepinephrine. Because patients with congestive heart
failure have increased sympathetic
activity,14 15 16 this
mechanism could also explain a differential effect of -adrenergic
receptor blockade in subjects with normal function compared with those
with congestive heart failure. Accordingly, we coupled these additional
hemodynamic measurements with measurements of
arterial and coronary sinus
catecholamine levels before and after the
intracoronary administration of phentolamine.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patients
The study population consisted of 32 patients divided into two groups. All patients were in normal sinus rhythm. Fourteen of the patients had been included in a prior study of the effects of
-adrenergic stimulation on left ventricular systolic
function.6 They were included in the results of the
present study because they had undergone left
ventricular pressure recordings that allowed
calculation of the rate of left ventricular relaxation
(data that were neither reported nor analyzed in the previous
investigation). The normal ventricular function group
(n=13) had no evidence of left ventricular dysfunction,
mitral insufficiency, or symptomatic congestive heart
failure. These patients (9 men and 4 women; mean age, 48±4 years) had
normal baseline hemodynamics (Table 1
).
Nine had normal coronary anatomy and 4 had significant
coronary artery disease. All had been taking nitrates, calcium
channel antagonists, and/or ß-adrenergic
antagonists; these medications were withheld for at least
18 hours before the investigation. The congestive heart failure group
(n=19) consisted of patients with idiopathic (n=12), peripartum
(n=1),
ethanol-related (n=1), or muscular dystrophy–related (n=1)
dilated
cardiomyopathy. The remaining 4 patients with
congestive heart failure had ischemic
cardiomyopathy. There were 11 men and 8 women (mean
age, 50±3 years). All had evidence of severe left
ventricular systolic dysfunction by two-dimensional
echocardiography or radionuclide ventriculography
(mean left ventricular ejection fraction, 25±2%).
Patients were in New York Heart Association functional class II (n=7),
III (n=8), or IV (n=4) of congestive heart failure. All patients
with
congestive heart failure were taking digoxin, diuretics, and
angiotensin-converting enzyme inhibitors. None
of these patients were taking ß-adrenergic–blocking agents, although
2 were receiving low-dose amiodarone. In the congestive heart
failure group, all medications were withheld on the morning of the
procedure.
|
The investigation was completed at two sites. Eighteen patients were studied at the Brigham and Women's Hospital, Boston, Mass, and the remaining 14 patients were studied at the Mount Sinai Hospital, Toronto, Ontario. At both centers, the protocol was approved by the ethical review committee for experimentation involving human subjects. Written, informed consent was obtained in all cases.
Hemodynamic Measurements
All patients initially underwent
routine diagnostic
left- and right-side heart catheterization with the
femoral approach. After the diagnostic procedure, at least
20 minutes elapsed before the beginning of this investigation. A 7F
micromanometer-tipped catheter was then placed into
the left ventricle. Femoral artery pressure was monitored via an 8F
side-arm sheath (Cordis Laboratories). A 7F left Judkins catheter
(Cordis Laboratories) was placed from the opposite femoral artery and
advanced to the ostium of the left main coronary artery as
would be done for routine contrast injection.
The ECG, femoral arterial pressure, left ventricular pressure, and the first derivative of left ventricular pressure continuous electronic differentiation were recorded on a strip-chart recorder. Measurements for heart rate, systolic arterial pressure, mean arterial pressure, left ventricular minimum diastolic pressure, left ventricular end-diastolic pressure, left ventricular peak +dP/dt (+dP/dt), and left ventricular peak -dP/dt (-dP/dt) were made by averaging at least 15 consecutive beats under each experimental condition.
The time constant of left ventricular isovolumic relaxation, Tau, was calculated in two ways. The first method is a modification of that described by Weiss et al17 in which Tau (TL) is equal to -1/slope of the regression line for the natural logarithm of left ventricular pressure versus time for the period from peak -dP/dt to 5 mm Hg above left ventricular end-diastolic pressure. The second method is the direct measurement of the pressure half-time (T1/2), as described by Mirsky.18 With this method, Tau is measured directly from the pressure tracing as the time required for left ventricular pressure to fall to one half of its value at -dP/dt. Left ventricle pressure recordings were recorded at a paper speed of 100 mm/s and subsequently digitized at 2- to 4-ms intervals with a digitizing tablet (Summagraphics, Summagraphics Corporation) interfaced with a Macintosh personal computer. Values for Tau represent the mean value calculated from four to eight cardiac cycles during each experimental condition.
Arterial and Coronary Sinus
Catecholamine Levels
In 8 patients with normal ventricular function
and
10 patients with congestive heart failure, a Simmons II catheter
(Cordis Laboratories) was placed into the coronary sinus via
the right femoral vein for sampling of coronary sinus blood. In
these cases, simultaneous femoral artery and
coronary sinus blood specimens were drawn immediately after
hemodynamic measurements at the end of both control and
phentolamine infusion periods. Plasma samples were subsequently
stored at -70°C and underwent subsequent analysis for
catecholamine levels with high-performance liquid
chromatography. The intra-assay coefficients of
variation for norepinephrine and epinephrine in our
laboratory are both less than 5%. The interassay coefficients of
variation for norepinephrine and epinephrine are
5.0% and 7.2%, respectively.
Infusion Protocol
Left main intracoronary infusions were
performed
with the 7F left Judkins diagnostic catheter and a Harvard
Apparatus infusion pump. Control measurements were made
during the intracoronary infusion of 5% dextrose in water
(D5W), the vehicle for intracoronary drug
infusion, given at a rate of 2 mL/min. Phentolamine was then
infused at a rate of 0.2 mg/min to yield a calculated coronary
concentration of approximately 5x10-6 mol/L.
Phentolamine was administered for a total of 5 minutes, with
hemodynamic measurements and blood sampling completed
during the last minute. After completion of the drug infusion protocol,
we injected radiographic contrast to confirm the position
of the JL-4 catheter in the left main coronary ostium. As
mentioned, 14 patients were part of a previously reported investigation
and had received sequential intracoronary infusions of
dobutamine and phenylephrine before
intracoronary phentolamine infusion.6
In these cases, repeat control measurements were made after infusion of
D5W for 3 to 5 minutes. In each case, heart rate, systemic
blood pressure, and +dP/dt had returned to within 5% of control values
before the subsequent infusion of phentolamine.
Hemodynamic measurements during this repeat control
period were used as control values in this report of
hemodynamic responses to phentolamine.
Statistical Analysis
All data are presented as
mean±SEM. Differences between
two observations for one variable within the same group were
determined with a two-tailed, paired t test. Differences
between two groups were determined with a two-tailed, nonpaired
t test. The change in catecholamine
concentrations caused by phentolamine in the two groups was
also compared with a two-tailed, nonpaired t test.
Differences were considered significant if the null hypothesis could be
rejected at the P=.05 level. The relation between the change
in the transcardiac gradient of norepinephrine
caused by phentolamine and control coronary sinus
norepinephrine levels was determined by simple linear
regression.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Baseline Hemodynamics
Patients in the control group had normal baseline hemodynamics (Table 1
). As expected, the patients in
the congestive heart failure group had markedly elevated left
ventricular filling pressures, lower resting cardiac index,
and higher resting heart rates. Left ventricular +dP/dt was
significantly reduced in the congestive heart failure patients.
TL, Tau by the method of Weiss et al,17
and T1/2, Tau by the method of
Mirsky,18 were each significantly increased in the
congestive heart failure group. The correlation coefficients for the
linear regression of time versus the logarithm of left
ventricular pressure during isovolumic relaxation were high
in both groups, averaging .993±.001 in the normal function group and
.991±.001 in the congestive heart failure group.
Hemodynamic Effects of
Intracoronary Phentolamine
In patients with normal ventricular
function, the
intracoronary infusion of phentolamine caused a
small but significant fall in systemic arterial blood
pressure (132±4 versus 126±4 mm Hg, control versus
phentolamine, P<.01; Table 2), along
with a small but significant fall in left ventricular
minimum pressure (5±1 versus 4±1 mm Hg, control versus
phentolamine, P=.03; Table 2). In this group,
there
was no change in heart rate, mean arterial pressure, or
left ventricular end-diastolic pressure.
|
In patients with congestive
heart failure, the administration of
phentolamine caused small reductions in both systolic and mean
arterial blood pressures that were of borderline
statistical significance (122±5 versus 118±4 mm Hg and
89±3 versus
87±2 mm Hg, control versus phentolamine, P=.06 and
.05, respectively; Table 3). Phentolamine caused
significant reductions in both left ventricular
end-diastolic and minimum pressures (24±3 versus 23±3
mm Hg and 14±2 versus 12±2 mm Hg, control versus
phentolamine, P=.02 and <.01, respectively; Table
3) along with a small but significant increase in heart rate
(92±3
versus 97±7 beats per minute, control versus phentolamine,
P=.02).
|
Effects of Intracoronary Phentolamine on Left
Ventricle Isovolumic Performance Indexes
In the normal ventricular
function group,
intracoronary phentolamine had no effect on +dP/dt
(1382±119 versus 1382±106 mm Hg/s, control versus
phentolamine, P=NS; Table 2). Similarly, in
this
group phentolamine caused no change in either -dP/dt
(-1783±152 versus -1694±150 mm Hg/s, control versus
phentolamine; P=NS) or the time constant of left
ventricular isovolumic relaxation (49±5 versus 47±4 ms
and 35±3 and 34±3 ms, control versus phentolamine,
TL and T1/2, respectively,
P=NS; Table 2).
In the congestive heart
failure group, intracoronary
phentolamine was associated with both a positive inotropic and
lusitropic response. Left ventricular +dP/dt increased from
797±63 to 849±74 mm Hg/s (P<.01; Table
3). Phentolamine also caused an increase in the
rate of left ventricular isovolumic relaxation as indicated
by an increase in -dP/dt (-878±63 versus
-965±87 mm Hg, control
versus phentolamine, P=.03; Table 3) and a
decrease
in the time constant of left ventricular isovolumic
relaxation (64±4 versus 55±4 ms and 45±3 versus
39±3 ms, control
versus phentolamine, TL and
T1/2, respectively, P<.01 for both;
Table 3).
Effects of Intracoronary Phentolamine on
Arterial and Coronary Sinus
Catecholamines
Both arterial and coronary sinus
norepinephrine levels were significantly higher in the
congestive heart failure group (Fig 1 and Table
4). In the patients with normal left
ventricular function, the administration of
phentolamine caused an increase in coronary sinus
norepinephrine levels that did not achieve statistical
significance (1.7±0.3 versus 2.5±0.7 nmol/L, control versus
phentolamine, P=NS; Fig 2 and Table
4). Phentolamine caused no change in arterial
norepinephrine levels in this group (Figs 1 and
2 and Table 4). In patients with congestive
heart failure, phentolamine
caused a marked increase in coronary sinus
norepinephrine levels (4.2±0.5 versus 8.3±1.2 nmol/L,
control versus phentolamine, P<.01; Table 4) but no
change in arterial norepinephrine levels (Figs 1 and
2 and Table 4). This increase in coronary sinus
norepinephrine concentration was greater than that seen in
the normal function group (Figs 1 and 2). The
increase
in the arterial-to-coronary sinus
norepinephrine gradient caused by phentolamine was
not significant in the group with normal ventricular
function (0.4±0.3 versus 1.3±0.5 nmol/L, control versus
phentolamine, P=NS; Fig 3). In the congestive
heart
failure group, the transcardiac gradient of
norepinephrine was significantly increased after
phentolamine (1.6±0.5 versus 5.4±1.2 nmol/L, control versus
phentolamine, P<.01; Fig 3), and an unpaired
analysis reveals that this increase was significantly greater
than that observed in the normal ventricular function group
(Fig 3).
|
|
|
|
There was a significant correlation between
control coronary
sinus norepinephrine levels and the increase in the
transcardiac norepinephrine gradient caused by
phentolamine (y=1.11x-0.97,
r2=.6, P<.01; Fig 4).
The correlation was somewhat weaker when
norepinephrine data from the congestive heart failure group
alone were (y=1.24x-1.42,
r2=.51, P=.02). There was no
significant correlation of these values in the normal function group
(y=0.4x+0.146,
r2=.07, P=NS).
|
There was no change in arterial or coronary sinus epinephrine levels during phentolamine infusion in either the normal ventricular function group or the congestive heart failure group.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The present study reveals that
-adrenergic receptor
blockade exerts positive chronotropic, inotropic, and lusitropic
effects on the failing human left ventricle. These
hemodynamic effects in patients with congestive heart
failure are accompanied by an increase in coronary sinus
norepinephrine. The effects were quite different than those
observed during myocardial -adrenergic receptor blockade in patients
with normal left ventricular function.
These results are consistent with the hypothesis that
phentolamine, a nonselective -adrenergic receptor
antagonist, causes increased cardiac neuronal release of
norepinephrine in patients with congestive heart failure
through blockade of presynaptic 2-adrenergic receptors
on postganglionic cardiac sympathetic nerves. Patients with congestive
heart failure have elevated systemic and cardiac sympathetic
tone14 15 16 and presumably have elevated
intrasynaptic
concentrations of norepinephrine. Neuronally released
norepinephrine stimulates inhibitory
presynaptic 2-adrenergic receptors, resulting in a local
negative feedback control mechanism limiting further release of
norepinephrine.19 20 21 22 23 24 25 26 27 28
Phentolamine,
through blockade of presynaptic 2-adrenergic receptors,
interrupted this local control mechanism and subsequently caused an
increase in cardiac neuronal release of norepinephrine.
This was reflected by the increase in coronary sinus
norepinephrine and the observed changes in heart rate and
ventricular performance.
In patients with normal left ventricular function, intracoronary phentolamine had no effect on heart rate or ventricular performance and caused a small increase in coronary sinus norepinephrine that did not achieve statistical significance. It is possible that this represents a type 2 statistical error and that this increase would achieve statistical significance if a larger number of patients were studied. Nevertheless, the increase in coronary sinus norepinephrine in patients with congestive heart failure was significantly greater than that observed in the normal ventricular function group. Taken together, these findings suggest that phentolamine had a more substantial effect on cardiac neuronal norepinephrine release in patients with congestive heart failure.
The presence of a presynaptic 2-adrenergic receptor
that, when stimulated, inhibits neuronal release of
norepinephrine has been demonstrated in a number of in
vitro preparations and in vivo animal
studies.23 24 25 26 27 28
Investigations in the forearm have confirmed the presence of this
presynaptic receptor system in
humans.19 20 21 22 In a
detailed
study involving healthy volunteers, Grossman et al21
demonstrated that the intra-arterial administration of
yohimbine, a selective 2-adrenergic receptor
antagonist, caused an increase in
norepinephrine spillover to plasma in the forearm that
could not be explained by the effect of the drug on local or systemic
hemodynamics. Kubo et al,22 in a study of
both healthy subjects and patients with congestive heart failure, found
that the intra-arterial infusion of yohimbine caused an
increase in forearm venous norepinephrine concentration in
both groups. It is of importance that yohimbine caused a greater
increase in forearm venous norepinephrine in patients with
congestive heart failure than in normal control subjects. Also, the
authors found a direct relation between basal venous
norepinephrine concentration and the increase in
norepinephrine concentration in response to
2-adrenergic receptor blockade. Their findings suggest
that presynaptic 2-regulation of adrenergic transmission
may be particularly important in situations of sympathetic activation
such as congestive heart failure.
This is the first study in the human heart to demonstrate the presence
and functional significance of a presynaptic
2-adrenergic receptor that controls the release of
norepinephrine. In the normal dog, Yamaguchi et
al28 demonstrated that -adrenergic receptor blockade
had no effect on coronary sinus norepinephrine
levels. However, -adrenergic receptor blockade caused a marked
potentiation of the increase in coronary sinus
norepinephrine associated with stimulation of
postganglionic cardiac nerves. This suggests that the response to
presynaptic 2-adrenergic receptor blockade is dependent
on the state of sympathetic activation and that increased sympathetic
nerve firing leads to recruitment of this negative feedback control
mechanism.
The observations of Kubo et al22 and Yamaguchi et
al28 are consistent with the present findings
in patients with congestive heart failure. These patients had elevated
arterial and coronary sinus
norepinephrine levels indicative of sympathetic activation.
We hypothesized that this heightened sympathetic tone was associated
with increased stimulation of presynaptic 2-adrenergic
receptors. Presynaptic receptor systems function by altering the
probability that a given action potential will result in any single
storage vesicle releasing its contents into the synaptic cleft.
Therefore, in the setting of sympathetic activation and increased
sympathetic nerve firing rate, presynaptic 2-adrenergic
stimulation is probably a very important modulator of
norepinephrine release. Phentolamine, by
interrupting this negative feedback system, causes increased neuronal
release of norepinephrine with resultant biochemical and
ventricular function responses. The relation between the
level of sympathetic activation and activation of presynaptic
2-adrenergic receptors appears to be a systematic one
since there was a significant correlation between basal
coronary sinus levels of norepinephrine and the
change in coronary sinus norepinephrine gradient
associated with phentolamine.
The positive inotropic effect of phentolamine in patients with
congestive heart failure cannot represent a postsynaptic effect
of -adrenergic receptor blockade because postsynaptic -adrenergic
receptor stimulation causes a positive inotropic response in
humans.6 Thus, this positive inotropic response to
phentolamine appears to be caused by increased synaptic
concentrations of norepinephrine, which has both ß- and
-adrenergic receptor activity. Similarly, the positive lusitropic
response to phentolamine was likely mediated by the
ß-adrenergic effects of increased norepinephrine
release.29 There are, however, theoretical reasons why the
positive lusitropic effect of phentolamine in patients with
congestive heart failure could have been contributed to by blockade of
postsynaptic myocardial -adrenergic receptors. Although the
biochemical responses to 1-adrenergic receptor
stimulation of the myocardium are incompletely understood,
all current proposals involve alterations in calcium handling or the
sensitivity of the contractile apparatus to
calcium2 30 31 32 33
and therefore could also have an effect on
isovolumic relaxation, an event that is modulated by
calcium.34 The difference in the responses to
phentolamine in normal and failing left ventricle might thus
reflect the effects of increased -adrenergic tone on
myocardium in patients with congestive heart
failure.14 15 16 Further investigations
with selective
1- and 2-adrenergic receptor
antagonists might provide information that is complementary
to the present set of experiments. The use of a selective
2-adrenergic receptor antagonist (eg,
yohimbine) would likely produce similar effects on cardiac
norepinephrine production with potentially greater
myocardial responses because postsynaptic 1-adrenergic
receptors would not be affected. Similarly, the use of a selective
1-adrenergic receptor antagonist (eg,
prazosin) would allow observations concerning the effects of blockade
of basal 1-adrenergic activity on cardiac
performance. Although the effects of -adrenergic receptor
blockade on resting coronary blood flow remain
controversial,35 it is possible that phentolamine
increased coronary blood flow in patients with congestive heart
failure, thereby relieving asymptomatic subendocardial
ischemia with subsequent effects on left
ventricular function. Myocardial ischemia in the
absence of obstructive coronary artery disease has been
documented to occur in animal models of congestive heart
failure36 and might occur in some patients with idiopathic
cardiomyopathy.37
A weakness of the present study is that although arterial and coronary sinus concentrations were quantified, we did not use measures of coronary blood flow combined with tracer doses of radiolabeled norepinephrine.15 16 38 The latter approach allows measurement of cardiac norepinephrine spillover, a more accurate index of the activity of cardiac sympathetic nerves. If phentolamine caused an increase in coronary blood flow, this may have reduced extraction of norepinephrine by myocardium, leading to an increase in coronary sinus norepinephrine concentration. This relation has been demonstrated in the human forearm, where increases in blood flow result in reduced extraction of circulating norepinephrine.39 Esler et al40 measured cardiac norepinephrine spillover in humans before and after administering desipramine to block neuronal reuptake of norepinephrine. In their experiment, desipramine reduced the fractional extraction of tritiated norepinephrine from 81% to 19% and increased coronary sinus plasma flow from 89 to 124 mL/min. This combination of blocking reuptake and increasing blood flow increased coronary sinus norepinephrine concentration from 212 to 304 pg/mL. Unfortunately, similar data are not available in patients with congestive heart failure, and the effects of coronary blood flow changes on coronary sinus norepinephrine levels might be different in this group. Therefore, it must be conceded that increased washout might explain an increase in coronary sinus norepinephrine concentration in the congestive heart failure group. Nevertheless, we believe that increased washout alone cannot explain the hemodynamic findings observed in this investigation. Critically, this mechanism would not increase the intrasynaptic concentration of norepinephrine. The increase in contractility demonstrated in this experiment implies greater myocardial adrenergic receptor stimulation, which would occur only with increased intrasynaptic concentrations of norepinephrine.
The administration of phentolamine was associated with small changes in left ventricular preload and afterload in both patient groups. We do not believe that this change in loading conditions is the cause of the change in left ventricular systolic and diastolic functions observed in the congestive heart failure group. First, the increase in +dP/dt cannot be explained by a decrease in either preload or afterload. Second, although changes in both afterload and preload have been shown to affect the rate of left ventricular relaxation,10 the changes observed in this investigation were small and unlikely to have caused the observed change in isovolumic relaxation.11 The congestive heart failure group also experienced a small increase in heart rate during phentolamine. Although increases in heart rate have been reported to have both positive inotropic and lusitropic effects, this is observed only with much greater increases in heart rate, and in patients with congestive heart failure such responses are blunted compared with in those with normal ventricular function.41 However, in the failing human left ventricle, isovolumic relaxation rates have been shown to be quite sensitive to changes in afterload,42 and in this group the combined effects of an increase in heart rate and a decrease in systolic pressure might have produced the observed increase in the rate of isovolumic relaxation.
Changes in loading conditions can also cause changes in sympathetic tone by reflex mechanisms. Although it is possible that the small decrease in systemic arterial blood pressure caused some increase in cardiac sympathetic tone by a baroreceptor-mediated mechanism, the fact that arterial catecholamine levels did not increase suggests that systemic sympathetic tone was not increased during phentolamine infusion. Furthermore, the normal ventricular function and congestive heart failure groups had similar decreases in arterial blood pressure during phentolamine administration. Because patients with congestive heart failure have blunted baroreceptor-mediated responses,43 the greater increase in coronary sinus norepinephrine concentration seen in this group must have been mediated by some other mechanism.
In the control group, baseline epinephrine levels were high, with a mean value of 1.1±0.5 nmol/L for the arterial sinus. In fact, four of the patients in the normal ventricular function group had epinephrine levels above the normal range. Norepinephrine levels within this group were all within the normal range. These elevated epinephrine levels presumably reflect adrenal release of epinephrine associated with the stress of the procedure. Although it is possible that this form of sympathetic activation may have had some impact on our results, the responses to the administration of phentolamine were not different from those by patients with normal epinephrine levels.
The effect of phentolamine on left ventricular
performance in the patients with congestive heart failure was
relatively small, and it is not certain that such an effect would be
maintained during sustained therapy. It should be noted that these
findings are consistent with prior observations concerning the
effects of phentolamine in patients with congestive heart
failure.44 45 Although direct evidence was lacking,
it was
suggested that phentolamine had direct myocardial effects that
were mediated by norepinephrine release.46
From a therapeutic perspective, it is also not clear that an
intervention that has positive inotropic effects and increases cardiac
sympathetic activity would be desirable. More important is the fact
that the present study demonstrates the presence of an presynaptic
2-adrenergic receptor system in congestive heart
failure, which serves to inhibit the release of
norepinephrine from cardiac nerves in patients with
congestive heart failure and sympathetic activation. Is it possible
that this pathway is dysfunctional in some patients with congestive
heart failure, leading to inappropriate levels of
norepinephrine release? Furthermore, this pathway may have
some therapeutic implications. Agents that inhibit
2-adrenergic receptors might be found to have
deleterious effects on cardiac sympathetic activity despite the fact
that they might have favorable effects on peripheral
vascular resistance. In contrast, an agent like clonidine might have
beneficial effects in this regard. This is of particular interest
because of the possibility that increased sympathetic activity is
deleterious in congestive heart failure and evidence that
ß-adrenergic receptor blockade may have favorable effects on
long-term outcome in this disease. Therefore, the presence of this
system has implications for understanding the pathogenesis of
congestive heart failure as it relates to the sympathetic nervous
system, and a better understanding of the functional integrity of this
autonomic receptor pathway may be of eventual clinical importance.
|
Acknowledgments |
|---|
This work was supported by a grant-in-aid from the Heart and Stroke Foundation of Ontario (HSFO grant 2220). Dr Parker is a Scholar of the Medical Research Council of Canada. Dr Colucci is a Sandoz Established Investigator of the American Heart Association. Dr Floras is a Career Scientist of the Ministry of Health of the Province of Ontario. The authors thank the staff of the Cardiac Catheterization Laboratory of the Brigham and Women's Hospital and the Cardiovascular Clinical Research Laboratory of the Mount Sinai Hospital for their help in the completion of these studies.
Received November 28, 1994; revision received February 14, 1995; accepted February 25, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Leier CV, Binkley PF, Cody RJ.
-Adrenergic component of the sympathetic nervous system in
congestive heart failure. Circulation.
1990;82(suppl I):I-168-I-176.
2.
Benfey RG. Function of myocardial
-adrenoceptors. J Auton Pharm. 1993;13:351-372.
3.
Bristow MR, Minobe W, Rasmussen R, Hershberger RE,
Hoffman BB. Alpha-1 adrenergic receptors in the nonfailing and
failing human heart. J Pharmacol Exp Ther. 1988;247:1039-1045.
4.
Vago T, Bevilacqua M, Norbiato G, Baldi G, Chebat E,
Bertora P, Baroldi G, Accinni R. Identification of
1-adrenergic receptors on sarcolemma from normal
subjects and patients with idiopathic dilated
cardiomyopathy: characteristics and linkage to
GTP-binding protein. Circ Res. 1989;64:474-481.
5.
Bohm M, Diet F, Feiler G, Kemkes B, Erdmann E.
-Adrenoceptors and
-adrenoreceptor-mediated positive inotropic effects
in failing human myocardium. J
Cardiovasc Pharmacol. 1988;12:357-364. [Medline]
[Order article via Infotrieve]
6.
Landzberg JS, Parker JD, Gauthier DF, Colucci WS.
Effects of myocardial 1-adrenergic receptor
stimulation and blockade on contractility in
man. Circulation. 1991;84:1608-1614.
7.
Aass H, Skomedal T, Osnes J. Demonstration of
an alpha-adrenoreceptor-mediated inotropic effect of
norepinephrine in rabbit papillary muscle.
J Pharmacol Exp Ther. 1983;226:572-578.
8.
Skomedal T, Schiander IG, Osner JB. Both alpha
and beta adrenoreceptor mediated component contribute
to final inotropic response to norepinephrine in rat
heart. J Pharmacol Exp Ther. 1988;247:1204-1210.
9.
Bruckner R, Meyer W, Mugge A, Schmitz W, Scholz H.
-Adrenoceptor-mediated positive inotropic effect of
phenylephrine in isolated human ventricular
myocardium. Eur J Pharm. 1984;99:345-347. [Medline]
[Order article via Infotrieve]
10. Karliner JS, LeWinter MM, Mahler F, Engler R, O'Rourke RA. Pharmacologic and hemodynamic influences on the rate of isovolumic left ventricular relaxation in the normal conscious dog. J Clin Invest. 1977;60:511-521.
11.
Starling MR, Montgomery DG, Mancini GBJ, Walsh RA.
Load independence of the rate of isovolumic relaxation in
man. Circulation. 1987;76:1274-1281.
12.
Shepherd JT, VanHoutte PM. Local modulation of
adrenergic neurotransmission. Circulaton. 1981;64:655-666.
13.
Parker JD, Landzberg JS, Bittl JA, Colucci WS.
Myocardial -adrenergic tone impairs isovolumic relaxation in
the failing human left ventricle. J Am Coll
Cardiol. 1991;17(suppl A):297A. Abstract.
14. Cohn JN, Levine TB, Olivari TB, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823. [Abstract]
15.
Merideth IT, Eisenhofer G, Lambert GW, Dewar EM,
Jennings GL, Esler MD. Cardiac sympathetic activity in
congestive heart failure: evidence for increased neuronal
norepinephrine release and preserved neuronal
uptake. Circulation. 1993;88:136-145.
16. Kaye DM, Lambert GW, Lefkovits J, Morris M, Jennings G, Esler MD. Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J Am Coll Cardiol. 1994;23:570-578. [Abstract]
17. Weiss JL, Frederickson JW, Weisfeldt ML. Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest. 1976;58:751-760.
18.
Mirsky I. Assessment of diastolic
function: suggested methods and future considerations.
Circulation. 1984;69:836-841.
19. Jie K, Timmermans PB, van Zwieten PA. Modulation of noradrenaline release by peripheral presynaptic alpha 2-adrenergic adrenoreceptors in humans. J Cardiovasc Pharmacol. 1987;9:407-413. [Medline] [Order article via Infotrieve]
20. Grossman E, Rea RF, Hoffman A, Goldstein DS. Yohimbine increases sympathetic nerve activity and norepinephrine spillover in normal volunteers. Am J Physiol. 1991;260(Regul Integ Comp Physiol 29):R142-R147.
21.
Grossman E, Chang PC, Hoffman A, Marye T, Goldstein DS.
Evidence for functional
2-adrenoreceptors on vascular
sympathetic nerve endings in the human forearm.
Circ Res. 1991;69:887-897.
22.
Kubo SH, Rector TS, Heifetz SM, Cohn JN.
2-Receptor–mediated vasoconstriction in patients
with congestive heart failure.
Circulation. 1989;80:1660-1666.
23.
Starke K, Endo T, Taube HD. Pre- and
post-synaptic components in effect of drugs with
-adrenoreceptor activity. Nature. 1975;254:440-441. [Medline]
[Order article via Infotrieve]
24. Gothert M, Schlicker E, Hentrich F, Rohm N, Zerkowski HR. Modulation of noradrenaline release in human saphenous vein via presynaptic alpha 2-adrenoreceptors. Eur J Pharmacol. 1984;102:261-267. [Medline] [Order article via Infotrieve]
25.
Wakade AR, Wakade TD. Reduction in
norepinephrine content of sympathetic neuroeffector organs
by alpha adrenergic antagonists and nerve stimulation:
evidence for presynaptic control of sympathetic transmitter release in
the intact animal. J Pharmacol Exp Ther. 1984;228:287-292.
26. Westfall TC. Evidence that noradrenergic transmitter release is regulated by presynaptic receptors. Fed Proc. 1984;43:1352-1357. [Medline] [Order article via Infotrieve]
27. Kahan T, Dahlof C, Hjemdahl. Prejunctional alpha-adrenoreceptor-mediated inhibition of norepinephrine released in blood-perfused skeletal muscle in situ. J Cardiovasc Pharmacol. 1987;9:555-562. [Medline] [Order article via Infotrieve]
28.
Yamaguchi N, Champlain J, Nadeau R. Regulation
of norepinephrine release from cardiac sympathetic nerves
in the dog by presynaptic - and ß-receptors.
Circ Res. 1977;41:108-117.
29.
Parker JD, Landzberg JS, Bittl JA, Mirsky I, Colucci
WS. The effects of ß-adrenergic stimulation with dobutamine on
isovolumic relaxation in the normal aand failing human left
ventricle. Circulation. 1991;84:1040-1048.
30. Benfey BG. Lack of relationship between myocardial cyclic AMP concentrations and inotropic effects of sympathomimetic amines. Br J Pharmacol. 1971;43:757-763. [Medline] [Order article via Infotrieve]
31. Exton JH. Mechanisms of calcium-mobilizing agonists: some variations on a young theme. FASEB J. 1988;2:2670-2676. [Abstract]
32. Minniman KP. Alpha 1-adrenergic receptor subtypes, inositol phosphates and sources of cell Ca++. Pharmacol Rev. 1988;40:87-119. [Medline] [Order article via Infotrieve]
33.
Endoh M, Blinks JR. Actions of sympathomimetic
amines on the Ca2+ transients and contractions of rabbit
myocardium: reciprocal changes in myofibrillar
responsiveness to Ca2+ mediated through alpha- and
beta-adrenoreceptors. Circ
Res. 1988;62:247-265.
34.
Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ, Feldman
MD, Grossman W, Morgan JP. Abnormal intracellular calcium
handling in myocardium from patients with end-stage heart
failure. Circ Res. 1987;61:70-76.
35.
Hodgson JM, Cohen MD, Szentpetery S, Thames MD.
Effects of regional - and ß-blockade on resting and
hyperemic coronary blood flow in conscious, unstressed
humans. Circulation. 1989;79:797-809.
36.
Hittinger L, Shannon RP, Kohin S, Lader AS, Manders WT,
Patrick TA, Kelly P, Vatner SF. Isoproterenol-induced
alterations in myocardial blood flow, systolic and
diastolic function in conscious dogs with heart
failure. Circulation. 1989;80:658-668.
37.
Pasternac A, Noble J, Streulens Y, Elie R, Henschke C,
Bourassa M. Pathophysiology of chest pain in patients with
cardiomyopathies and normal coronary
arteries. Circulation. 1982;65:778-789.
38. Rose CP, Burgess JH, Cousineau D. Tracer norepinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic pressure and volume overload. J Clin Invest. 1985;76:1740-1747.
39.
Chang PC, Kriek E, Van Der Krogt JA, van Brummelen P.
Does regional norepinephrine spillover
represent local sympathetic activity?
Hypertension. 1991;18:56-66.
40.
Esler MD, Wallin G, Dorward PK, Eisenhofer G, Westerman
R, Meredith I, Lambert G, Cox HS, Jennings G. Effects of
desipramine on sympathetic nerve firing and norepinephrine
spillover to plasma in humans. Am J Physiol. 1991;260:R817-R823.
41.
Ellenbogen RA, Mohanty PK, Szentepetery S, Thames MD.
Arterial baroreflex abnormalities in heart failure:
reversal after cardiac transplantation.
Circulation. 1989;79:51-58.
42.
Eichhorn EJ, Willard JD, Alvarez L, Kim AS, Glamman DB,
Risser RC, Grayburn PA. Are contraction and relaxation coupled
in patients with and without congestive heart failure?
Circulation. 1992;85:2132-2139.
43. Feldman MD, Alderman JD, Aroesty JM, Royal HD, Ferguson JJ, Owen RM, Grossman W, McKay RG. Depression of sytolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy. J Clin Invest. 1988;82:1661-1669.
44.
Miller RR, Vismara LA, Williams DO, Amsterdam EA, Mason
DT. Pharmacologic mechanisms for left ventricular
unloading in clinical congestive heart failure: differential effects of
nitroprusside, phentolamine, and nitroglycerin
on cardiac function and peripheral circulation.
Circ Res. 1976;39:127-133.
45.
Stern MA, Gohlke HK, Loeb HS, Croke RP, Gunnar RM.
Hemodynamic effects of intravenous
phentolamine in low output cardiac failure.
Circulation. 1978;58:157-163.
46. Gould L, Reddy CVR. Phentolamine. Am Heart J. 1976;92:397-402. [Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  W. S. Akers and L. A. Cassis Presynaptic modulation of evoked NE release contributes to sympathetic activation after pressure overload Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2151 - H2158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Small, L. E. Wagoner, A. M. Levin, S. L.R. Kardia, and S. B. Liggett Synergistic Polymorphisms of {beta}1- and {alpha}2C-Adrenergic Receptors and the Risk of Congestive Heart Failure N. Engl. J. Med., October 10, 2002; 347(15): 1135 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.F. Notarius, E.R. Azevedo, J.D. Parker, and J.S. Floras Peak oxygen uptake is not determined by cardiac noradrenaline spillover in heart failure Eur. Heart J., May 2, 2002; 23(10): 800 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Aggarwal, M. D. Esler, F. Socratous, and D. M. Kaye Evidence for functional presynaptic alpha-2 adrenoceptors and their down-regulation in human heart failure J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1246 - 1251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Notarius and J. S. Floras Limitations of the use of spectral analysis of heart rate variability for the estimation of cardiac sympathetic activity in heart failure Europace, January 1, 2001; 3(1): 29 - 38. [Abstract] [PDF]
|
|
|
|
 |
|
 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Newton, E. R. Azevedo, and J. D. Parker Inotropic and Sympathetic Responses to the Intracoronary Infusion of a ß2-Receptor Agonist : A Human In Vivo Study Circulation, May 11, 1999; 99(18): 2402 - 2407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Azevedo, G. E. Newton, and J. D. Parker Cardiac and systemic sympathetic activity in response to clonidine in human heart failure J. Am. Coll. Cardiol., January 1, 1999; 33(1): 186 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Lang, C. M. Stein, R. A. Nelson, H. B. He, F. J. Belas, I. A. Blair, M. Wood, and A. J. J. Wood Sympathoinhibitory Response to Clonidine Is Blunted in Patients With Heart Failure Hypertension, September 1, 1997; 30(3): 392 - 397. [Abstract] [Full Text]
|
|
|
|
|
|
G. E. Newton and J. D. Parker Acute Effects of ß1-Selective and Nonselective ß-Adrenergic Receptor Blockade on Cardiac Sympathetic Activity in Congestive Heart Failure Circulation, August 1, 1996; 94(3): 353 - 358. [Abstract] [Full Text]
|
|
|
|
|
|
G. L. Stiles `A Riddle Wrapped in a Mystery Inside an Enigma' : Winston S. Churchill, October 1, 1939 Circulation, October 1, 1995; 92(7): 1678 - 1679. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||