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(Circulation. 2000;101:2277.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Modulation of Sympathetic Coronary Vasoconstriction by Cardiac Renin-Angiotensin System in Human Coronary Heart Disease
From Centro di Fisiologia Clinica e Ipertensione, Università di Milano, Ospedale Maggiore IRCCS, Milan, Italy (A.S., G.P., R.P., A.M., L.T., G.M.); and Clinica Medica, Università di Milano-Bicocca, Ospedale San Gerardo, Monza, Milan (A.S., G.M.).
Correspondence to Prof Giuseppe Mancia, Clinica Medica, Ospedale San Gerardo, Via Donizetti 106, 20052 Monza, Milano, Italy.
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Abstract |
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Background—In humans, angiotensin II enhances the sympathetic coronary vasoconstriction elicited by the cold pressor test (CPT) and diving. Whether this enhancement depends on the circulating angiotensin II or on the locally produced angiotensin II is unknown, however.
Methods and Results—We addressed this issue in 14 patients with severe coronary artery disease by evaluating the effects of a 2-minute CPT (n=14) and a 30-second dive (n=8) on mean arterial pressure (MAP, arterial catheter), heart rate (ECG), coronary sinus blood flow (CBF, thermodilution technique), and coronary vascular resistance (MAP/CBF ratio). The 2 stimuli were applied at the end of left intracoronary infusion of either saline or benazeprilat diluted at the concentration of 25 µg/mL. The rate of benazeprilat infusion had been preliminarily demonstrated to reduce angiotensin II concentration in the coronary sinus without affecting its arterial concentration. The changes in MAP and heart rate induced by CPT and diving were superimposable during saline and benazeprilat infusions. The decrease in CBF induced by CPT and diving during saline infusion was changed into an increase during benazeprilat infusion with a significant attenuation of the coronary vasoconstrictor response.
Conclusions—In patients with coronary artery disease, an attenuation of sympathetic coronary vasoconstriction can be obtained by reducing cardiac angiotensin II formation without involving circulating angiotensin II. This suggests a role of the tissue renin-angiotensin system in modulating autonomic cardiac drive in humans.
Key Words: circulation • nervous system, sympathetic • renin • angiotensin • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In subjects with mild coronary atherosclerotic lesions, the intracoronary infusion of angiotensin II at doses devoid of systemic and local hemodynamic effects enhances coronary vasoconstriction induced through activation of the sympathetic nervous system by the cold pressor test or diving.1 Furthermore, in patients with severe coronary atherosclerosis, the sympathetic coronary vasoconstrictor responses to these stimuli are attenuated after an oral dose of an ACE inhibitor.2 Thus, the renin-angiotensin system exerts an important facilitating action on sympathetic vascular modulation of the human heart, which can be offset by reduction of angiotensin II production.
No information exists as to whether the renin-angiotensin system affects sympathetic influences on coronary vasomotor tone exclusively through circulating angiotensin II or through the local production of this substance. This is an important question because animal and human studies have provided evidence that angiotensin II can indeed be produced in the heart.3 4 5 6 Furthermore, data from isolated perfused rabbit hearts have shown that the cardiac effects of sympathetic stimulation are attenuated by ACE inhibition,7 which means that the cardiac production of angiotensin II might have a functional role. Finally, ACE inhibitors are known to differ in their ability to affect the tissue production of angiotensin II8 and thus presumably for their interference with any local angiotensin II modulation of sympathetic influences.
In the present study, we have examined the role of local angiotensin II on sympathetic cardiac influences by evaluating, in patients with severe coronary atherosclerosis, the effects of the intracoronary infusion of benazeprilat on the coronary vascular responses to the sympathetic activation induced by the cold pressor test and diving. The dose of benazeprilat infused was such as to reduce angiotensin II in the coronary sinus without affecting its arterial concentration.
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Methods |
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Population
We studied 14 male patients (mean age [±SD] 59.5±9.6 years) who underwent cardiac catheterization because of anginal chest pain and myocardial ischemia detected at exercise stress test and/or thallium scintigraphy. No patient had history, clinical, or laboratory evidence of valvular heart disease, previous myocardial infarction, or congestive heart failure, and none had hypertension, diabetes mellitus, or other major noncardiovascular diseases.
For all patients, the recruitment criterion was represented
by the presence of a significant (
75%) stenosis of the left
anterior descending coronary artery, whereas occlusion of this
artery and/or a stenosis of the left main trunk
represented exclusion criteria. The
hemodynamic and angiographic data obtained in each
patient are reported in Table 1
.
All patients agreed to participate in the study after explanation of
its nature and purpose. The protocol of the study was approved by the
ethics committee of our institution.
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Measurements
Arterial blood pressure was measured through the 8F
arterial sheath used to perform coronary
angiography through connection with an MX8004 Medex pressure transducer
(Medex Medical Inc). Heart rate was calculated as the reciprocal of the
R-R interval (ECG lead). Coronary blood flow was measured by a
7F Wilton-Webster thermodilution catheter inserted
percutaneously into an antecubital vein and guided
under fluoroscopy to lie deep within the coronary sinus. The
position of the catheter was checked at the beginning of the study by
injection of a small bolus of contrast medium (iopamidol 75.5 g/100 mL)
and confirmed periodically thereafter to ensure that no displacement
had occurred with respect to the surrounding reference points. Blood
flow measurements were obtained by the continuous thermodilution method
described by Ganz et al,9 that is, by infusing a 5%
glucose solution kept at room temperature at a rate of 1 mL/s through
the catheter tip and sampling the temperature of the venous blood by a
thermistor closer to the right atrium. Arterial blood
pressure, heart rate, and the conductance at the injection and sampling
sites of the thermodilution catheter were all recorded on a
polygraph (Mingograph 7, Siemens Elema) at a paper speed of 10
mm/s.
Other direct or indirect measurements were (1) rate-pressure product (systolic blood pressure times heart rate), which was taken as an index of myocardial metabolic requirements,10 (2) coronary vascular resistance, which was calculated by the ratio between mean arterial pressure (diastolic blood pressure plus one third of pulse pressure) and coronary blood flow, and (3) left ventricular end-diastolic pressure, left ventricular ejection fraction, and cardiac output, which were obtained at the time of cardiac catheterization.
Protocol
In all patients, antianginal drugs were withdrawn 72 hours
before the study, and only nitrate therapy was allowed when needed.
Cardiac catheterization was performed in the morning
after an overnight fast. The study proper began 45 minutes after
completion of cardiac catheterization (to minimize the
effect of contrast medium on coronary and systemic
circulations11 ) with the positioning of the
thermodilution catheter in the coronary sinus and the
advancement of a 6F left Judkins catheter from the femoral artery to
the ostium of the left main trunk. Blood pressure, heart rate, and
coronary blood flow were measured (1) 3 to 4 times both before
and after 15 minutes of infusion of saline in the left main trunk at
the rate of 60 mL/h and (2) while saline continued to be infused
immediately before and at the end of a cold pressor test (2-minute
immersion of one patient’s hand into melting ice water, n=14) or a
diving maneuver (30-second positioning of a thin plastic bag filled
with ice and water to the patient’s nose and mouth, n=8). Measurements
at points 1 and 2 were repeated before and during intracoronary
infusion benazeprilat diluted into saline (25 µg/mL) at the rate of
60 mL/h. The rate at which benazeprilat was infused had been
preliminarily determined in 6 additional male patients (age 60±11.4
years), also with significant left anterior descending coronary
artery stenosis, as the one that was capable of reducing
angiotensin II concentration in the coronary sinus
without affecting arterial angiotensin II
concentration, coronary blood flow, and systemic
hemodynamics (see Results). In these patients, aortic
and coronary sinus blood samples were obtained (1) in the
control condition, (2) at the end of a 15-minute intracoronary
infusion of saline (60 mL/h), and (3) at the end of 15-minute infusions
of a benazeprilat solution (25 µg/mL) at the increasing rates of 30,
60, and 120 mL/h. Arterial and venous plasma concentrations
of angiotensin II were measured by radioimmunoassay after
extraction from 7 to 8 mL of blood. The cross-reactivity of our
antiserum with angiotensin I is 0.26%; the sensitivity and
interassay variability of our method are 1.25 pg and 16%,
respectively.12
In 6 of the 14 patients of the study (age 60±8.4 years), myocardial
oxygen consumption (M
O2)
was measured by oximetric determination on aortic and coronary
sinus blood samples according to the following formula:
Coronary blood flowx(arterial
O2 saturation-coronary sinus
O2 saturation)xhemoglobin concentrationx1.36.
Measurements were obtained after 15 minutes of intracoronary
infusion of saline or benazeprilat (25 µg/mL at the rate of 60 mL/h).
In either condition, data were collected before and at the end of the
cold pressor test.
Data Analysis
Coronary blood flow was calculated over periods of 10
seconds. Arterial blood pressure and heart rate were also
averaged over 10-second periods, which were thus also the time windows
used for calculation of coronary vascular resistance. Data from
individual subjects were averaged to obtain mean values for the group
as a whole. The values obtained at the end of the cold pressor test and
diving were compared with those immediately before the application of
these stimuli. Comparisons were also made of data before and during
saline and before and during benazeprilat infusion. The differences in
the mean responses were assessed by ANOVA and the t test
for paired observations. A value of P<0.05 was taken as the
level of statistical significance. Unless otherwise indicated, the
symbol ± refers to SEM.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effect of Benazeprilat on Arterial and Coronary Sinus Angiotensin II
As shown in Figure 1
, plasma
concentration of angiotensin II in the control condition
was slightly greater in the coronary sinus (12.4±2.6 pg/mL)
than in the arterial blood (10.7±2.2 pg/mL). These values
were not significantly modified during saline infusion and when
benazeprilat was infused at the rate of 30 mL/h. When the infusion rate
was increased to 60 mL/h, the venous angiotensin II
concentration decreased in all subjects, with the arterial
concentration showing no change in 4 subjects, an increase in 1
subject, and a decrease less than the decrease in the venous
concentration in the remaining subject, with the average
arterial concentration remaining unaffected. Both
concentrations were on the other hand reduced when benazeprilat was
infused at the rate of 120 mL/h. The reductions were not due to an
increase in coronary blood flow because compared with baseline
values, coronary blood flow was not altered by the infusions of
benazeprilat, the value at the greater infusion rate versus baseline
being 151.3±12.0 and 139.6±11.4 mL/min, respectively.
|
) and
coronary sinus (
) in control condition and at end of saline
infusion or benazeprilat infusion at increasing doses. Right,
Individual values of plasma angiotensin II in
arterial blood and coronary sinus in control
condition (
) and at end of intracoronary infusion of
benazeprilat at rate of 60 mL/h (•). Data from 6 subjects
investigated separately and preliminarily to study proper. Note
that at infusion rate of 60 mL/h, benazeprilat always reduced
venous-arterial difference of angiotensin
II.
Cardiac Oxygen Consumption During Saline and Benazeprilat
Infusions
As shown in Table 2, baseline blood
pressure, heart rate, and rate-pressure product were similar during
infusion of saline and benazeprilat. This was the case also for
baseline coronary blood flow, coronary sinus
PO2, oxygen extraction across the
coronary circulation, and
MO2. The cold pressor test
caused a similar increase in blood pressure, heart rate, and
rate-pressure product during saline or benazeprilat infusion.
During benazeprilat infusion, however, coronary blood flow
increased at variance with the decrease seen during saline
infusion. Compared with saline infusion, in most individual
patients and in the group as a whole, this was accompanied by a lesser
reduction in oxygen saturation in the coronary sinus, by an
increase (rather than a decrease) of the
PO2 value in the coronary
sinus, and by a greater increase in calculated
MO2 (Figure 2).
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Saline Infusion: Cold Pressor Test and Diving
Table 3 shows that blood pressure,
heart rate, rate-pressure product, coronary blood flow, and
coronary vascular resistance were similar before and after 15
minutes of saline infusion. During saline infusion, the cold pressor
test caused in all patients a marked increase in mean
arterial pressure, heart rate, and rate-pressure
product (38±8.2%), a small and variable change in
coronary blood flow, and thus a marked increase in
coronary vascular resistance (Figure 3). In all patients, diving caused
a marked increase in mean arterial pressure, a reduction in
heart rate, an increase in rate-pressure product that was less than
that during the cold pressor test (+12±3.2%), and a decrease in
coronary blood flow that also led to an increase in
coronary vascular resistance (Figure 4).
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Benazeprilat Infusion: Cold Pressor Test and Diving
As shown in Table 3
, systemic and coronary
hemodynamics were similar before and after 15 minutes
of the benazeprilat infusion, which led to a consistent
decrease in the venous-arterial difference of
angiotensin II (Figure 1), all values being
superimposable to the values observed at corresponding times of saline
infusion. As shown in Figures 3 and 4, the blood
pressure, heart rate, and rate-pressure product responses to the
cold pressor test and diving seen during the benazeprilat infusion were
also superimposable to those seen during the saline infusion. In
contrast, during the benazeprilat infusion, coronary blood flow
increased significantly with the cold pressor test and did not change
with diving, with a resulting marked attenuation of the
coronary vasoconstrictor responses elicited by the 2 stimuli
during saline infusion. The differences with the vasoconstrictor
responses observed during saline infusion were visible in all patients
and statistically significant.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In our patients with angiographically documented severe stenosis of the left anterior descending coronary artery, the cold pressor test caused, as expected,13 14 a marked increase in coronary vascular resistance, namely, a coronary vasoconstriction that has been shown to be due to an increase in sympathetic drive.2 15 16 This response was markedly reduced by an intracoronary infusion of a dose of benazeprilat that (1) did not alter coronary or systemic hemodynamics, (2) did not modify baseline rate-pressure product, coronary sinus and arterial oxygen saturation, and cardiac oxygen consumption as compared with what was seen during saline infusion, thereby not altering cardiac metabolic needs, and (3) in a separate group of patients with similar angiographic alterations of the coronary arteries, caused a reduction of angiotensin II concentration in the coronary sinus but not in the arterial blood, thereby presumably reducing selectively the cardiac generation of this substance. This allows us to conclude that the vasoconstrictor influence exerted by the sympathetic nervous system on the human coronary circulation can be attenuated by intracoronary administration of a small dose of an ACE inhibitor and that this is mediated by a reduction in the production of angiotensin II in the human heart; namely, that the well-known sympathostimulating effect of angiotensin II can derive from its cardiac generation rather than from the amount secreted by a variety of organs and available in the systemic circulation. This clearly supports the hypothesis of a functional significance of the cardiac renin-angiotensin system in humans.
Several other results of our study deserve to be mentioned. (1)
On the basis of the present findings, one cannot exclude that the
effects of the intracoronary administration of benazeprilat are
due also to an increase in concentration of bradykinin (caused by an
ACE inhibitor–dependent reduction of bradykinin
breakdown17 ) because this substance has been shown to
attenuate neurohumoral transmission at the sympathoeffector junctions.
However, a sympathoattenuating effect of bradykinin thus far has been
shown only in animal studies.18 19 Furthermore, in some
animal studies, an opposite (ie, a sympathofacilitating) effect of this
substance has been reported,20 21 which implies that the
increase in bradykinin levels during ACE inhibition might have resulted
in a facilitation of sympathetic coronary responses and should
have led to a potentiation rather than to an attenuation of sympathetic
vasoconstriction. Finally, even accepting that bradykinin might exert a
sympathomoderating influence, this mechanism does not seem likely to
play a major role in modulating sympathetic coronary responses
because we have previously shown that sympathetic influences on
coronary circulation are not only markedly attenuated by ACE
inhibition2 but are markedly enhanced by
intracoronary infusion of minute doses of
angiotensin II,1 that is, they are exquisitely
related to the final product of the renin-angiotensin
cascade. (2) Animal studies have shown that in the normal heart, the
amount of angiotensin II detectable in the coronary
sinus is greater than the arterial one because the local
release of angiotensin II exceeds the uptake of this
substance by the myocardium.4 22 Our
observation of consistently positive veno-arterial
differences of angiotensin II indicates that this may be
the case also in the human heart, in which a positive balance between
angiotensin II generation and uptake exists also in the
presence of coronary disease. (3) Our data cannot contribute to
clarification of whether the delivery of angiotensin II
from the heart into the coronary venous outflow depends on the
conversion of locally synthesized or circulating
angiotensin I.23 24 Our findings suggest,
however, that with regard to the
sympathoexcitatory influence, the
angiotensin II produced by the action of ACE on
angiotensin I is probably more important than that produced
through alternative pathways such as those acting by
chymase.25 On the basis of in vitro studies, this pathway
has been reported to be responsible for 80% of the total
angiotensin II formation of the human heart, the fraction
produced through ACE accounting for only a small
fraction.26 It would seem unlikely, however, that if so
much local angiotensin II were still available after ACE
inhibition, its enhancing effect on the sympathetic coronary
vasomotor tone would not be largely preserved unless one speculates
that a functional compartmentalization exists between the
angiotensin II produced by ACE and that produced by
chymase. This is a very unlikely speculation, however, because the
chymase-dependent angiotensin II has been reported to be
formed largely at the adventitial level,26 that is, at a
site nearby the termination of sympathetic nerve fibers where, if
anything, its influence should be even greater. (4) The reduction of
the cardiac angiotensin II production that was
obtained by the intracoronary infusion of benazeprilat markedly
attenuated the sympathetic vasoconstrictor response to the cold pressor
test and diving without significantly affecting baseline
coronary blood flow and vascular resistance. This suggests that
in the heart, the sympathomodulatory influence of local
angiotensin II becomes manifest when this substance does
not yet contribute to modulation of baseline coronary
hemodynamics. We can speculate that this occurs because
local angiotensin II modulates peripheral
sympathetic functions (secretion of norepinephrine,
responsiveness of adrenergic receptors, and so forth)27 at
concentrations that are lower than those needed to directly affect
vasomotor tone. It is possible, however, that any influence of local
angiotensin II on baseline coronary
hemodynamics is compensated for by many other factors
that control coronary vasomotor tone.28 (5) During
the intracoronary infusion of the dose of benazeprilat that
reduced cardiac production of angiotensin II, the
increase in blood pressure, heart rate, and rate-pressure product
induced by the cold pressor test allowed coronary blood flow to
increase rather than diminish, as during saline infusion. This was
accompanied by lesser oxygen desaturation and reduction in
PO2 in the blood refluent from the
heart, indicating that the sympathoinhibitory effect of
local ACE inhibition plays a favorable metabolic role
insofar as it allows the increased oxygen demand to be more adequately
met. It should be emphasized that this occurred together with an
increase in the calculated11
MO2 greater than that
observed when the cold pressor test was performed under saline
infusion. It is therefore possible that metabolic factors
also participated in the attenuated sympathetic vasoconstrictor
influences that were seen after ACE inhibition. Clearly, however, this
participation did not originate from greater myocardial work after ACE
inhibition, because in our patients the rate-pressure product
during the cold pressor test (and diving) was superimposable during
saline and benazeprilat infusion. Furthermore, in previous studies,
myocardial contractility and left
ventricular end-systolic wall
stress/end-systolic volume ratio (ie, other determinants of
myocardial oxygen consumption in addition to cardiac afterload and
heart rate) were reduced by intracoronary
enalaprilat.6 Finally, ACE inhibition is known not to
increase but to reduce the secretion of substances with direct
O2-wasting properties such as
norepinephrine.29 30
In conclusion, our study provides evidence that in patients with coronary heart disease, the sympathetic coronary vasoconstrictor influences are markedly attenuated by selectively reducing the local production of angiotensin II through intracoronary ACE inhibition. Thus, at the cardiac level, the sympathomodulatory effect of angiotensin II can be explained by the tissue renin-angiotensin system. The demonstration that the cardiac renin-angiotensin system exerts a noticeable role in patients with coronary heart disease revives the issue of the possible importance of ACE inhibitors to oppose the tissue production of angiotensin II because of a greater diffusion, membrane permeability, and tissue affinity. The modification of the coronary vasoconstrictor responses to the cold pressor test and diving might be used for this purpose, although different ACE inhibitors would have to be tested as administered in the clinical setting.
Received September 22, 1999; revision received December 13, 1999; accepted December 13, 1999.
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