(Circulation. 1995;92:3424-3430.)
© 1995 American Heart Association, Inc.
Articles |
Role of Endogenous Bradykinin in Human Coronary Vasomotor Control
From the Medizinische Klinik III, Universität Freiburg, Germany.
Correspondence to Helmut Drexler, MD, Medizinische Klinik, Abteilung Kardiologie, Universität Freiburg, Hugstetterstr 55, 79106 Freiburg, Germany.
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Abstract |
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Background Bradykinin is a potent vasodilator that acts through B2 kinin receptors to stimulate the release of endothelium-derived nitric oxide, prostacyclin, and hyperpolarizing factor. In this study, we investigated the contribution of endogenous bradykinin to vasomotor control in the human coronary circulation.
Methods and Results The selective bradykinin B2 receptor antagonist HOE 140 was infused into the left main coronary artery (200 µg/min for 15 minutes) in 15 patients without significant coronary stenoses. Epicardial responses were evaluated by quantitative coronary blood flow with a Doppler flow-velocity wire. Flow-dependent dilation (n=10; intracoronary papaverine) and acetylcholine responses (n=5) were assessed before and after HOE 140. After HOE 140, there was a reduction in luminal area in the proximal (P<.001), mid (P<.001), and distal (P<.05) coronary arteries. HOE 140 led to an increase in coronary vascular resistance (P<.001) and a decrease in coronary blood flow (P<.001). After bradykinin B2 receptor blockade, there was a reduction in flow-dependent dilation (23.4±6.9% to 3.9±6.0%, P<.001), the extent of which correlated with the degree of basal vasoconstriction after HOE 140 in the same vessel segment (P<.05). Acetylcholine responses were unchanged after HOE 140.
Conclusions The results of this study demonstrate for the first time a role for endogenous bradykinin in mediating normal vasomotor responses in resistance and epicardial coronary vessels under basal and flow-stimulated conditions in the human coronary circulation.
Key Words: bradykinin • blood flow • vasodilation • endothelium
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Introduction |
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The endothelium plays a fundamental and obligatory role in the regulation of vascular tone throughout the circulation as a result of the release of a variety of substances that modulate the contractile behavior of underlying vascular smooth muscle cells.1 The phenomenon of endothelium-dependent relaxation has been demonstrated in human coronary arteries2 and has been attributed to the actions of the endogenous vasodilators such as endothelium-derived NO and prostacyclin.1 3 Recent evidence has also emerged of an EDHF4 that also causes vasodilation and is distinct from NO and prostacyclin.4 5 NO is released constantly in the basal state,6 but the release of endothelium-derived vasodilators is also influenced by dynamic factors. The change in coronary tone in response to changes in flow7 that has been documented in the human coronary circulation8 is also mediated through and by endothelium-dependent mechanisms.9 Although the importance of the endothelium in regulating the aggregate hemodynamic properties of vascular networks is therefore beyond doubt,10 the specific role of endogenous agents in mediating vasodilator responses in the human coronary circulation remains poorly understood.
Bradykinin is a vasoactive kinin that is liberated from its substrate kininogen by the action of kallikrein11 and is known to be involved in a wide range of biological processes. Bradykinin is a potent vasodilator that acts through endothelial B2 kinin receptors to stimulate the release of endothelium-derived NO, prostacyclin,12 and EDHF.4 Since there is evidence of basal bradykinin release in the heart13 and of an endogenous kininogen/kinin system within the vascular wall,14 it is possible that bradykinin may play an important role in mediating vasomotor responses in vivo. In this study, we therefore investigated the contribution of endogenous bradykinin to vasomotor control by documenting the effects of HOE 140, a selective bradykinin B2 receptor antagonist,15 on epicardial and resistance vessel function in the human coronary circulation.
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Methods |
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Patient Cohort
Fifteen patients (9 men; mean age, 54±2 years) were studied who were undergoing routine diagnostic coronary arteriography for the investigation of chest pain. Only patients without angiographic evidence of obstructive coronary artery disease (<30% luminal narrowing) were included in the study. Exclusion criteria included unstable angina, previous myocardial infarction, valvular heart disease, diabetes mellitus, and clinical evidence of heart failure. Left ventricular hypertrophy was excluded by echocardiography, and none of the patients had regional wall motion abnormalities on left ventriculography. The study protocol was approved by the Ethical Committee of the University of Freiburg, and all patients gave written informed consent before their inclusion. The critical characteristics of the patients are shown in Table 1
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Study Protocol
Patients were studied in the fasting state and
without
premedication. Vasoactive drugs were discontinued 48 hours before the
study in 5 hypertensive patients and for at least 18 hours before
catheterization in 3 patients. Seven patients did not
receive vasodilating drugs. None of the patients were receiving ACE
inhibitors. Nine of the patients were taking regular
aspirin. After completion of diagnostic
catheterization, an additional 10 000 U heparin was
given, and a 7F or 8F guiding catheter was introduced into the left
main coronary artery. A 3.6F infusion catheter (Medtronic, USA)
was advanced over a 0.014-in Doppler flow-velocity guide wire
(FlowMAP, Cardiometrics Inc; see below) and positioned in a
nonbranching segment of the mid LAD (n=12) or circumflex artery
(n=3).
Normal saline, acetylcholine, and papaverine were administered
selectively into the coronary artery via the lumen of the
infusion catheter, and HOE 140 and nitroglycerine were
given into the left main coronary artery through the guiding
catheter.
After initial measurements were taken, acetylcholine was
given.
Acetylcholine was obtained from Dispersa and was prepared with serial
dilutions of normal saline to achieve infused concentrations of 0.036
µg/mL (10-6 mol/L), 0.36 µg/mL (10-5
mol/L), and 3.6 µg/mL (10-4 mol/L). At an infusion rate
of 2 mL/min and an assumed coronary blood flow of 80 to 100
mL/min, the local intracoronary concentrations of
acetylcholine were 
10-8,
10-7, and 10-6 mol/L, respectively.
Increasing concentrations of acetylcholine (3 minutes each) were
infused in a stepwise manner and were terminated only if vessel
occlusion occurred or when the highest dose was reached. Further basal
measurements were taken after saline infusion for 5 minutes.
Papaverine (25 mg/mL) was then given as a bolus dose (8 mg) to stimulate a maximal increase in coronary blood flow and to allow the assessment of flow-dependent dilation in the proximal segment of the vessel.8 Papaverine was obtained from Karlspharma. This agent has a short duration of action (<2 minutes), has few side effects, and at the dose used causes a maximal increase in coronary blood flow without altering systemic hemodynamics.8 16 In these patients, further basal measurements were taken after a saline infusion for 10 minutes. HOE 140 was obtained from Hoechst AG, was diluted in normal saline, and was administered as a continuous infusion (2 mL/min) at a dose of 200 µg/min. This dose was selected on the basis of pilot studies in the human forearm and by taking into account the known differences in forearm and coronary blood flow. The preliminary studies (n=5) had shown that a dose of 90 µg/min administered into the brachial artery for 15 minutes was well tolerated, caused a 5% reduction in radial artery diameter and a 24% reduction in forearm blood flow, and inhibited flow-dependent dilatory responses (unpublished data, 1995). A similar dose of HOE 140 has also been shown in a previous study to significantly inhibit the forearm vasodilatory responses to exogenously administered bradykinin.17 In the 10 patients in whom flow-dependent dilation was studied at baseline, a further bolus (8 mg) of papaverine was given 15 minutes after HOE 140 was begun. In the remaining 5 patients, acetylcholine infusions (0.36 µg/mL [10-5 mol/L] and 3.6 µg/mL [10-4 mol/L]) were repeated in the presence of HOE 140. Finally, nitroglycerine (0.25 mg) was administered as a bolus to assess endothelium-independent vasodilation. Blood pressure (via the guiding catheter), heart rate, and ECG were recorded continuously throughout the study. As in previous studies,8 18 19 the intracoronary infusion of acetylcholine and the bolus administration of papaverine at the doses used did not significantly alter arterial blood pressure or heart rate.
Doppler Flow Wire and Calculation of Coronary
Blood Flow
Coronary blood flow velocity was determined with a
0.014-in Doppler flow wire incorporating a 12-MHz pulsed
Doppler velocimeter at its tip and interfaced with
a real-time spectral analysis system (FlowMAP,
Cardiometrics, Inc). The technical details of this system and its
validation for the accurate measurement of coronary blood flow
have recently been described in detail.20 The Doppler
wire was manipulated 1 cm distal to the tip of the infusion catheter
into a position that gave a stable velocity signal and that was
documented angiographically with each contrast injection. The average
peak velocity was determined during the last 30 seconds of each
infusion. Coronary blood flow was calculated by multiplying one
half this value by the calculated coronary artery area at the
tip of the Doppler flow wire on the corresponding
angiogram.20
Quantitative Coronary Angiography
Quantitative coronary
angiography was performed with a
biplanar isocentric radiographic system (Siemens Bicor) and
hand injection, through a guiding catheter, of nonionic contrast
material (Omnipaque).8 18 19 Serial
angiograms (25 frames
per second) were recorded in each patient, with the artery in
question positioned near the isocenter of the x-ray system and
avoiding vessel overlap whenever possible. The angle of projection
was identical from one angiogram to the next. Angiograms were taken at
the end of each infusion, after nitroglycerin, and 80
seconds after the injection of papaverine. The duration of this delay
was based on knowledge of the time course of both the maximal
vasodilatory effect of papaverine in humans (25 to 30
seconds)16 and the maximal flow-dependent dilatory
response (50 to 60 seconds) in conscious dogs.7
For
analysis, end-diastolic frames were
video-digitized and stored in an image analysis system
(Mipron 1, Kontron Electronics) in a 512x512 matrix with an 8-bit gray
scale. Diameter measurements were made by a previously described and
validated method incorporating geometric edge
detection.8 18 19 Calculation of the
radiological
magnification of the measured segment was used to scale the data from
pixels to millimeters.18 19 For each angiogram,
diameter
measurements were obtained in two end-diastolic frames
and averaged. In each frame, mean diameter measurements were taken at
three points (proximal, mid, and distal) in the vessel under study and
at one point in a control uninstrumented vessel (circumflex or LAD). In
1 patient, the control vessel was poorly visualized, and measurements
were therefore not obtained. Measured segments were 5 mm long.
Proximal measurements were made at a point 2 to 3 mm distal to the tip
of the Doppler flow wire, since the transducer of this device has a
range depth of 5 mm.20 Distal and control measurements
were made on straight segments of artery in the respective vessels.
Whenever possible, quantification was performed in corresponding
segments of the artery in both views of the biplanar angiogram, with
the position of side branches, infusion catheter, and Doppler
flow-wire tip acting as anatomic landmarks. Cross-sectional
area was calculated on the assumption of an elliptical lumen. When this
was not possible because of some degree of vessel overlap,
single-planar analysis was performed, and
cross-sectional area was calculated on the assumption of a circular
lumen. With measurements made at a total of 45 different sites in the
15 study vessels, this was the case at 7 of these locations (16%).
These methods of quantification have been validated in previous studies
and have been shown to be precise, accurate, and reproducible when
applied to serial measurements in the same
patient.8 18 19
The arteries were analyzed by one coinvestigator who was
unaware of the study's hypothesis and design. In addition, 30 randomly
selected digitized frames were analyzed by one of us,
confirming the results.
HOE 140 and NO Synthase Activity in Cultured
Endothelial Cells
Bovine aortic endothelial cells were isolated
and cultured in 10% FCS-supplemented medium as previously
described.21 At the sixth passage,
endothelial cells were washed three times in PBS and
centrifuged at 10 000g for 10 minutes. Cell pellets
were resuspended in ice-cold buffer composed of 50 mmol/L Tris-HCl,
0.1 mmol/L EGTA (pH 7.4) and containing 1 µmol/L pepstatin A, 2
µmol/L leupeptin, 1 µmol/L bestatin, 1 mmol/L PMSF, and 0.1%
ß-mercaptoethanol and were then sonicated.
Endothelial NO synthase activity was determined in
100-µL samples over a 15-minute period either in the presence of HOE
140 (1 µmol/L; n=4) or in its absence (n=4) by
quantification of the
extent of conversion of L-[14C]arginine to
L-[14C]citrulline by a commercially available
radioimmunoassay kit obtained from Amersham International.
Statistics
Data are expressed as mean±SEM. Coronary
artery
dimensions, measurements of coronary blood flow, and
hemodynamic parameters were compared before
and after HOE 140 administration by a paired t test. All
measurements of proximal coronary artery diameter before and
after papaverine (flow-dependent dilation) first in the absence and
then in the presence of HOE 140 were compared by a one-way ANOVA
for repeated measures followed by the Student-Newman-Keuls test to
identify significant differences. Regression lines were fitted by the
method of least squares. A value of P<.05 was considered to
represent statistical significance.
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Results |
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There were no complications, and all patients remained asymptomatic throughout. No side effects of HOE 140 were encountered, and there were no ECG changes to suggest coronary ischemia during its administration.
Hemodynamic Parameters
The data are summarized in Table
2. Although there
was a tendency for systolic blood pressure to increase in some
patients during HOE administration, this was not consistent,
and therefore a statistically significant change was not observed in
the group as a whole. There were no significant changes in
diastolic and mean arterial blood pressure or
in heart rate from baseline values after the intracoronary
administration of HOE 140.
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HOE 140 and Basal Coronary Vasomotor Tone
The administration
of HOE 140 into the left main coronary
artery led to a significant reduction in the luminal area of the vessel
under study (Fig 1 and Table 3). This
reduction was observed in proximal (P<.001), mid
(P<.001), and distal (P<.05) vessel segments.
There was also a significant reduction in the caliber of the control
uninstrumented vessel (P<.001; Fig 1 and Table
3). At the
end of the protocol, the capacity of the coronary arteries to
dilate to nitroglycerin was normal, as reflected by an
increase in luminal area from baseline in proximal (8.2±0.8 to
10.3±3.3 mm2, P<.001), mid (4.4±0.4 to
5.5±0.5 mm2, P<.001), distal (2.7±0.4
to 3.7±0.4 mm2, P<.01), and control
(4.5±0.6 to 6.5±0.6 mm2, P<.001)
vessels.
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HOE 140 led to a significant increase in coronary vascular
resistance (P<.001; Table 2
) that was associated
with a
corresponding reduction in coronary blood flow from baseline
values (P<.001; Table 2).
HOE 140 and Flow-Dependent Dilation
In 10 patients,
flow-dependent dilation was determined in the
proximal segment of the study vessel that was exposed to changes in
flow but not to papaverine itself.8 Before HOE 140 was
administered, papaverine delivered in this manner led to a 382±37%
increase in coronary blood flow (38.0±3.5 to 182±19.2 mL/min,
P<.001), indicating a normal basal coronary
reserve. This increase in flow was accompanied by a significant
increase in proximal luminal area (8.2±1.0 to 10.0±1.1
mm2, P<.01). After HOE 140
administration, papaverine led to a 270±45% increase in
coronary blood flow (40.3±2.9 to 143.4±18.6 mL/min,
P<.001). This increase in flow (P=.06 versus
before HOE 140), however, was accompanied by a relatively minor and
statistically insignificant increase in proximal luminal diameter
(9.0±1.1 to 9.2±1.1 mm2, P=NS). After
HOE 140, the degree of flow-dependent dilation in response to
papaverine (3.9±6.0%) was thus significantly reduced compared with
the baseline response (P<.001; Fig 2). Thus,
the maximal luminal area of the proximal vessel after
flow-dependent dilation was significantly less in the presence than
in the absence of HOE 140 (9.2±1.1 versus 10.0±1.1
mm2, P<.01). In 5 of the 10 patients in
whom flow-dependent dilation was assessed before and after
bradykinin B2, the increase in coronary
blood flow in response to papaverine was found to be similar before and
after HOE 140 (323±54% versus 312±75%, P=NS).
Subgroup
analysis in these patients showed that the flow-dependent
dilatory response was also impaired in the presence of the bradykinin
B2 antagonist (30.5±11.5% versus 6.9±9.8%,
P<.005).
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In the proximal segment of the study vessel, HOE 140 led to significant reduction both in basal luminal area and in stimulated flow-dependent dilation. The magnitude of the effects of HOE 140 on luminal area correlated significantly with its inhibitory influence on flow-dependent dilation at the same site in the vessel studied (r=.59; P<.05).
HOE 140 and Acetylcholine Responses
In 5 patients, the
response to acetylcholine was studied before
and after HOE 140. At baseline, acetylcholine led to an overall
reduction in epicardial luminal area (-8.5±2.9% at
10-6
mol/L intracoronary concentration) and an increase in
coronary blood flow (90.5±34.3% at 10-6 mol/L).
This was also the case after HOE 140, with changes in epicardial
luminal area (-13.0±12.2% at 10-6 mol/L,
P=NS versus baseline) and coronary blood flow
(96.3±49.7% at 10-6 mol/L, P=NS versus
baseline) similar to those observed at baseline.
HOE 140 Effects and Basal Endothelial
Function
Of the 15 patients, 5 had no risk factors (such as
hypertension,
hypercholesterolemia, or diabetes),
demonstrated angiographically smooth coronary arteries without
any luminal irregularities, and showed a normal, vasodilatory
epicardial coronary artery response to acetylcholine (range,
+9.9% to +47.6% at 10-6 mol/L) and a normal
coronary flow reserve in response to papaverine (4.3; range,
3.4 to 6.3). The remainder experienced acetylcholine-induced
vasoconstriction (range, -2.7% to -46.1% at 10-6
mol/L) and had one or more known risk factors for
endothelial dysfunction. However, the vasoconstrictor
effect of HOE 140 was similar in the 5 patients with `normal'
coronary responses and absence of risk factors compared with
the 10 patients with paradoxical vasoconstrictor responses to
acetylcholine and a variable number of risk factors (-16% versus
-17%). In addition, there was no correlation between the
coronary responses to acetylcholine (reflecting a marker of
endothelial function) and the vascular effect to HOE
140. The effects of HOE 140 were not statistically different between
patients with (n=9) or without (n=6) aspirin, although the
vasoconstrictor response tended to be stronger in patients without
aspirin (-19% versus -15%).
HOE 140 and NO Synthase Activity in Cultured
Endothelial Cells
Cultured endothelial cell NO synthase activity was
similar in the presence (n=4) or absence (n=4) of HOE 140
(106.0±7.5
versus 94.7±6.6 pmol citrulline · mg
protein-1 · min-1,
P=NS).
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Discussion |
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The important new findings of this study are that bradykinin B2 receptor blockade leads to a reduction in basal epicardial luminal area, an increase in coronary vascular resistance, and a corresponding reduction in coronary blood flow in the human coronary circulation. The results also imply a blunting of the flow-dependent dilatory response of conduit coronary arteries after bradykinin B2 receptor antagonism. These data therefore suggest that endogenous bradykinin is involved in mediating vasomotor responses in the human coronary circulation under both basal and flow-stimulated conditions.
There is experimental evidence of continuous bradykinin release from the heart that is substantially reduced by deendothelialization and increased in the presence of ischemia.13 It was shown previously that bradykinin is released from endothelial cells22 23 and that cultured human endothelial cells are able to generate vasoactive kinins in basal conditions.24 However, determining the relative contribution of bradykinin to the regulation of coronary vascular tone has only recently been possible, since the development of selective bradykinin antagonists, specifically those directed at the B2 receptor, through which bradykinin mediates its endogenous physiological actions. In this regard, the development of HOE 140 has represented a major advance, since it has been shown to be highly specific, to be 500 times more potent than the early bradykinin B2 receptor antagonists,15 25 and to abolish cardiac bradykinin-mediated effects in rats26 as well as inhibit the vasodilatory actions of exogenous bradykinin in humans.17 HOE 140 has recently become available for use in humans, and the present study represents its first administration into the human coronary circulation and therefore the first demonstration of the endogenous role of bradykinin in human coronary vasomotor control. The results revealed that after bradykinin B2 receptor blockade, there is a consistent reduction in epicardial coronary area. Since flow is determined largely by changes in the caliber of resistance vessels (those <400 µm in diameter27 ), the reduction in coronary blood flow implies that endogenous bradykinin is also important in the regulation of normal basal vascular tone at the level of resistance vessels. These findings are consistent with the results of experimental studies that have also shown that bradykinin B2 receptor antagonism leads to a significant reduction in coronary blood flow in normotensive rats.28 Similarly, HOE 140 has recently been shown to decrease basal diameter of muscular arterioles, suggesting that bradykinin participates actively in the development of basal vascular tone in the skeletal muscle microcirculation.29 In contrast, in isolated perfused human placenta, bradykinin induced a thromboxane-mediated constriction,30 suggesting that differences exist in the effects and mechanisms of action of bradykinin in different vascular regions.
In addition to the influence on basal coronary tone, HOE 140 also reduced the flow-dependent dilatory response to papaverine. Flow-dependent dilation is proposed as an important mechanism in regulating the aggregate hemodynamic properties of vascular networks, and recent studies have shown that it is present in resistance as well as in epicardial vessels.31 The degree of flow-dependent dilation observed in the present study (23.4±7.0%) is equivalent to that reported in our previous studies of patients with normal coronary arteries.8 18 The magnitude of the effects of HOE 140 on basal epicardial coronary area correlated significantly with its effects on flow-dependent dilation at the same site in the proximal vessel. These findings imply that the vasoconstrictive effects of the bradykinin B2 receptor antagonist may be due to negation of the effects of endogenous bradykinin released in response to increases in flow at the level of both conduit and resistance vessels. Indeed, Mombouli and Vanhoutte32 recently showed that a bradykinin antagonist decreased the basal production (or release) of EDRF in perfused canine carotid arteries, suggesting the existence of local kinin-generating systems that would contribute to basal flow-dependent release of EDRF.
It should be noted, however, that when flow-dependent dilation is assessed before and after HOE 140, there was a tendency for the papaverine-induced increase in blood flow to be less in the presence than in the absence of the bradykinin B2 receptor antagonist. We previously showed that repeated measurements of papaverine-induced flow-dependent dilation are highly reproducible in the same patient,8 but a linear relationship has been observed between the extent of increase in flow and the subsequent dilatory response in experimental studies.7 In the present study, the maximal blood flow increase in response to papaverine was similar before and after HOE 140 in one half of the patients studied, and in these, a reduction in the flow-dependent dilator response was apparent to a degree comparable to that in the group as a whole. Therefore, the apparent reduction in flow-dependent dilation after HOE 140 was unlikely to be merely a reflection of a change in the papaverine-induced coronary flow reserve after bradykinin B2 receptor antagonism.
The present study did not specifically address the underlying mechanisms by which HOE 140 influences coronary vasomotor tone, although the absence of any significant changes in blood pressure or heart rate during HOE 140 administration makes it reasonable to assume that they were truly attributable to the withdrawal of the local vasodilatory actions of bradykinin rather than the result of hemodynamic compensatory mechanisms. Similarly, the presence of a normal dilator response to the endothelium-independent vasodilator nitroglycerin after HOE 140 suggests that the effects were not a result of a change in the sensitivity of vascular smooth muscle cells. The vasodilatory actions of bradykinin are mediated largely through the stimulated release of endothelium-derived NO, prostacyclin, and EDHF,4 12 and it is therefore likely that the actions of HOE 140 were to reduce the endogenous bradykinin-stimulated release of one or more of these endothelium-derived vasodilators.
HOE 140 had no effect on acetylcholine-induced changes in epicardial or resistance vessel tone. This finding implies that its actions were specifically mediated through bradykinin B2 receptor blockade, as opposed to a nonspecific antagonism of endothelial muscarinic receptors. The absence of an effect of HOE 140 on acetylcholine responses, the decrease of forearm diameters by bradykinin B2 receptor antagonism in the human forearm, and the reduction in luminal area in control arteries after HOE 140 would all imply that the results of this study were not merely a consequence of intracoronary instrumentation.
The effects of HOE 140 did not differ significantly in patients with or without aspirin, although a trend was observed for increased HOE 140-induced vasoconstriction in patients whose endogenous prostaglandin synthesis was not inhibited by aspirin. However, the number of patients is too small to draw definite conclusions concerning the contribution of prostacyclin to bradykinin-mediated vascular responses in the human coronary circulation. In this respect, intraindividual studies before and after inhibition of prostaglandin synthesis are warranted. The fact that HOE 140 had no influence on NO synthase activity in cultured endothelial cells implies that its effects were not attributable to a nonspecific inhibition of enzymatic NO formation.
NO undoubtedly plays a fundamental role in the control of coronary vasomotor tone, although its relative contribution to basal and stimulated endothelial responses as well as its respective sites of action within the coronary circulation remains controversial. In dogs, inhibition of NO synthesis constricted conduit coronary arteries but did not affect flow,33 whereas acetylcholine-induced epicardial coronary artery dilation in humans was shown to be NO dependent but resistance vessel dilation was not.34 Since flow-dependent dilation is abolished by the removal of the endothelium, it has also been suggested that this phenomenon is mediated by the release of one or more EDRFs.9 Early experimental evidence suggested an important role for endothelium-derived NO,7 9 but more recent studies have shown that different mechanisms may be responsible for flow-mediated dilation in coronary conduit and resistance vessels.35 Similarly, although NO is undoubtedly important in the flow-mediated dilator responses to an increase in pulse frequency, it does not appear to be essential to the normal dilator response to sustained increases in mean flow.36 Although prostaglandins may also affect basal tone, previous evidence suggests that they are unlikely to be involved in epicardial flow-dependent dilation.7 When residual endothelium-dependent dilatory responses are present despite NO synthase and cyclooxygenase blockade, it is suggested that they may occur as a result of the actions of the soluble hyperpolarizing factor EDHF.4
The cohort of patients exhibited a wide range of baseline endothelial function despite the absence of angiographically important coronary artery disease. Five of these patients demonstrated angiographically smooth coronary arteries and normal vascular responses to acetylcholine and papaverine (similar to our previously characterized control patient population18 , while the remaining 10 patients had a variable degree of endothelial dysfunction and minor luminal irregularities. The results of this study showed that the degree to which HOE 140 altered vasomotor function was independent of whether vascular responses to acetylcholine were normal or abnormal. In this respect, our results are consistent with previous observations that endothelium-dependent hyperpolarization in response to bradykinin occurs in human coronary arteries from patients with different cardiac diseases, including dilated and ischemic cardiomyopathy.4 These data suggest that endogenous bradykinin has a role in modulating coronary tone in healthy human vessels as well as in diseased arteries. Since bradykinin is inactivated by the enzyme kininase II, which is identical to ACE, the present findings also add further weight to the notion that endogenous bradykinin accumulation may explain some of the vascular effects of ACE inhibition,37 including those observed in the human coronary circulation.38
In summary, the results of this study show that the intracoronary administration of bradykinin B2 receptor antagonist led to an increase in vasomotor tone in human conduit and resistance vessels and a corresponding reduction in coronary blood flow. Bradykinin B2 blockade also resulted in a blunting of the dilator response of epicardial arteries to an increase in flow, the magnitude of which correlated significantly with the extent of the vasoconstrictor response. These data imply a role for endogenous bradykinin in mediating vasomotor responses in resistance and epicardial coronary vessels under both basal and flow-stimulated conditions in the human coronary circulation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Groves was an Alexander von Humboldt Scholar. This work was supported, in part, by grants from the Deutsche Forschungsgemeinschaft (Dr 148/5-2). We are grateful to Hoechst AG for supplies of HOE 140 and to the staff of the cardiac catheterization laboratory in the University Clinic in Freiburg for their excellent technical assistance.
Received April 25, 1995; revision received June 7, 1995; accepted August 3, 1995.
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