Vol. 276, Issue 3, H1049-H1057, March 1999
Coronary vasodilator effects of BNP: mechanisms of action in
coronary conductance and resistance arteries
Christian
Zellner1,
Andrew A.
Protter2,
Eitetsu
Ko1,
Madhusudhan R.
Pothireddy1,
Teresa
DeMarco1,
Stuart J.
Hutchison1,
Tony M.
Chou1,
Kanu
Chatterjee1, and
Krishnankutty
Sudhir3
1 The Vascular Research
Laboratory, Division of Cardiology, University of California at San
Francisco, San Francisco 94143-0124;
2 Scios Incorporated, Mountain
View, California 94043; and
3 The Hormones and Vasculature
Laboratory, Baker Institute, Melbourne, Victoria 3181, Australia
 |
ABSTRACT |
Brain
natriuretic peptide (BNP), a hormone secreted predominantly in
ventricular myocytes, may influence coronary vascular tone. We studied
the coronary vasodilatory response to BNP under physiological
conditions and after preconstriction with endothelin-1 (ET-1) in
anesthetized pigs. Average peak-flow velocity (APV) was measured using
intracoronary Doppler, and cross-sectional area (CSA) was measured
using intravascular ultrasound. Coronary blood flow (CBF) was
calculated. Intracoronary BNP induced dose-dependent increases in CSA,
APV, and CBF similar in magnitude to those induced by nitroglycerin
(NTG). The magnitude of BNP-induced vasodilation was accentuated after
preconstriction with ET-1. Pretreatment with either the nitric oxide
synthase inhibitor
N
-nitro-L-arginine methyl ester
or the cyclooxygenase inhibitor indomethacin attenuated the coronary
vasodilator effect of BNP in resistance arteries without influencing
epicardial vasodilation. Pretreatment with the ATP-sensitive
potassium-channel blocker glibenclamide enhanced epicardial
vasodilation in response to BNP. We conclude that BNP exerts coronary
vasodilator effects, predominantly in epicardial conductance vessels.
An accentuated vasodilatory response to BNP occurs in
ET-1-preconstricted arteries. BNP-induced vasodilation in coronary
resistance arteries may be partially mediated via nitric oxide
and/or prostaglandin release.
brain natriuretic peptide; vascular reactivity; pig; endothelin-1; N-nitro-L-arginine methyl ester; indomethacin
| |
INTRODUCTION |
BRAIN NATRIURETIC PEPTIDE (BNP) is a cardiac
tissue-derived peptide hormone that participates in the maintenance of
body fluid and electrolyte homeostasis (3). BNP is structurally and
functionally related to atrial natriuretic peptide (ANP); however, it
has a distinct pharmacological profile with regard to binding of the known natriuretic peptide receptors (NPRs) (2, 45). Animal and human
studies have demonstrated the diuretic, natriuretic, and hemodynamic
effects of BNP (16, 29, 50), whereas the direct vasodilator effects of
BNP have recently been reported in isolated human arterial and venous
tissue preparations (38). BNP has been suggested to induce vasodilation
in vivo in the human forearm and in pulmonary circulation (5, 35), and
the density of NPRs in the heart, especially in the coronary
vasculature, suggests that BNP may also exert coronary vasoactive
effects (7). Okumura et al. (37) showed that administration of BNP
induces vasodilation in coronary conductance arteries. In patients with variant angina, hyperventilation-induced anginal attacks and
electrocardiogram (ECG) changes are reportedly suppressed by
intravenous infusion of BNP in supraphysiological doses (21). However,
the mechanisms underlying these observed coronary responses are not clear.
BNP activates the membrane-bound guanylyl cyclase-A (GC-A) receptor,
which results in the accumulation of intracellular cGMP in target
tissues (27). It is generally believed that cGMP mediates the vascular
smooth muscle relaxant effect of BNP, presumably in a manner similar to
nitric oxide donors such as nitroglycerin (NTG). Increases in coronary
resting tone, induced by the novel natriuretic peptide antagonist
HS-142-1 (46, 48), suggest that natriuretic peptides also play a
role in the regulation of basal coronary blood flow and vascular tone.
In addition, human BNP relaxes human arteries and veins precontracted
with phenylephrine or the endogenous peptide endothelin-1 (ET-1) (4,
38). Although secretion of ET-1 is reportedly inhibited by both ANP and
BNP (12), the effects of BNP on ET-1-mediated coronary vasoconstriction remain unclear.
In this study we investigated the coronary vasodilator properties of
BNP in domestic swine in vivo. We examined the effects of BNP on
coronary conductance and resistance arteries under conditions of both
normal vascular tone and ET-1-induced preconstriction. We also studied
the possible contributions of nitric oxide, prostaglandins, and
ATP-sensitive potassium channels to BNP-induced coronary vasodilation.
| |
METHODS |
Twenty-three female domestic swine (mean wt 42 ± 0.8 kg) were
anesthetized with Innovar (0.04 mg/kg sc) and 
-chloralose (100 mg/kg
iv), with additional doses of -chloralose given as needed to
maintain the level of anesthesia. Animals were mechanically ventilated
with room air. Heart rate was monitored from the ECG, and blood
pressure was monitored from a cannula placed in the left femoral
artery. All studies conformed to the "Position of the American Heart
Association (AHA) on Research Animal Use" adopted November 11, 1984, by the AHA. The protocol was approved by the University of California
at San Francisco Committee on Animal Research (approval no.
A7916-12776-01).
Catheterization procedures.
Under fluoroscopic guidance, the left main coronary artery was
cannulated via the transfemoral approach using an 8-Fr Amplatz R-1
guiding catheter (Advanced Cardiovascular Systems, Temecula, CA). As
previously described (9), a 0.014-in. Doppler wire (Endosonics, Rancho Cordova, CA) was first introduced through the
guiding catheter, after which a 3.2-Fr 30-MHz ultrasound
imaging catheter (Boston Scientific, Sunnyvale, CA) was introduced
directly over the Doppler wire into the circumflex coronary artery. The Doppler transducer was positioned 2 cm distal to the tip of the imaging
catheter (9). Transvenous atrial pacing at a rate of 110 beats/min was
used during the entire study to prevent changes in heart rate.
Experimental protocols.
Unless otherwise indicated, pharmacological agents were administered
directly into coronary circulation through the guiding catheter in the
ostium of the left main coronary artery. Measurements of coronary
artery cross-sectional area (CSA) and flow velocity were made at 30-s
intervals after each administration. Intracoronary drug infusions were
made over a 1-min period unless otherwise specified; final
concentrations in the coronary artery are indicated, assuming a flow
rate of 50 ml/min, as previously described (9, 44). Saline infusions
given before drug administration served as control. Human BNP was
obtained from Scios (Mountain View, CA), and, unless otherwise noted,
other pharmacological agents were obtained from Sigma
Pharmaceutical (St. Louis, MO).
In 11 pigs, BNP was infused at concentrations increasing from 1 pM to
0.1 µM. NTG was infused at concentrations increasing from 0.1 nM to
10 µM. For each infusion concentration, sufficient time (range
5-9 min) was allowed for epicardial coronary dimensions and flow
velocity to return to baseline before the next dose was administered.
The vasodilator effects of BNP and NTG were also assessed after
preconstriction with 10 nM ET-1 (n = 11 for BNP; n = 8 for NTG) as a
continuous intracoronary infusion over 10 min. In an additional five
pigs, the effects of concentrations of BNP at the peak of the
dose-response curve (10 nM to 0.1 µM) were assessed after the
following three pharmacological interventions, performed in random
order. 1) Nitric oxide
synthesis was inhibited by intracoronary administration of
N-nitro-L-arginine methyl ester
(L-NAME) to obtain a final
concentration of 10 mM in the coronary artery (43). In a separate set
of eight pigs, NTG was infused at concentrations increasing from 0.1 nM to 10 µM before and after
L-NAME.
2) Prostaglandin synthesis was inhibited by intravenous infusion of indomethacin (2 mg/kg iv over 5 min; Dupont-Merck Pharmaceuticals, West Point, PA). Although a dose of
3 mg/kg body wt was used to block prostaglandin production in previous
studies of the coronary vasculature in pigs (17), we used a lower dose
to minimize systemic effects, particularly a rise in blood pressure.
3) ATP-sensitive potassium channels were inhibited by intracoronary administration of glibenclamide (15,
31, 33, 42) to obtain a final concentration of 10 µM in the coronary
artery. A washout period of at least 60 min was allowed between the
administration of antagonists.
Two-dimensional ultrasound system description and
image analysis.
The ultrasound catheter (3.2 Fr) has a fixed 30-MHz transducer and a
rotating mirror assembly. Images were displayed on a video monitor;
axial resolution was ~150 µm, and lateral resolution was ~250
µm. Gain, contrast, and reject settings were adjusted by the operator
to yield a well-balanced gray-scale appearance on the video display.
Real time images were stored on high-quality super-VHS (S-VHS)
videotape for subsequent off-line analysis. As previously described
(9), selected portions of the videotape were digitized (12 bits,
Rasterops 324, Santa Clara, CA) in real time (30 frames/s) and stored
on a computer disk for off-line determination of luminal area.
Doppler ultrasound system description.
Doppler-derived blood flow velocities were measured using a 0.014-in.
steerable Doppler guide wire (FloWire, Endosonics). This guide-wire
system has a miniature Doppler ultrasound crystal that transmits
signals at a carrier frequency of 15 MHz and receives pulsed-wave
ultrasound signals, sampled at a distance of 5 mm from the guide-wire
tip. The Doppler signals are analyzed by a FloMap instrument
(Endosonics) in which dedicated digital signal-processing chips perform
the fast Fourier transformation required for the spectral display. The
signals are transformed into gray scale, and the resultant spectrum is
displayed on a monitor. In our study, the ECG was simultaneously
displayed on the monitor. Also displayed were quantitative measurements
of average peak velocity (APV) throughout the cardiac cycle. The
monitor display was continuously recorded on an S-VHS videotape for
further off-line analysis and for comparison with corresponding
cross-sectional ultrasound images.
Calculations and statistical analysis.
Luminal CSAs at baseline and after administration of drugs were
determined by computer-assisted planimetry using specialized software.
Volumetric coronary blood flow (CBF) was calculated from the
relationship CBF = CSA × APV × 0.47, as previously
validated (9). Dose-response relationships with BNP, NTG, and ET-1 were examined by ANOVA for repeated measures followed by a post hoc Student-Newman-Keuls test. Overall effects of
L-NAME, glibenclamide, and
indomethacin on BNP-induced vasodilation were analyzed by two-way
repeated-measures ANOVA. Specific comparisons between the maximal
effect before and after the antagonist were also assessed using a
Student's t-test for paired
observations. Values are means ± SE.
| |
RESULTS |
Effect of BNP and NTG on coronary artery dimensions
and flow. Baseline measurements are shown in Tables
1 and 2.
With concentrations of 1 pM and higher, BNP caused significant
increases in CSA, APV, and CBF as shown in Fig.
1. No significant changes in systemic arterial pressure or heart rate were observed with any dose. NTG also
caused significant increases in CSA and CBF, without changes in
systemic arterial pressure. The maximum response to BNP over the range
examined was similar to that induced by NTG (Fig 1).
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Table 1.
MAP and HR changes induced by NTG and BNP before and after
pharmacological antagonism of prostaglandins, nitric oxide synthase,
and ATP-sensitive potassium channels
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Table 2.
Baseline values after saline infusions, and changes in CSA, APV, and
CBF in response to ET-1, L-NAME, Indo, and Glib
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Fig. 1.
Effect of increasing concentrations of intracoronary brain
natriuretic peptide (BNP; A)
and nitroglycerin (NTG; B) on
coronary cross-sectional area (CSA), Doppler-derived average peak
velocity (APV), and calculated coronary blood flow (CBF) in domestic
swine (n = 11).
Responses are %change from baseline (saline infusion as vehicle
control). Baseline values (means ± SE) for BNP: CSA, 10.81 ± 1.14 mm2; APV, 17.5 ± 1.3 cm/s; CBF, 56.35 ± 6.48 ml/min. Baseline values (mean ± SE)
for NTG: CSA, 10.63 ± 0.74 mm2; APV, 16.6 ± 1.4 cm/s; CBF, 54.66 ± 6.46 ml/min.
C: maximal responses to BNP
(10 7 M) and NTG
(105 M) were similar
in magnitude. * Significant increase in CBF vs. baseline
(P < 0.05). APV increased
significantly in response to BNP
(1011 M to
108 M) but not in
response to NTG. CSA increased significantly in response to NTG at
doses  107 M and to
BNP at doses 108
M.
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Effect of ET-1 on BNP- and NTG-induced coronary
vasodilation.
After intracoronary infusion of ET-1, there was a significant reduction
in coronary artery CSA (8.6 ± 1.8% decrease;
P < 0.05), baseline APV (13.2 ± 1.7% decrease; P < 0.05), CBF (15.3 ± 4.2% decrease; P < 0.05), and mean arterial pressure (Table 1). The magnitude
of the BNP-induced increase in epicardial coronary CSA was
significantly (P < 0.05) enhanced
after pretreatment with ET-1 (%increases: CSA, 13.0 ± 6.1; APV,
12.1 ± 5.0; and CBF, 27.7 ± 6.2) (Fig.
2). However, in a separate group of
animals, response to NTG before and after administration of ET-1
remained unchanged (Fig. 3).
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Fig. 2.
After preconstriction with endothelin-1 (ET-1;
108 M), intracoronary BNP
at doses 1011 M
significantly increased CSA, APV, and calculated CBF
(n = 11). * Significant
difference vs. baseline (P < 0.05.)
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Fig. 3.
NTG-induced increases in CSA, APV, and calculated CBF before
(A) and after
(B) administration of ET-1 (10 nM).
Responses before and after administration of ET-1 did not differ
(n = 8). * Significant
difference vs. baseline (P < 0.05).
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Effect of
L-NAME on BNP- and NTG-induced
coronary vasodilation.
L-NAME did not induce any
significant changes in the baseline CSA [0.38 ± 8.4%
decrease, P = not significant
(NS)], APV (16.1 ± 10.7% decrease,
P = NS), CBF (22.7 ± 18.5%
decrease, P = NS), blood pressure, or
heart rate (Table 1). L-NAME did
not attenuate the epicardial vasodilator response to BNP but did result
in significant attenuation of BNP-induced increases in APV and CBF
(Fig. 4). In contrast, the vasodilator
response to NTG remained unchanged before and after administration of
L-NAME (Fig.
5).
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Fig. 4.
BNP-induced increases in CSA (A),
APV (B), and calculated CBF
(C) before (pre) and after (post)
administration of 100 µM
N-nitro-L-arginine methyl ester
(L-NAME). BNP-induced increase
in APV and CBF is attenuated after
L-NAME
(n = 5). * Significant
difference vs. pre-L-NAME
(P < 0.05).
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Fig. 5.
NTG-induced increases CSA (A), APV
(B), and calculated CBF
(C) before and after administration
of 100 µM L-NAME
(n = 5). Administration of
L-NAME did not alter responses
to NTG.
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Effect of indomethacin on BNP-induced coronary
vasodilation.
After intravenous infusion of indomethacin, there was a significant
decrease in APV (19.2 ± 6.0% decrease,
P < 0.05) and a tendency to a
decreased baseline CBF (28.9 ± 9.9% decrease,
P = 0.07) associated with a transient
increase in blood pressure (Table 1). Baseline CSA (1.3 ± 9.6% increase, P = NS) remained unchanged. To avoid the confounding effect of the indomethacin-induced increase in blood pressure, the vasodilator effect of BNP was examined
when blood pressure changes had returned to baseline. The
magnitudes of BNP-induced increases in CSA, APV, and CBF were all
attenuated by indomethacin; the attenuation of APV and CBF was
statistically significant (P < 0.05)
(Fig. 6).
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Fig. 6.
BNP-induced increases in CSA (A),
APV (B), and calculated CBF
(C) before and after administration
of indomethacin [Indo, 2 mg/kg iv
(n = 5)]. BNP-induced increases
in APV and CBF are significantly attenuated after Indo.
* Significant difference vs. pre-Indo
(P < 0.05).
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Effect of glibenclamide on BNP-induced coronary
vasodilation.
After administration of glibenclamide there was a trend toward a
decrease in baseline CBF (10.2 ± 5.1% decrease,
P = 0.18 ), but there were no
significant changes in baseline APV (1.2 ± 9.4% decrease,
P = NS) or CSA (7.6 ± 4.4%
decrease, P = NS). Baseline blood
pressure and heart rate remained unchanged with glibenclamide.
Glibenclamide enhanced the epicardial vasodilator response to BNP (CSA
increase of 13.9 ± 7.9%) but did not influence the effects of BNP
on APV or CBF (Fig. 7). However, in
absolute terms, the maximum response to BNP (CSA increase in
mm2) was not significantly
greater after glibenclamide. At the highest dose of BNP, there was a
small but significant drop in mean arterial pressure after
glibenclamide (Table 1).
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Fig. 7.
BNP-induced increases in CSA (A),
APV (B), and calculated CBF
(C) before and after administration
of glibenclamide (Glib; n = 5).
BNP-induced increases in CSA are accentuated after Glib.
* Significant difference vs. pre-Glib
(P < 0.05).
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| |
DISCUSSION |
This study demonstrates that human BNP exerts direct vasodilatory
effects on coronary conductance and resistance arteries in vivo (37).
At the highest dose of BNP, there was an increase in coronary blood
flow in the absence of any significant change in the determinants of
myocardial oxygen demand, namely, in blood pressure or in heart rate.
Consistent with previous studies of differential effects of vasoactive
agents on coronary conductance and resistance arteries (43), BNP caused
dilation of resistance vessels at lower doses, whereas at higher doses
epicardial coronary vasodilation appeared to be predominant. The
magnitudes of coronary epicardial vasodilation and augmentation in
coronary blood flow in response to BNP were comparable to those of NTG.
Cellular mechanisms: receptors and
signaling. NTG and BNP are thought to act via the
second messenger cGMP on vascular smooth muscle cells, but with
distinct differences in cGMP activation. The GC-A receptor, a
biological receptor for BNP, is part of a receptor class of proteins
termed particulate guanylyl cyclase. It is a membrane-bound protein
with guanylyl cyclase activity. Binding of BNP to the extracellular
domain of the GC-A receptor activates the intracellular guanylyl
cyclase domain, resulting in the catalysis of cGMP from GTP (28). NTG,
which also acts via the second messenger cGMP in vascular smooth muscle
cells (19), appears to activate an intracellular cytosolic form called soluble guanylyl cyclase (39). The so-called particulate guanylyl cyclase is distinct from the cytosolic soluble form of guanylyl cyclase, which may provide one possible explanation for the differences between BNP and NTG in the onset and duration of coronary vasodilation (37) that was observed in this study.
BNP effects in ET-1-preconstricted
arteries. The vasodilator effects of BNP were
accentuated when coronary arteries were preconstricted with ET-1. This
accentuated response to BNP might be explained by either
optimal-receptor presentation of the transmembrane receptor or
participation of an allosteric binding site of a ligand such as ATP.
ATP increases guanylyl cyclase activity of natriuretic peptides in the
rat (23). Recently, natriuretic peptides have been shown to inhibit
local production of ET-1 by protein kinase C inactivation (14). Another
possible explanation is that the cGMP-dependent pathway used by BNP
opposes a cellular state associated with constriction but has less
effect on cellular states associated with less tone. Within the range
of doses examined, ET-1 did not enhance coronary vasodilation in
response to NTG. Thus the observed effects of BNP on preconstricted
epicardial coronary arteries might be of importance in the context of
coronary spasm, such as in variant coronary angina and acute ischemic syndromes.
Role of nitric oxide in BNP-induced
vasodilation. Although both ANP (34, 47, 49) and
porcine BNP (51) appear to induce endothelium-independent
vasorelaxation in a variety of species, there is evidence that ANP
could act as a stimulus for nitric oxide production. In cultured human
proximal tubular cells, ANP stimulated nitric oxide production in a
dose-dependent manner, which was apparently related to binding to the
natriuretic peptide clearance receptor (NPR-C) (30). These effects may
vary depending on the tissue studied. In our study, BNP appears to
induce differential vasodilator effects in conductance and resistance
arteries. In resistance arteries, BNP-induced vasodilation was largely
blocked by L-NAME, suggesting
that endothelium-derived nitric oxide contributes to such vasodilation.
In conductance vessels, the preserved vasodilation after
L-NAME suggests that release of
nitric oxide does not participate in BNP-induced vasodilation. These
observations are consistent with in vitro studies showing that the
vasodilatory response to BNP in conductance arteries is largely
endothelium independent (51). However, the administration of
L-NAME induced nonsignificant decreases in APV and CBF; it is therefore possible that
L-NAME exerts a constricting
effect that supersedes the vasodilator effect of BNP.
Role of potassium channels in BNP-induced
vasodilation. In addition to nitric oxide, potassium
channels contribute to regulation of coronary vascular tone. Potassium
channels are present in vascular smooth muscle and in high density in
the coronary microcirculation (41) and mediate vasodilation. Increased
potassium conductance and hyperpolarization in response to BNP have
been shown in mesangial cells, the main target cell for natriuretic
peptides in the kidney (6). In the present study, however,
glibenclamide did not attenuate the vasodilator effects of BNP in the
microcirculation. BNP-induced vasodilation in epicardial coronary
arteries was enhanced after pretreatment with glibenclamide, which is
consistent with accentuated effects of BNP in constricted arteries and
previously described coronary vasoconstrictor effects observed with
glibenclamide (13). The maximum response to BNP (in terms of absolute
effects on CSA) was not increased after glibenclamide, which also
suggests that the percentage increase in epicardial coronary dimensions
after glibenclamide administration probably resulted from a decrease in
baseline values.
Role of prostaglandins in BNP-induced
vasodilation. Inhibition of prostaglandins attenuated
BNP-induced vasodilation in coronary resistance arteries in the current
study. These findings suggest that BNP may exert its coronary effects,
in part, via a mechanism involving prostaglandin release. In the rat
kidney, C-type natriuretic peptide-induced arteriolar vasodilation was
abolished by pretreatment with either
L-NAME or indomethacin (1).
Additionally, ANP fragments have been shown to inhibit
Na+-K+-ATPase
by release of PGE2 in the kidney
(8). Similar mechanisms might contribute to
BNP-induced coronary vasodilation and thus require further investigation.
Limitations. The structure of BNP is
poorly conserved across species (22), which is consistent with reports
of species-specific potencies of BNPs from different species in various
activity assays (20). For example, human BNP has potent hemodynamic and
renal effects in rabbits (11) and dogs (10), but not in rats (20). Compared with the effects of rat BNP, human BNP exerts more potent effects on porcine vessels. Human BNP can relax porcine coronary artery tissue preparations in vitro with an estimated
EC50 of 0.02 nM, whereas rat BNP
is much less potent in this assay
(EC50 = 1.1 nM) (20). This
suggests that human BNP will have potent cardiovascular effects in
pigs, consistent with the coronary vasorelaxant effects described in
this report.
BNP may compete with ANP for metabolism by the natriuretic peptide
clearance receptor (32) or neutral endopeptidase (26), resulting in
higher ANP plasma levels, as reported after infusion of pharmacological
doses of BNP (50). Thus ANP might contribute to the vasodilation in
response to administration of BNP. Part of the increase in epicardial
CSA and CBF might be the result of flow-mediated, endothelium-dependent
vasodilation (18) rather than a direct effect of BNP. An inhibitory
influence of L-NAME is
consistent with this possibility. However,
L-NAME did not influence NTG-induced epicardial coronary vasodilation. Finally, the vascular and
humoral alterations that occur in patients with coronary artery disease
and heart failure might modify coronary response to BNP and limit the
implications of this study.
Clinical significance.
The vasodilator effects of BNP in coronary conductance and resistance
arteries raise the possibility of its use in patients with epicardial
coronary vasospasm and in patients with microvascular angina. Kato et
al. (21) found that intravenous infusion of synthetic BNP suppressed
hyperventilation-induced angina. ET-1 contributes to coronary spasm in
conductance and resistance vessels (36) and may play a role in variant
angina. In this study, after pretreatment with ET-1, BNP increased CBF
substantially and reversed endothelin-mediated vasoconstriction
completely. In heart failure, BNP levels have been shown to increase
with the severity of the disease (50) and plasma levels are reportedly
elevated (40). In two double-blind, placebo-controlled randomized
studies involving patients with congestive heart failure, BNP treatment
was reported to reduce right atrial pressures, pulmonary capillary
wedge pressures, and systemic vascular resistance and to increase
cardiac output (29, 50). Recent studies also suggest that low-dose
infusion of BNP causes favorable hemodynamic changes without
influencing cardiac output (25). The direct vasodilator effects of BNP
probably contributed to the reduction in preload and afterload observed in these patients. These findings, observed even in the presence of the
vasoconstricting peptide ET-1, suggest that coronary vasodilator effects of synthetic BNP, the enhanced natriuretic effects of BNP (24,
29), and the prolonged half-life compared with ANP might favor BNP as a
future treatment option in patients with this syndrome. Further studies
in humans are required to examine the applicability of our findings to
pathophysiological states, such as angina and heart failure.
| |
ACKNOWLEDGEMENTS |
We acknowledge the assistance of James Stoughton in the
Cardiovascular Research Institute animal fluoroscopy laboratory.
| |
FOOTNOTES |
This study was supported through grants from the Foundation for Cardiac
Research and the George W. Smith Fund, Univ. of California at San
Francisco, and Scios (Mountain View, CA). S. J. Hutchison was partially
funded by a traveling fellowship from the R. S. McLaughlin Foundation
(Toronto, ON, Canada). C. Zellner was partially funded by a grant from
the Philips Multimedia Center (Palo Alto, CA).
Address for reprint requests: K. Chatterjee, Box 0124, Univ. of
California at San Francisco, 505 Parnassus Ave., San Francisco, CA
94143-0124.
Received 28 October 1997; accepted in final form 2 December 1998.
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