| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53227; and 2 Division of Experimental Cardiology, Thoraxcenter, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Coronary tone is determined by a balance between endogenously produced endothelin and metabolic dilators. We hypothesized that coronary vasodilation during augmented metabolism is the net result of decreased endothelin production and increased production of vasodilators. Isolated rat myocytes were stimulated at 0, 200, and 400 beats/min to modify metabolism. Supernatant from these preparations was added to isolated coronary arterioles with and without blocking vasoactive pathways (adenosine, bradykinin, and endothelin). Chronically instrumented swine were studied while resting and running on a treadmill before and after endothelin type A (ETA) receptor blockade. The vasodilatory properties of the supernatant increased with increased stimulation frequencies. Combined blockade of adenosine and bradykinin receptors abolished vasodilation in response to supernatant of stimulated myocytes. ETA blockade increased vasodilation to supernatant of unstimulated myocytes but did not affect dilation to supernatant of myocytes stimulated at 400 beats/min. In vivo, ETA blockade resulted in coronary vasodilation at rest, which waned during exercise. Thus endothelin has a tonic constrictor influence through the ETA receptor at low myocardial metabolic demand but its influence decreased during increased metabolism.
coronary circulation; coronary microcirculation; coronary arterioles
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
CORONARY BLOOD FLOW
is tightly coupled to myocardial oxygen consumption
(M
O2), a process termed metabolic
dilation. Despite the seminal importance of metabolic dilation in
titrating flow to changes in metabolism, it is incompletely understood
how cardiac myocytes communicate a change in metabolic activity to the
coronary vasculature. One consensus is that cardiac myocytes produce
vasodilatory substances, such as adenosine, nitric oxide (NO),
prostacyclin, bradykinin, and CO2 in direct relation to
MO2 (3, 7-9). In
addition to the production of dilators, cardiac myocytes also produce
constrictors, such as angiotensin II (6). Moreover, we
have evidence to suggest that cardiac myocytes produce substances that
induce endothelin-mediated constriction of the coronary vasculature. Specifically, we (1, 17) previously found that
-adrenergic stimulation of cardiac myocytes resulted in
endothelin-dependent vasoconstriction both in vivo and in vitro. A
recent study showed that cardiac myocytes in vitro respond to changes
in PO2 by altering the balance of vasoactive
factors that they secrete. In quiescent noncontracting myocytes, an
increased PO2 results in decreased production
of dilatory substances (including adenosine) and an increased
production of a constrictor (22, 23). This constrictor was
identified as angiotensin I, which was converted by the vasculature to
angiotensin II, which then caused vasoconstriction in an
endothelin-dependent manner. We hypothesized that an increase in
metabolic activity of cardiac myocytes would decrease the influence of
these vasoconstrictive factors and increase the influence of
vasodilators. Thus alterations in the production of vasoconstrictors
could contribute to metabolic regulation. Therefore, we measured the
contribution of endothelin to metabolic regulation both in vitro and in
vivo. We first ascertained the contribution of endothelin to regulation
of coronary arteriolar diameter in an in vitro preparation, in which
isolated cardiac myocytes were electrically stimulated to contract at
different rates and aliquots of the fluid bathing the myocytes were
administered to isolated coronary arterioles in the presence and
absence of an endothelin type A (ETA) receptor antagonist.
To understand whether the in vitro results would be applicable to the
in vivo setting, coronary hemodynamics were evaluated in chronically
instrumented swine running on a treadmill before and after the blockage
of endothelin-mediated constriction with an ETA receptor
antagonist. Results from our study demonstrate that endothelin
contributes to the regulation of vascular tone but the contribution of
this constrictor wanes as metabolism increases. Thus it appears that during increases in cardiac metabolism, there is concomitant increased production of vasodilators and decreased production of
vasoconstrictors. We propose that regulation of coronary blood flow
involves dynamic regulation of productions of constrictors and dilators
by cardiac myocytes depending on the myocardial oxygen metabolism.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
All experimental procedures and protocols used in this study were reviewed and approved by the Animal Care and Use Committees of our institutions and conformed to the "Guiding Principles in the Care and use of Animals" of the American Physiological Society.
In Vitro Experiments
General procedures. Male Wistar rats (175-250 g; Harlan Sprague Dawley) were anesthetized with pentobarbital sodium (75 mg/kg ip) and decapitated. The thorax was opened and the heart was removed and placed in ice-cold physiological saline solution (PSS). The hearts were then used for either dissection of coronary arterioles or isolation of cardiac myocytes.
Isolation of cardiac myocytes. Myocytes were isolated using a modified Langendorff setup. Briefly, the heart was perfused with buffer containing (in mM) 123 NaCl, 2.6 KCl, 1.2 KH2PO4, 7 MgSO4, 1.2 H2O, 25 HEPES, 11 glucose, 20 taurine, 20 creatine, and 1 CaCl2 (pH 7.4) for 3 min, after which the buffer was replaced by one with the same composition but without calcium for 6 min. Collagenase type II (0.6 mg/ml; Worthington) and CaCl2 (30 µM) were then added, and the heart was perfused for another 15 min. The heart was then cut into small pieces and resuspended in perfusion buffer to which BSA (1%) was added. After 5 min, during which the suspension was gently triturated, the buffer containing the myocytes was filtered through surgical gauze to remove big clumps of myocytes and gently spun down. Calcium was reintroduced to the myocytes in a stepwise manner (200 µM, 500 µM, and 1 mM CaCl2, respectively). The myocytes were allowed to settle under gravity between the CaCl2 steps. The supernatant was removed and the pellet resuspended in buffer containing more calcium. Because rod-shaped living cells settle faster than dead cells, this increased the percentage of living cells in the suspension. Only preparations containing at least 70% rod-shaped cells were used.
Myocytes (500,000 cells in 4 ml) were stimulated for 20 min at different rates (0, 200, and 400 beats/min) in a custom-designed chamber, and their production of vasoactive factors was measured by the withdrawal of the myocyte supernatant, which was then added (in a bioassay) to the isolated arterioles (see below). MO2 was measured by stimulating
myocytes in an airtight chamber and withdrawing supernatant at fixed
time intervals. The supernatant was then injected into an ABL5
automated blood gas analyzer (Radiometer) and
PO2 was measured. PO2
was converted into MO2 per myocyte using the following formula
|
PO2 is the change in
PO2 between two measurements, and
t is the time between two measurements.
Dissection of coronary arterioles. Single arterioles (40-130 µm passive diameter) were dissected from the left ventricle or the septum of the rat heart, as previously described for other species (11), and placed in ice-cold PSS containing 1% BSA (USB-Amersham). The PSS was composed of (in mM) 145.0 NaCl, 4.7 KCl, 2.0 CaCl2, 1.17 MgSO4, 1.2 NaH2PO4, 5.0 glucose, 2.0 pyruvate, 0.02 EDTA, and 3.0 3-(N-morpholino)propanesulfonic acid, buffered to pH 7.4 at 4°C and filtered (dissection buffer). Unless otherwise mentioned, all drugs were obtained from Sigma.
The vessels were cannulated on both ends with micropipettes (~20-60 µm outer diameter, depending on the size of the vessel) connected to pressurized reservoirs filled with PSS buffered at pH 7.4 at 37°C. The height of these reservoirs was set to obtain the desired intraluminal pressure (60 mmHg). Vessels that failed to maintain pressure were excluded from analysis. The internal diameter of coronary microvessels was measured with a videomicroscope (Zeiss Inverted Scope and Sony CCD-IRIS camera and videocaliper). The vessel was slowly warmed to 37°C and allowed to develop spontaneous tone.Protocol. Aliquots of myocyte supernatant (100, 200, and 500 µl) were added to the vessel bath (4 ml vol). Vascular diameter was measured 5 min after the addition of the supernatant and after 10 min of washout. The addition of the supernatant was repeated in the presence of various receptor antagonists in the following concentrations: adenosine receptor antagonist 8-(parasulfophenyl)theophylline (8PSPT; 50 µM), bradykinin B2 receptor antagonist HOE-140 (1 µM), ETA receptor antagonist JKC-301 (5 µM; American Peptide) (15, 16, 21), and angiotensin AT1 receptor antagonist losartan (1 µM).
In Vivo Experiments
General preparation.
Seven Landrace × Yorkshire pigs of either sex were used in the
present study. Adaptation of animals to the laboratory conditions started 1 wk before the day of surgery and continued until 7 days postoperatively. Full details of the experimental procedures have been
published previously (2). After an overnight fast, the pigs were sedated with ketamine (30 mg/kg im; Apharmo), anesthetized with thiopental sodium (10 mg/kg iv), intubated, and mechanically ventilated with a mixture of O2 and NO2 (1:2),
to which 0.2-1% (vol/vol) isoflurane (Abbott) was added.
Anesthesia was further maintained with midazolam (2 mg/kg + 1 mg · kg
1 · h1 iv; Roche)
and fentanyl (10 µg · kg1 · h1 iv;
Janssen-Cilag). Under sterile conditions, the chest was opened via the
fourth left intercostal space and an 8-Fr fluid-filled polyvinylchloride catheter was inserted into the aortic arch for the
measurement of central aortic blood pressure and collection of arterial
blood samples and secured with a purse-string suture. After the
pericardium was opened, a high-fidelity pressure transducer (model
P4.5; Konigsberg Instruments) was inserted into the left ventricle via
the apical dimple for recording of left ventricular (LV) pressure and
its first derivative (LV dP/dt; obtained via electrical
differentiation). Polyvinylchloride catheters (8-Fr) were inserted into
the left ventricle for calibration of the Konigsberg transducer signal,
into the pulmonary artery for administration of drugs, and into the
left atrium for measurement of left atrial pressure. A Transonic flow
probe (2.5 or 3.0 mm ID) was placed around the proximal part of the
left anterior descending coronary artery to measure the coronary blood
flow. A small angiocatheter (0.8 mm ID and 1.1 mm OD) connected to a
larger Tygon catheter (0.8 mm ID and 2.4 mm OD) was inserted directly
into the anterior interventricular vein to allow sampling of coronary
venous blood. Electrical wires and catheters were tunneled
subcutaneously to the back, the chest was closed, and the animals were
allowed to recover. All electrical wires and catheters were protected
with a vest.
Protocol. Studies were performed 1 to 2 wk after surgery with animals exercising on a motor-driven treadmill. With swine lying quietly on the treadmill, resting hemodynamic measurements consisting of LV dP/dt, aortic blood pressure, left atrial pressure, and coronary blood flow were obtained, and arterial and coronary venous blood samples were collected. Subsequently, the animals ran on a treadmill at 5 km/h until hemodynamic parameters had reached a new stable level. LV dP/dt, aortic blood pressure, and coronary blood flow were continuously measured and blood samples collected when hemodynamics had reached a steady state. After completing the exercise protocol, the animals were allowed to rest on the treadmill for 90 min, after which the swine received the selective ETA receptor antagonist EMD-122946 [3 mg/kg; a gift from Dr P. Schelling, Merck Darmstadt (12)] infused intravenously over 10 min, and 5 min later the exercise protocol was repeated.
Data Analysis and Statistics
All statistical analyses were performed on StatView software (Abacus Concepts; Berkeley, CA). Data from the in vivo experiments were compared using ANCOVA with MO2
as covariate, whereas data from the in vitro experiments were
compared using ANOVA with repeated measures with Scheffé's
test as a post hoc multiple-comparison test. Vascular diameters were
normalized to the diameter with tone before administration of the
supernatant. Data are presented as means ± SE. Significance was
accepted at P < 0.05 in all experiments.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
In Vitro Experiments
Quiescent myocytes consumed 23 ± 15 nl O2/min per 100,000 cells. MO2 increased
dramatically when the myocytes were electrically stimulated. The
increase in MO2 was dependent on
contraction rate. Stimulation of myocytes at 100, 200, and 400 beats/min resulted in 20-, 29-, and 41-fold increases in
MO2, respectively.
Supernatant of cardiac myocytes (either quiescent or stimulated to
contract at 200 or 400 beats/min) was added to isolated coronary
arterioles, and the vasodilatory response was graded to metabolism
(Fig. 1). Supernatant from myocytes
stimulated at 200 beats/min caused modest dilation (compared with 0 beat/min) and that from myocytes stimulated at 400 beats/min resulted
in a further increase in vasodilator properties of the supernatant (P < 0.05).
|
To assess the possible contributions of adenosine and bradykinin in
mediating dilation with increased stimulation rate (oxygen metabolism),
we performed experiments in the presence and absence of the adenosine
receptor antagonist 8PSPT and the bradykinin B2 receptor
antagonist HOE-140 (Fig. 2).
Administration of 8PSPT and HOE-140 decreased the dilation of the
coronary arterioles to the supernatant of myocytes stimulated at 400 beats/min (P < 0.05), whereas a combination of 8PSPT
and HOE-140 completely abolished the dilation (Fig. 2)
(P < 0.05 vs. 400 beats/min).
|
Administration of JKC-301 to the coronary arterioles increased the
vasodilator properties of the supernatant (Fig.
3). This increase was inversely related
to the rate of stimulation, i.e., the increased dilation was
significantly larger in quiescent myocytes and myocytes stimulated at
200 beats/min than in myocytes stimulated at 400 beats/min (P
< 0.05). Thus it appears that the vasoconstrictor effects of
endothelin decreased during augmented oxygen metabolism.
|
Previously, a paradigm for the production of endothelin was found to be
related to the production of angiotensin I by cardiac myocytes, which
is converted to angiotensin II in vascular tissues, leading to the
stimulation of endothelin-1 production (22). However, our
examination of this possibility was negative (Fig. 4). Specifically, the angiotensin
receptor antagonist losartan did not further the vasodilatory
properties of the supernatant from unstimulated myocytes. In contrast,
the ETA antagonist JKC-301 increased arteriolar
vasodilation to the supernatant. If angiotensin were involved and
stimulated endothelin production, then losartan should have produced a
similar effect as JKC-301.
|
In Vivo Experiments
The increase in MO2 during
exercise resulted in vasodilation leading to an increase in myocardial
oxygen supply (Table 1), whereas
myocardial oxygen extraction was unaltered (Fig.
5). Blockade of ETA receptors
resulted in an increase in myocardial oxygen supply in excess of
MO2 (P < 0.05, Table 1), so that myocardial oxygen extraction was reduced and coronary
venous O2 saturation increased (Fig. 5). In support of our
hypothesis, the effect of ETA receptor blockade decreased
during exercise (P < 0.05).
|
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The present study demonstrates that (in vitro) endothelin-mediated coronary constriction is initiated by a signal from the cardiac myocytes that induces the release of endothelin from the arteriolar endothelium. Moreover, this vasoconstrictor activity is inversely related to cardiac metabolic activity. These in vitro observations have significance to the intact coronary circulation because in vivo endothelin contributes to the regulation of vascular tone at rest and, to a lesser extent, during exercise. This implies a regulatory scheme for the control of coronary vascular tone that includes a balance between the release of constrictors and dilators, depending on metabolic rate. Before discussing the implications of our findings, we will first compare the in vitro and in vivo results and evaluate the potential pitfalls in both systems.
Methodological Considerations
Because both ETA receptor antagonists used in this study are relatively new, we tested in separate experiments if they block the constrictor response to ET-1 (Fig. 6). Both EMD-122946 (20 µg/ml) and JKC-301 (5 µM) completely abolished the endothelin-induced constriction, indicating that the doses we used were sufficient. Also, in experiments from other investigators, JKC-301 has been used as an endothelin antagonist (15, 16), whereas EMD-122946 has been shown to inhibit the pressor response to endothelin both in vivo and in vitro (12, 21).
|
We found that endothelin-1 contributes to the regulation of coronary
vascular tone in vivo. This observation is in accordance with the study
by Takamura et al. (14), showing that combined blockade of
the ETA and ETB receptors with tezosentan
resulted in coronary vasodilation. In our study and that of Takamura et al. (14), the contribution of endothelin-1-mediated
constriction decreased during exercise, indicating that metabolic
dilation may be the result of increased production of vasodilators and decreased production of endothelin. It is difficult to estimate the
contribution of cardiac myocytes to this decreased production of
endothelin (via a yet-to-be identified factor that stimulates the
release of endothelin from the vascular endothelium) because an
increase in MO2 may increase
vascular shear stress, thereby augmenting NO production. Increased NO
production decreases endothelin release from the vascular endothelium,
which could explain our in vivo but not in vitro findings
(10). Also, vasodilator substances produced during
heightened metabolic demand may directly counteract the vasoconstrictor
effect of endothelin, thereby complicating the interpretation of the
results. Furthermore, it is difficult to identify the main contributors
to metabolic regulation in vivo because metabolic regulation
encompasses redundant systems that act in concert to regulate vascular
tone; inhibition of one pathway might be compensated by altered output
of the others. Unless more pathways are blocked simultaneously,
metabolic regulation appears to be maintained (9). Also,
changes in production of vasoactive substances are difficult to
measure. The endothelium forms a two-way barrier between the
bloodstream and the myocardial interstitium, and can actively
metabolize and produce vasoactive and cardioactive substances.
Therefore, concentrations of vasoactive substances as measured in the
coronary sinus do not necessarily reflect concentrations in the interstitium.
In addition, many substances are both vasoactive and cardioactive
because their receptors are present both on vascular and cardiac
myocytes. This is especially important for the ETA
receptor, which, when stimulated, causes vasoconstriction as well as an increase in inotropy of the myocytes (5), which in turn
increases the production of vasodilators. The effect of ETA
receptor blockade in vivo may therefore underestimate the true vascular
effects of endothelin. With our in vitro system, we can block the
receptors on the vasculature without affecting the myocytes and vice
versa and thus investigate the communication from myocytes to the
coronary vasculature (17). In this in vitro system, the
majority of the cells are cardiac myocytes; however, other cell types
such as fibroblasts and endothelial cells may be present in small
amounts, and may therefore contribute to the vasoactive factors
secreted into the supernatant. A study by Emerson and Segal
(4) showed that in an intact vessel, endothelial cells can
respond to electrical activation but the stimulus in that study was of
a much higher frequency and magnitude than that used in our study.
Moreover, the response of the vessel was local, suggesting a direct
effect rather than secretion of vasoactive factors. Electrically
stimulated fibroblasts are capable of secreting transforming growth
factor (TGF)-
(18). However, the increase in TGF- is
small compared with control conditions. Moreover, we never actually
observed fibroblasts in our setup, so if they are present, there are
very few of them. The majority of vasoactive factors will therefore be
secreted by cardiac myocytes. Compared with the in vivo situation, the
in vitro system has both advantages and disadvantages. The main
disadvantage is that by removing the myocytes and coronary arterioles
from their natural environment, we lose the close proximity between
vessels and myocytes. We thereby introduce the possibility that some
short-lived vasoactive factors, such as NO and CO, will not be
preserved. Furthermore, it is difficult to mimic in vivo concentrations
of endogenous substances. The changes in vascular diameter in response
to administration of the supernatant are, therefore, qualitative rather
than quantitative. However, because we used the same concentration of
cardiac myocytes throughout our protocols, it is possible to compare
vasoactive substances produced at the different contraction rates.
Another problem is that enzymatic isolation of cardiac myocytes can cause cell death or injury. Although we minimize the number of dead cells in our preparation by using only preparations with 70% or more alive rod-shaped cells, there is the possibility that dead cells may release vasoactive substances that could potentially complicate our findings. However, the supernatant from preparations with mainly dead cells (80% or more) was not vasoactive (data not shown). Therefore, we believe that the responses to the supernatant are the result of vasoactive substances released by viable cells. This conclusion is strengthened by the observation that adenosine and bradykinin are the main factors involved in the vasodilatory response to the supernatant. These factors were shown to be released in vivo and to contribute to regulation of coronary vascular tone (2, 3, 7). The main advantage of the in vitro system is that metabolic activity of the myocytes can be changed independently of coronary blood supply, and alterations in vascular diameter (i.e., in vascular resistance) do not influence the oxygen supply to the myocytes. Thus, in contrast to the in vivo situation, when receptors on the arterioles are blocked in vitro, the oxygen supply to the cardiac myocytes or the metabolism of the myocytes is not influenced. Hence, the effect of the mediators that are released during increased metabolic activity can be blocked without affecting their production. Thus, by combining in vivo and in vitro measurements, a more complete view of the involvement of endothelin in the process of metabolic regulation can be obtained.
Implications of Our Findings
Our experiments support the concept that cardiac myocytes, when acting as oxygen sensors in the heart, produce a vasodilator when PO2 decreases and a vasoconstrictor when PO2 increases. Although our results suggest the involvement of endothelin, the mechanism for endothelin production is yet unresolved. We do not believe that cardiac myocytes produce endothelin directly because we (17) reported previously that endothelin concentrations in the myocyte supernatant were too low to cause net constriction, despite the observation that the constrictor influence could be unmasked by using an ETA receptor antagonist. Moreover, another recent study (13) maintained that adult cardiac myocytes do not produce endothelin because they do not express preproendothelin. This implies a process involving the production of a factor (or factors) by cardiac myocytes that induces the release of endothelin from the vasculature. Unfortunately, in our experiments we were unable to identify the endothelin-releasing factor secreted by the cardiac myocytes. In contrast to the study mentioned above, blockade of the angiotensin AT1 receptor with losartan failed to enhance the vasodilatory properties of supernatant from quiescent myocytes in our experiments (Fig. 4), whereas subsequent blockade of the ETA receptor did increase the dilation. These differences may be due to different receptor expression on the coronary arterioles in our experiments versus the aorta in the other study. Nevertheless, blockade of the ETA receptor resulted in coronary vasodilation both in vivo and in vitro, indicating that endothelin is involved in determining basal coronary arteriolar tone, and a reduction of its influence does contribute to metabolic regulation.Conventionally, metabolic regulation of coronary blood flow is
thought of in terms of vasodilation, via the production of vasodilators
in response to increases in myocardial work. The vasodilator pathways
have, therefore, been the main focus of attention. Adenosine,
bradykinin, and NO have each been reported to contribute to metabolic
dilation under control conditions or when one or more pathways are
blocked (3), although the role of especially adenosine
remains controversial (7-9, 19, 20). Interestingly, our in vitro experiments also suggest that release of adenosine and
bradykinin contributes to metabolic dilation of the arterioles. For
dilation to occur, it is implicit that intrinsic vasomotor tone is
present. Also, when myocardial work decreases to basal levels coronary
flow needs to return to baseline as well. Thus if coronary flow
regulation is considered to be a dynamic control system, the advantages
of having both vasodilators and vasoconstrictors involved become
obvious. This way, changes in vascular tone can be fine tuned more
quickly by involving simultaneous augmented production of vasodilators
and decreased production of vasoconstrictors during elevations in
metabolism. Conversely, during decreases in metabolism, rather than
waiting for vasodilator influences to dwindle, myocytes can actually
actively increase vascular tone and thereby actively decrease coronary
blood flow as MO2 decreases.
In conclusion, because endothelin is a very potent and long-lasting vasoconstrictor, its production and release need to be carefully regulated. Therefore, the myocytes, which are the beneficiaries of coronary blood flow, are given the ability to fine tune the production of endothelin according to their metabolic status.
| |
ACKNOWLEDGEMENTS |
|---|
This study was supported by American Heart Association Grant 9920433Z, National Heart, Lung, and Blood Institute Grants HL-32788 and HL-65203, and by The Netherlands Heart Foundation Grants 2000D038 and 2000D042.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: D. Merkus, Division of Experimental Cardiology, Thoraxcenter, Erasmus Medical Center, Box 1738, 3000 DR Rotterdam, The Netherlands (E-mail: merkus{at}tch.fgg.eur.nl).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
July 18, 2002;10.1152/ajpheart.00223.2002
Received 13 March 2002; accepted in final form 14 July 2002.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
DeFily, DV,
Nishikawa Y,
and
Chilian WM.
Endothelin antagonists block 1-adrenergic constriction of coronary arterioles.
Am J Physiol Heart Circ Physiol
276:
H1028-H1034,
1999
2.
Duncker, DJ,
Stubenitsky R,
and
Verdouw PD.
Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise.
Am J Physiol Heart Circ Physiol
275:
H1663-H1672,
1998
3.
Duncker, DJ,
van Zon NS,
Pavek TJ,
Herrlinger SK,
and
Bache RJ.
Endogenous adenosine mediates coronary vasodilation during exercise after KATP channel blockade.
J Clin Invest
95:
285-295,
1995[ISI][Medline].
4.
Emerson, GG,
and
Segal SS.
Electrical activation of endothelium evokes vasodilation and hyperpolarization along hamster feed arteries.
Am J Physiol Heart Circ Physiol
280:
H160-H167,
2001
5.
Endoh, M,
Fujita S,
Yang HT,
Talukder MA,
Maruya J,
and
Norota I.
Endothelin: receptor subtypes, signal transduction, regulation of Ca2+ transients and contractility in rabbit ventricular myocardium.
Life Sci
62:
1485-1489,
1998[ISI][Medline].
6.
Fischer, TA,
Ungureanu-Longrois D,
Singh K,
de Zengotita J,
DeUgarte D,
Alali A,
Gadbut AP,
Lee MA,
Balligand JL,
Kifor I,
Smith TW,
and
Kelly RA.
Regulation of bFGF expression and ANG II secretion in cardiac myocytes and microvascular endothelial cells.
Am J Physiol Heart Circ Physiol
272:
H958-H968,
1997
7.
Groves, P,
Kurz S,
Just H,
and
Drexler H.
Role of endogenous bradykinin in human coronary vasomotor control.
Circulation
92:
3424-3230,
1995
8.
Hecker, M,
Fleming I,
and
Busse R.
Kinin-mediated activation of endothelial NO formation: possible role during myocardial ischemia.
Agents Actions Suppl
45:
119-127,
1995[Medline].
9.
Ishibashi, Y,
Duncker DJ,
Zhang J,
and
Bache RJ.
ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise.
Circ Res
82:
346-359,
1998
10.
Kuchan, MJ,
and
Frangos JA.
Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells.
Am J Physiol Heart Circ Physiol
264:
H150-H156,
1993
11.
Kuo, L,
Davis MJ,
and
Chilian WM.
Myogenic activity in isolated subepicardial and subendocardial coronary arterioles.
Am J Physiol Heart Circ Physiol
255:
H1558-H1562,
1988
12.
Mederski, WW,
Dorsch D,
Osswald M,
Anzali S,
Christadler M,
Schmitges CJ,
Schelling P,
Wilm C,
and
Fluck M.
Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist.
Bioorg Med Chem Lett
8:
1771-1777,
1998[Medline].
13.
Preisig-Muller, R,
Mederos y Schnitzler M,
Derst C,
and
Daut J.
Separation of cardiomyocytes and coronary endothelial cells for cell-specific RT-PCR.
Am J Physiol Heart Circ Physiol
277:
H413-H416,
1999
14.
Takamura, M,
Parent R,
Cernacek P,
and
Lavallee M.
Influence of dual ETA/ETB-receptor blockade on coronary responses to treadmill exercise in dogs.
J Appl Physiol
89:
2041-2048,
2000
15.
Tanus-Santos, JE,
Gordo WM,
Udelsmann A,
and
Moreno H, Jr.
The hemodynamic effects of endothelin receptor antagonism during a venous air infusion in dogs.
Anesth Analg
90:
102-106,
2000
16.
Tanus-Santos, JE,
Sampaio RC,
Hyslop S,
Franchini KG,
and
Moreno H, Jr.
Endothelin ETA receptor antagonism attenuates the pressor effects of nicotine in rats.
Eur J Pharmacol
396:
33-37,
2000[ISI][Medline].
17.
Tiefenbacher, CP,
DeFily DV,
and
Chilian WM.
Requisite role of cardiac myocytes in coronary 1-adrenergic constriction.
Circulation
98:
9-12,
1998
18.
Todd, I,
Clothier RH,
Huggins ML,
Patel N,
Searle KC,
Jeyarajah S,
Pradel L,
and
Lacey KL.
Electrical stimulation of transforming growth factor-1 secretion by human dermal fibroblasts and the U937 human monocytic cell line.
Altern Lab Anim
29:
693-701,
2001[Medline].
19.
Tune, JD,
Richmond KN,
Gorman MW,
and
Feigl EO.
KATP channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation.
Am J Physiol Heart Circ Physiol
280:
H868-H875,
2001
20.
Tune, JD,
Richmond KN,
Gorman MW,
Olsson RA,
and
Feigl EO.
Adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise.
Am J Physiol Heart Circ Physiol
278:
H74-H84,
2000
21.
Widdowson, PS,
and
Kirk CN.
Characterization of [125I]-endothelin-1 and [125I]-BQ3020 binding to rat cerebellar endothelin receptors.
Br J Pharmacol
118:
2126-2130,
1996[ISI][Medline].
22.
Winegrad, S,
Henrion D,
Rappaport L,
and
Samuel JL.
Self-protection by cardiac myocytes against hypoxia and hyperoxia.
Circ Res
85:
690-698,
1999
23.
Winegrad, S,
Henrion D,
Rappaport L,
and
Samuel JL.
Vascular endothelial cell-cardiac myocyte crosstalk in achieving a balance between energy supply and energy use.
Adv Exp Med Biol
453:
507-514,
1998[ISI][Medline].
This article has been cited by other articles:
|
|
 |
|
  D. J. Duncker and R. J. Bache Regulation of Coronary Blood Flow During Exercise Physiol Rev, July 1, 2008; 88(3): 1009 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. de Beer, O. Sorop, D. A. Pijnappels, D. H. Dekkers, F. Boomsma, J. M. J. Lamers, D. J. Duncker, and D. Merkus Integrative control of coronary resistance vessel tone by endothelin and angiotensin II is altered in swine with a recent myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2069 - H2077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Saitoh, T. Kiyooka, P. Rocic, P. A. Rogers, C. Zhang, A. Swafford, G. M. Dick, C. Viswanathan, Y. Park, and W. M. Chilian Redox-dependent coronary metabolic dilation Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3720 - H3725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Duncker and D. Merkus Exercise hyperaemia in the heart: the search for the dilator mechanism J. Physiol., September 15, 2007; 583(3): 847 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-i. Saitoh, C. Zhang, J. D. Tune, B. Potter, T. Kiyooka, P. A. Rogers, J. D. Knudson, G. M. Dick, A. Swafford, and W. M. Chilian Hydrogen Peroxide: A Feed-Forward Dilator That Couples Myocardial Metabolism to Coronary Blood Flow Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2614 - 2621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, O. Sorop, B. Houweling, B. A. Hoogteijling, and D. J. Duncker KCa+ channels contribute to exercise-induced coronary vasodilation in swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2090 - H2097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, O. Sorop, B. Houweling, F. Boomsma, A. H. van den Meiracker, and D. J. Duncker NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2075 - H2081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, D. B. Haitsma, O. Sorop, F. Boomsma, V. J. de Beer, J. M. J. Lamers, P. D. Verdouw, and D. J. Duncker Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2082 - H2089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Tune Withdrawal of vasoconstrictor influences in local metabolic coronary vasodilation Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2044 - H2046. [Full Text] [PDF]
|
|
|
|
|
|
N. Westerhof, C. Boer, R. R. Lamberts, and P. Sipkema Cross-talk between cardiac muscle and coronary vasculature. Physiol Rev, October 1, 2006; 86(4): 1263 - 1308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Brzezinska, D. Merkus, and W. M. Chilian Metabolic communication from cardiac myocytes to vascular endothelial cells Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2232 - H2237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Shipley and J. M. Muller-Delp Aging decreases vasoconstrictor responses of coronary resistance arterioles through endothelium-dependent mechanisms Cardiovasc Res, May 1, 2005; 66(2): 374 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, A. K. Brzezinska, C. Zhang, S. Saito, and W. M. Chilian Cardiac myocytes control release of endothelin-1 in coronary vasculature Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2088 - H2092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Gorman, M. Farias III, K. N. Richmond, J. D. Tune, and E. O. Feigl Role of endothelin in {alpha}-adrenoceptor coronary vasoconstriction Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1937 - H1942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, B. Houweling, A. H. van den Meiracker, F. Boomsma, and D. J. Duncker Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H871 - H880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Okajima, R. Parent, E. Thorin, and M. Lavallee Pathophysiological plasma ET-1 levels antagonize {beta}-adrenergic dilation of coronary resistance vessels in conscious dogs Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1476 - H1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. C. Alders, A. B. J. Groeneveld, F. J. J. de Kanter, and J. H. G. M. van Beek Myocardial O2 consumption in porcine left ventricle is heterogeneously distributed in parallel to heterogeneous O2 delivery Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1353 - H1361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Tune, M. W. Gorman, and E. O. Feigl Matching coronary blood flow to myocardial oxygen consumption J Appl Physiol, July 1, 2004; 97(1): 404 - 415. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||
P < 0.05 vs. 200 beats/min.
P < 005 vs. HOE-140.
