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Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial hypoperfusion is accompanied
by concomitant increases in adenosine and endothelin-1 (ET-1)
production, but the vasodilatory effect of adenosine prevails over that
of ET-1. Therefore, we hypothesized that adenosine-induced or ischemic
preconditioning reduces the vasoconstrictive effect of ET-1. Coronary
arteriolar diameter in vivo was measured using fluorescence
microangiography in anesthetized open-thorax dogs. ET-1 (5 ng · kg
1 · min1
administered intracoronary, n = 10) induced progressive
constriction over 45 min [25 ± 6% (SE)]. The constriction was
blocked by preconditioning with adenosine (25 µg · kg1 · min1
administered intracoronary) for 20 min and 10 min of washout (n = 10) or attenuated by ischemic preconditioning
(four 5-min periods of ischemia, 9 ± 5% at 45 min). To
investigate the receptor involved in this process, coronary arterioles
(50-150 µm) were isolated and pressurized at 60 mmHg in vitro.
The ET-1 dose-response curve (1 pM-5 nM) was rightward shifted
after preconditioning with adenosine (1 µM) for 20 min and 10 min of
washout (n = 11). Blockade of A2 receptors
[8-(3-chlorostyryl)caffeine, 1 µM, n = 9] but not
A1 receptors (8-cyclopentyl-1,3-dipropylxanthine, 100 nM,
n = 7) prevented this shift. These results suggest that adenosine confers a vascular preconditioning effect, mediated via the
A2 receptor, against endothelin-induced constriction. This
effect may offer a new protective function of adenosine in preventing
excessive coronary constriction.
coronary microcirculation; coronary blood flow; vasodilation; vasoconstriction; ischemic preconditioning
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ONE PUZZLING ATTRIBUTE of coronary insufficiency is the production of the vasoconstrictor endothelin-1 (1). Hypothetically, the production of endothelin-1 under these conditions would exacerbate the hypoperfusion. However, in addition to the production of endothelin-1, the potent coronary vasodilator adenosine is produced during myocardial hypoperfusion. In addition to its vasodilator properties, adenosine is cardioprotective. Administration of adenosine before an ischemic episode reduces infarct size and improves recovery of myocardial function preconditioning (14). Some studies have shown that preconditioning is accompanied by an increase in coronary perfusion in the recovery from prolonged ischemia (7, 16), whereas others have failed to show such an effect (4). Nevertheless, the salutary effects of adenosine prevail over those of endothelin-1 during myocardial ischemia and reperfusion. We therefore hypothesized that preconditioning with adenosine attenuates the vasoconstrictive actions of endothelin-1. Additionally, we investigated whether the actions of exogenously administered adenosine would be mimicked by ischemic preconditioning.
We tested these hypotheses by measuring endothelin-induced constriction of coronary arterioles with and without preconditioning with adenosine in vivo and in vitro and after ischemic preconditioning. To identify the adenosine receptor involved in this response, the in vitro experiments were repeated in the presence of an A1- or A2-receptor antagonist.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In Vivo Coronary Microvascular Preparation
Twenty-six adult mongrel dogs (5-15 kg) were anesthetized with pentobarbital sodium (Nembutal, 30 mg/kg iv). The animals were placed on a homeothermic blanket to maintain a core body temperature of 37°C. The right femoral artery and vein were cannulated for measurements of aortic pressure and arterial blood gases and the administration of drugs, respectively. A 5-F fluid-filled catheter was advanced into the left ventricle from the left carotid artery to measure left ventricular pressure. The first derivative of the left ventricular pressure signal (LV dP/dt) was obtained by an on-line differentiator. A snare was placed around the vena cava to maintain aortic pressure constant by regulating venous return. Hemodynamic data were acquired continuously using ACODAS data acquisition software (DATAQ, Akron, OH). A tracheotomy was performed, and high-frequency jet ventilation was used. With the use of the maximum LV dP/dt as a timing reference, a solenoid connected to a pressure source (100% O2, 6-12 psi) was triggered to open for 20-35 ms at the same time in each cardiac cycle. The small tidal volume minimizes respiratory movement, which occurs at the same frequency as the heartbeat. Arterial pH and blood gases were monitored frequently and maintained within the following ranges by adjustment of the tracheal catheter or by administration of sodium bicarbonate: 25-40 mmHg PCO2, 100-200 mmHg PO2, pH 7.35-7.45. All animals routinely received propranolol (1 mg/kg), indomethacin (10 mg/kg), and the H1-histamine receptor antagonist diphenhydramine (1 mg/kg) to limit tissue motion, reduce inflammatory reactions, and prevent anaphylactic reactions to the high-molecular-weight dextrans, respectively.To visualize the epicardial surface, the heart was exposed by a left thoracotomy at the fifth intercostal space and stabilized in a partial pericardial cradle. A large coronary artery [left anterior descending coronary (LAD) or circumflex] was exposed, and a 24-gauge cannula was inserted to allow the measurement of coronary arterial pressure and the administration of intracoronary drugs and fluorochromes. For ischemic preconditioning, a snare was placed around a marginal or diagonal branch, which then was occluded to obtain ischemic preconditioning (see Protocols). After an area of easily visible epicardial microvessels was identified, four 22-gauge pins were passed horizontally through the left ventricle to minimize vertical cardiac motion. Neither maneuver appears to compromise coronary tone, because resting blood flow and vasodilator reserve are unaffected in each case (2).
Measurement of Coronary Microvascular Diameter
To measure coronary microvascular diameter, the cardiac surface was illuminated by a stroboscope (100-W Xe arc, Chadwick-Helmuth, El Monte, CA) that was triggered by the maximum LV dP/dt signal to flash once for 20-30 µs at the same point during each cardiac cycle. The strobe trigger signal was monitored in relation to left ventricular pressure for a precise determination of the strobe's position in the cardiac cycle. The combined use of low tidal volume jet ventilation and brief epicardial illumination both synchronized to the cardiac cycle causes the surface coronary microvessels to appear virtually motionless when viewed through an intravital microscope (Leitz Ploemopak, Wild Leitz) (2). The microscope objectives used were the Leitz EF4 (×4, NA 0.22) and the Leitz L10 (×10, NA 0.22).To illuminate the inner diameters of the microvessels, 50- to 100-µl aliquots of FITC-dextran (25 mg/ml, mol wt 500,000) in 0.9% saline were injected through the coronary cannula. A Leitz H2 excitation-barrier filter was used to activate the fluorescein and receive the emitted light. Each injection causes arterial and venous vessels to fluoresce sequentially for 5-10 s. The anatomic landmarks of a particular vessel were identified, and five to eight images were obtained over a period of <1 min by using a Cohu silicone-intensified tube videocamera. The images were digitized directly from the camera by a frame digitizer (Scion Image) and transferred to a Macintosh computer (Apple Computer, Cupertino, CA) for diameter measurements using appropriate software (Image 2.18, National Institutes of Health Research Services Branch) (2). Diameters were measured by aligning cursors at the vessel edges. Measurements in pixels were converted to micrometers using a conversion factor determined from a micrometer grid. Typically, microvascular measurements over each image acquisition period vary by less than ±3% from the average value. Vessels were excluded from analysis if control microvascular diameters after interventions varied from the prior baseline by >10%.
Protocols
Endothelin alone. After acquisition of baseline data, endothelin (5 ng/kg/min administered into the heart) was infused for 45 min. Diameter measurements (10 vessels in 5 dogs, average diameter 112 ± 13 µm) and hemodynamic data were obtained at 15, 30, and 45 min.
Endothelin with adenosine.
After acquisition of baseline measurements, adenosine (25 µg · kg1 · min1) was
infused for 20 min and then washed out for 10 min, during which
diameter returned to control (10 vessels in 4 dogs, average baseline
diameter 111 ± 20 µm). Vessels were excluded from analysis if
diameter did not return to within 10% of the control diameter (n = 4). Endothelin-1 was then infused, and diameter
measurements and hemodynamic data were obtained at 15, 30, and 45 min.
Endothelin after ischemic preconditioning. After acquisition of baseline measurements, a marginal or diagonal branch was occluded for 5 min and then reperfused for 5 min. This occlusion-reperfusion sequence was repeated three more times, then the occlusion was released and reperfusion was allowed for 20 min, during which diameter returned to baseline (10 vessels in 5 dogs). Vessels were excluded from analysis if diameter did not return to within 10% of the control diameter (n = 2). Endothelin-1 was then infused, and diameter measurements and hemodynamic data were obtained at 15, 30, and 45 min.
In preliminary experiments we found that endothelin-1 infusion caused a 20- to 30-mmHg increase in left ventricular and systemic pressure. Since changes in these pressures affect the vasculature, we maintained systemic pressure at baseline values by constriction of the inferior vena cava during administration of endothelin-1.Isolated Arterioles
Coronary arterioles were isolated as previously described (11) and placed in ice-cold physiological saline solution 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 MOPS, buffered to pH 7.4 at 4°C and filtered (dissection buffer). A section of the myocardium was placed under a dissection microscope in a 4°C chamber, and vessels were carefully dissected free from the surrounding myocardial tissue and placed in dissection buffer containing 1% BSA. The vessels were cannulated on both ends with micropipettes (~50 µm OD) connected to pressurized reservoirs filled with physiological saline solution buffered at pH 7.4 at 37°C. The height of these reservoirs was varied to obtain the desired intraluminal pressure (60 mmHg). Vessels that failed to maintain pressure were excluded from analysis. Internal diameter of coronary microvessels was measured under a charge-coupled device camera (Sony CCD-IRIS) using a video caliper system. The vessel was slowly warmed to 37°C and allowed to develop spontaneous tone.Protocol
Diameter changes in response to endothelin-1 (1012-108 M) were measured in one
group of vessels (n = 9, average diameter 111 ± 9 µm). The second group of vessels (n = 11, average
diameter 94 ± 9 µm) was preconditioned with adenosine (1 µM)
for 20 min and then subjected to 10 min of washout, during which the
vessel diameter returned to control. Subsequently, the response to
endothelin-1 (1012-108 M) was
measured. To identify the adenosine receptor involved in the effect of
adenosine, vessels were incubated with the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 107
M, n = 7, average diameter 81 ± 8 µm) and the
A2-receptor antagonist 8-(3-chlorostyryl) caffeine (CSC,
106 M, n = 9, average diameter 98 ± 11 µm) together with adenosine, DPCPX and CSC were washed out, and
endothelin-1 was administered. Responses of the arterioles to the
various treatments are expressed as percentage of resting diameter.
Drugs
All drugs except indomethacin were dissolved in 0.9% saline solution. Indomethacin was dissolved in 95% ethanol and raised to pH 8.5 with 1 NaOH. The final concentration was diluted to 10 mg/ml with 0.9% saline. Propranolol, indomethacin, endothelin-1, DPCPX, CSC, and all buffer components were purchased from Sigma Chemical. Adenosine was purchased from Research Biochemicals.Statistics
All statistics were performed on StatView software for the Macintosh (Abacus Concepts, Berkeley, CA). Differences in vascular diameter were evaluated by ANOVA with Fisher's test as the post hoc multiple comparison test. Values are means ± SE. Significance was accepted at P < 0.05 in all experiments.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of Endothelin-1 on Hemodynamics
To eliminate any complicating consequences of acute endothelin-induced hypertension in our study, we maintained aortic pressure constant by reducing venous return with a snare around the vena cava during endothelin-1 administration (Table 1).
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Effect of Adenosine-Induced and Ischemic Preconditioning on Endothelin-1-Induced Constriction In Vivo
Administration of endothelin-1 resulted in progressive constriction of the arterioles over the duration of the experiment (25.1 ± 6.2% after 45 min of infusion; Fig. 1). Adenosine induced dilation of the arterioles (11 ± 4%), but after washout, diameter returned to its baseline value (diameter within 2% of first measurement). This "adenosine" preconditioning eliminated the constriction to endothelin-1 over the entire time course (1.1 ± 5.7% constriction after 45 min of infusion). Because adenosine is released during myocardial ischemia, we investigated whether ischemic preconditioning would mimic the effects of adenosine. Indeed, ischemic preconditioning significantly reduced the constriction to endothelin-1 (8.7 ± 4.8% constriction after 45 min of infusion).
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Effect of Adenosine on Endothelin-1-Induced Constriction In Vitro
Endothelin-1 dose-response curves are shown in Fig. 2. Endothelin-1 caused dose-dependent constriction at >100 pM. Administration of adenosine caused dilation of the arterioles, but after washout, basal tone returned within 10 min. After this treatment, subsequent constriction to endothelin-1 was attenuated (P < 0.05), as illustrated by the rightward shift of the endothelin-1 dose-response curve. Since coronary microvessels possess A1 and A2 receptors, we investigated which receptor was responsible for this effect. Incubation of the vessels with an A2-receptor antagonist, but not with an A1-receptor antagonist, prevented the adenosine-induced shift of the endothelin-1 dose-response curve. This indicated that the preconditioning effect of adenosine was mediated by A2 receptors.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We observed in this study that ischemic preconditioning and preconditioning with adenosine reduced the vasoconstrictive effects of endothelin-1. This effect of adenosine was mediated through the A2 receptor. As such, adenosine may act to mitigate the very potent constriction of endothelin-1 during hypoperfusion, when both substances are released. Before discussing the implications of our findings, we first describe some limitations that bear on the results and conclusions.
Methodological Limitations
The interstitial adenosine concentration in our ischemic preconditioning experiments is unknown. Measurements of interstitial adenosine during preconditioning yield concentrations in the micromolar range (5). In our experiments, in which we exogenously administered adenosine, we used concentrations in this range. We used an adenosine concentration of 1 µM in vitro, and we administered 25 µg · kg1 · min1 adenosine
in the in vivo experiments. This dose corresponds to a dose of
50-100 µM (on the basis of an estimated LAD flow of 10-20
ml/min in a 10-kg dog). Although adenosine is rapidly metabolized in
vivo, this dose should be sufficient to mimic the concentration of
interstitial adenosine during ischemia, as is corroborated by the
observation that ischemic preconditioning and adenosine preconditioning
yield similar results.
In the in vivo experiments, we administered only one dose of
endothelin-1. The in vivo dose of 5 ng · kg1 · min1 gives an
estimated intracoronary concentration of ~1-2 nM (on the basis
of an estimated LAD flow of 10-20 ml/min in a 10-kg dog). This
dose also induces robust constriction in vitro, whereas preconditioning
with adenosine almost completely blocked constriction to this dose of
endothelin-1 in vitro and in vivo. Although we acknowledge the
constraints of drawing conclusions on the basis of a single dose of
endothelin-1, our data show that constriction to this potent in vivo
dose was completely abolished by preconditioning with adenosine.
Furthermore, the seriousness of this in vivo limitation is lessened by
the corroborating results of the complete dose-response relationships
to endothelin-1 in vitro.
Another limitation of our in vivo results is that we can only measure diameter of epicardial arterioles. Differences between endocardial and epicardial arterioles have been reported but consist mainly of differences in sensitivity rather than different pathways. Studies by other laboratories have shown that the dose of endothelin-1 that we administered decreased coronary blood flow significantly (3); thus it is likely that endocardial and epicardial vessels constrict to endothelin-1 (9). Adenosine and endothelin-1 are agonists that appear to act in coronary resistance vessels (12); thus it is likely that the effect we observed in epicardial vessels can be extrapolated to endocardial vessels as well.
Implications of the Study
The exogenous administration of adenosine clearly shows that adenosine plays a role in preventing endothelin-induced constriction. The results of the ischemic preconditioning are more difficult to interpret, because ischemia stimulates the production of many substances, including endothelin-1 and adenosine (10, 15, 22). Endothelin-1 in itself is also able to induce preconditioning against ischemia-induced myocardial injury (21). However, we do not know its role in our experiments. Nevertheless, ischemic preconditioning clearly decreases the sensitivity of the coronary vasculature to endothelin. Adenosine-induced protection against endothelin-1-induced constriction may be an explanation for the observation that endothelin receptor antagonism reduced infarct size in control, but not in preconditioned, hearts (10). We speculate that the reduced susceptibility to endothelin-induced constriction may be beneficial to coronary blood flow. Indeed, several studies have shown that ischemic preconditioning is capable of improving coronary flow to the area at risk during recovery from a prolonged period of ischemia (7, 16), although others fail to find such an effect (4). The different findings may be attributed to different preconditioning and reperfusion protocols.In cardiac myocytes the preconditioning effect of adenosine appears to be primarily mediated by A1 receptors (14, 17). However, the adenosine A2 receptor predominates in the coronary vasculature (8, 19). Preconditioning of endothelial cells against anoxia and reoxygenation injury in vitro is mediated by activation of this receptor (24). Furthermore, activation of this receptor protects the endothelium against neutrophil adherence during ischemia-reperfusion and may, therefore, protect the coronary vasculature against neutrophil-related damage (6, 20, 23). It is therefore not surprising that the adenosine-induced protection against endothelin-1-induced constriction is also mediated through the A2 receptor. In accordance with our findings, a study by Peng et al. (18) showed that ischemic preconditioning in isolated, perfused hearts is capable of reducing endothelin-1-induced cardiac injury and that this was mediated through calcitonin gene-related peptide and protein kinase C. Since adenosine A2 receptors also activate protein kinase C (13, 24), modulation of protein kinase C may be a uniform way of protecting against endothelin-1-induced constriction.
Taken together, activation of A2 receptors via adenosine protects the vasculature from excessive constriction produced by endothelin-1. We speculate that this preconditioning against constriction may facilitate or restore flow to areas of compromised perfusion.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-59448 and HL-32788 and American Heart Association Grants 9920433Z and 9807894X.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. Merkus, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: dmerkus{at}mcw.edu).
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.
Received 6 June 2000; accepted in final form 9 August 2000.
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METHODS
RESULTS
DISCUSSION
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