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Departments of 1 Physiology and 2 Surgery, University of Kentucky College of Medicine, Lexington, Kentucky 40536
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Adenosine A3 agonists have been shown to protect ischemic rat and rabbit myocardium. However, these agonists have been reported to exert A3 independent effects, and no cardiac A3 receptor has yet been identified. We thus tested whether A3 agonist protection is due to A1 receptor activation. Isolated rat and rabbit hearts were subjected to 25 and 45 min of global ischemia, respectively. Rat hearts pretreated with adenosine (100 µM), the A3 agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA, 50 nM), and vehicle recovered 73 ± 2%, 75 ± 4%, and 46 ± 4%, respectively, of preischemic left ventricular developed pressure (LVDP) after 30 min of reperfusion. The A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM) blocked the beneficial effects of Cl-IB-MECA (51 ± 5%) and adenosine (47 ± 6%). In rabbit hearts, the beneficial effects of the A3 agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (50 nM) and the A1 agonist 2-chloro-N6-cyclopentyladenosine (100 nM) on postischemic LVDP (75 ± 4 and 74 ± 5%, respectively) were blocked by DPCPX (34 ± 4 and 36 ± 3%, respectively). The reduction in infarct size with both agonists was also completely blocked by DPCPX. These results suggest that these A3 agonists protect ischemic myocardium via A1 receptor activation.
ischemia; reperfusion; cardiac receptor
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ADENOSINE INFUSION BEFORE ISCHEMIA (i.e., pretreatment) has been shown to reduce both reversible and irreversible myocardial ischemia-reperfusion injury in numerous species (14). The majority of evidence has implicated the activation of the A1 receptor subtype, presumably in the myocyte, in the mediation of this effect. This hypothesis is supported by evidence that pretreatment with A1 receptor agonists mimics the cardioprotective effect of adenosine, whereas A1 receptor antagonists such as 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) block this effect (8, 16, 19, 20, 23, 29, 35). Endogenous adenosine also appears to play a role in the protective effects of ischemic preconditioning (22, 23, 36).
Although A1 receptor antagonists block the beneficial effects of adenosine pretreatment, several studies in isolated rat and rabbit hearts indicate that the A1 receptor antagonist DPCPX did not block ischemic preconditioning (1, 2, 15, 19, 22). More recent studies have furthered the concept of an A1 receptor-independent mediation by showing that agonists such as N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB- MECA) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), which exhibit selectivity for the cloned A3 receptor, mimic the cardioprotective effects of adenosine (3, 4, 13, 30-32). Although A3 receptors could be expressed on numerous cell types in the heart, the results of isolated myocyte studies (1, 4, 28, 34) have led to the hypothesis that the myocyte adenosine A3 receptor subtype is involved in adenosine cardioprotection.
A fundamental deficiency in the hypothesis of A3 receptor
cardioprotection is that although cardiac A3 receptor mRNA
expression has been observed in rat and rabbit myocardium (34,
37), a cardiac A3 receptor has yet to be identified.
The lack of potent, selective, and species-independent A3
receptor antagonists has also hampered studies of A3
receptor-mediated effects. However, cloned-rat and -rabbit adenosine
A3 receptors have been characterized by a lack of
sensitivity to well-studied, methylxanthine-based, adenosine-receptor
antagonists, a property that was used to provide the initial
pharmacological evidence for the existence of A3 receptors in the rat cardiovascular system (6). The methylxanthine
DPCPX has an inhibition constant (Ki) value in
the low nanomolar range for rat and rabbit A1 receptors,
but Ki 
5 µM for A3 receptors (12). Despite this insensitivity of A3
receptors to the well-characterized A1 antagonist DPCPX,
there has been only one study (in human atrial trabeculae) in which the
cardioprotective effects of IB-MECA or Cl-IB-MECA have been tested in
the presence of this methylxanthine (4). Thus in the
present study we tested the cardioprotective effects of these two
A3 receptor agonists in the absence and presence of the
selective A1 antagonist DPCPX to determine the role of A3 receptors in adenosine cardioprotection in rat and
rabbit ventricular myocardium.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All animals in this study received humane care according to the guidelines set forth in the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council (National Institutes of Health Publication No. 85-23, Revised 1996) and according to the guidelines of the Department of Laboratory Animal Resources of the University of Kentucky.
Isolated heart preparation. Experiments were conducted on adult male Sprague-Dawley rats (350-400 g body wt) and New Zealand White rabbits of either sex (2.5-3.0 kg body wt). Animals were heparinized and then anesthetized with pentobarbital sodium (65 mg/kg ip). The heart was rapidly excised and immediately placed into ice-cold Krebs-Henseleit buffer (KHB) to produce cardiac arrest. The aorta was cannulated and the heart was perfused at a constant pressure of 65 mmHg (70 mmHg in rabbits) with KHB consisting of (in mM): 118 NaCl, 4.7 KCl, 1.2 MgSO4, 1.2 KH2PO4, 1.5 CaCl2, 25.0 NaHCO3, 11.0 glucose, 1.0 pyruvate, and 0.005 EDTA. The perfusate was maintained at 37°C in a constant-temperature reservoir and was bubbled with 95% O2-5% CO2, which resulted in a pH of 7.4. Myocardial temperature was maintained at 37°C by partially submersing the heart into a water-jacketed chamber filled with KHB.
Rat hearts were paced at 300 beats/min and rabbit hearts at 200 beats/min via electrodes placed on the right ventricle. Pacing was continued for the first 5 min of ischemia and throughout reperfusion. Ventricular function was assessed by measuring left ventricular developed pressure (LVDP) with a fluid-filled latex balloon that was connected via polyethylene tubing to a pressure transducer (model P23 XL; Statham). The balloon was inserted into the left ventricle via the left atrium and was inflated to yield an end-diastolic pressure of 5 mmHg (for the rat) or 10 mmHg (for the rabbit). LVDP was calculated as the difference between the end-systolic and end-diastolic pressures. Coronary flow rate was determined via timed collection of effluent overflow from the heart bath. Coronary perfusion pressure was measured via a sideport in the aortic cannula connected to a second pressure transducer. All transducers were connected to a WindoGraf 900 recorder (Gould Instrument Systems; Valley View, OH).Rat heart studies. Isolated hearts were allowed a 15-min equilibration period after which the hearts were perfused with KHB containing either vehicle (n = 9), Cl-IB-MECA (50 nM, n = 8), adenosine (100 µM, n = 5), or 2-chloro-N6-cyclopentyladenosine (CCPA; 200 nM, n = 4) for 5 min immediately before ischemia. Two additional groups were administered a 5-min infusion of DPCPX (100 nM) before Cl-IB-MECA + DPCPX (n = 8) or adenosine + DPCPX (n = 6) were administered for 5 min immediately before ischemia (i.e., no drug washout). Hearts were then submitted to 25 min of global ischemia and 30 min of reperfusion. Postischemic function was expressed as the percent recovery of preischemic LVDP.
Rabbit heart studies. Isolated hearts (n = 5-7 per group) were provided a 20-min equilibration period before being perfused with KHB containing either vehicle, IB-MECA (50 nM), or CCPA (100 nM) for 5 min immediately before ischemia. Two additional groups received a 5-min perfusion with DPCPX (100 nM) before the administration of Cl-IB-MECA + DPCPX or CCPA + DPCPX for 5 min before ischemia. Hearts were then submitted to 45 min of global normothermic ischemia and 120 min of reperfusion. Postischemic function was expressed as the percent recovery of LVDP.
After 2 h of reperfusion, rabbit hearts were stained with triphenyltetrazolium chloride (TTC, 1% in phosphate-buffered saline, 37°C) to estimate global infarct size. The TTC solution was infused for 5 min at a constant pressure of 70 mmHg, after which the heart was removed and placed in 10% formalin overnight. The next day the heart was sliced into four pieces from base to apex. The slices were flattened between two Plexiglas plates separated by an exact 2-mm distance and were photographed with a video camera. The images were then digitized and analyzed by computerized planimetry. The extent of infarction (lack of TTC-positive brick-red staining) was normalized to the area of the entire left ventricle. The planimetry was performed by an individual blinded to the various treatments.Materials. Adenosine was obtained from Sigma (St. Louis, MO). Adenosine-receptor agonists (CCPA, Cl-IB-MECA, and IB-MECA) and the antagonist DPCPX were obtained from RBI (Natick, MA). Adenosine was dissolved directly in the Krebs buffer. Adenosine agonists and antagonists were solubilized as concentrated solutions in DMSO; these solutions were then added to the KHB to produce the final concentrations indicated.
Statistical analysis. Results are expressed as means ± SE. Ischemia-reperfusion data were analyzed by two-way ANOVA with repeated measures in time. Tukey's honestly significant difference post hoc test was performed to determine pairwise differences between groups. A P value of <0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Isolated rat heart studies. The control group baseline values of LVDP (108 ± 2 mmHg) and coronary flow (15.2 ± 0.6 ml/min) were not significantly different from the baseline LVDP values in the treated groups. DPCPX treatment did not affect either LVDP or coronary flow. Coronary flow increased after agonist administration (adenosine, 34.6 ± 6.8%; CCPA, 32.5 ± 4.2%; Cl-IB-MECA, 22.7 ± 2.9%; adenosine + DPCPX, 22.6 ± 6.6%; and Cl-IB-MECA + DPCPX, 2.2 ± 2.8%), whereas the mean LVDP decrease was 8 ± 1%.
The A3 receptor agonist Cl-IB-MECA significantly improved the recovery of preischemic LVDP compared with control rat hearts (75 ± 4% vs. 46 ± 4% at 30 min reperfusion; P < 0.05; Fig. 1A). The preservation of postsichemic LVDP with Cl-IB-MECA was equivalent to that produced by treatments with the adenosine A1 agonist CCPA (77 ± 5%; P < 0.05 vs. control) and adenosine (73 ± 2%; P < 0.05 vs. control; Fig. 1B). Pretreatment with the A1 receptor antagonist DPCPX blocked the protective effects of both Cl-IB-MECA and adenosine on LVDP. Recovery of function was reduced to 51 ± 5% (not significant vs. control; Fig. 1A) and 47 ± 6% (not significant vs. control; Fig. 1B) after 30 min of reperfusion, respectively. LVEDP was also protected by Cl-IB-MECA pretreatment (39 ± 3 mmHg at 30 min reperfusion; P < 0.05; Fig. 2A) to the same degree as both adenosine (39 ± 2 mmHg; P < 0.05; Fig. 2B) and CCPA (44 ± 2 mmHg; P < 0.05) vs. control (60 ± 5%; Fig. 2A). With DPCPX pretreatment, LVEDP in both the Cl-IB-MECA- and adenosine-treated groups increased to levels not significantly different from control [51 ± 4 mmHg (Fig. 2A) and 49 ± 4 mmHg (Fig. 2B), respectively].
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Isolated rabbit heart studies. In rabbits, the baseline LVDP ranged from 104 ± 1 to 116 ± 3 mmHg and did not differ between the groups. Likewise, baseline coronary flow was not different (range = 39.2 ± 3.8 to 47.1 ± 3.0 ml/min). Neither DPCPX nor agonist treatment altered LVDP or coronary flow.
Similar to the results obtained with rat hearts, IB-MECA-pretreated rabbit hearts exhibited significantly improved postischemic LVDP (75 ± 4% of preischemic LVDP at 2 h reperfusion; Fig. 3A) compared with control untreated hearts (35 ± 4%; Fig. 3A). This protection was identical to that obtained with the A1 receptor agonist CCPA (74 ± 5%; Fig. 3A). Reperfusion LVEDP values were also significantly reduced in hearts treated with IB-MECA (23 ± 2 mmHg at 2 h of reperfusion) and CCPA (24 ± 4 mmHg) compared with control hearts (44 ± 2 mmHg; Fig. 3B). Infarct size was reduced from 69 ± 3% in control hearts to 17 ± 1 and 19 ± 4% in IB-MECA- and CCPA-treated hearts, respectively (see Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study indicate that pretreatment with A1- and A3-receptor agonists exert similar cardioprotection against ischemia-reperfusion injury in isolated rat and rabbit hearts. The A1 agonist CCPA and the A3 agonists IB-MECA and Cl-IB-MECA increased recovery of postischemic LVDP and decreased LVEDP after global ischemia. In rat hearts, protection induced with both receptor agonists was similar to that obtained with adenosine pretreatment. In rabbit hearts, CCPA and IB-MECA reduced infarct size to the same extent. The novel findings of this study were that the A1 receptor antagonist DPCPX blocked the protective effects of the A3 receptor agonists in both species, which suggests that these agents mediated the effects via A1 rather than A3 receptor activation.
Initial support for the hypothesis of A3 receptor-mediated cardioprotection was based primarily on observations in rabbit myocardium that ischemic preconditioning could be mimicked by adenosine and A1 agonists, but this protection (which could be blocked by the nonselective adenosine-receptor antagonist 8-SPT) could not be blocked by the A1 receptor antagonist DPCPX (19, 22, 23). Additional studies in isolated rat hearts demonstrated that DPCPX was unable to block ischemic and hypoxic preconditioning (2, 15, 24). Numerous reports of cardioprotection in rabbit myocardium with the A3 receptor agonists IB-MECA and Cl-IB-MECA, which exhibit selectivity for cloned A3 receptors, have further bolstered this hypothesis (3, 4, 13, 30-32). Despite the fact that the first evidence (nearly a decade ago) suggestive of a cardiac A3 receptor was in the rat heart (37), only in the last year has there been a study with A3 receptor agonists in this species (30). These observations are all consistent with the hypothesis that A3 receptors play a role in adenosine cardioprotection.
The results of this study are consistent with previous reports of Cl-IB-MECA and IB-MECA protection in rat and rabbit myocardium. These effects were essentially identical to those achieved with the A1 agonist CCPA and adenosine. However, our data indicate that the beneficial effects of these A3 agonists in both species were blocked by the A1 antagonist DPCPX (at a concentration of 100 nM). This same dose of DPCPX completely blocked adenosine protection in the isolated rat heart and the beneficial effects of CCPA in the rabbit heart. From the reports that the rat- and rabbit-cloned A3 receptors have Ki values for DPCPX that are >5 µM and >1 µM, respectively (9, 12), these findings suggest that Cl-IB-MECA and IB-MECA exerted protective effects by activating A1 rather than A3 receptors.
Despite the insensitivity of rat- and rabbit-cloned A3 receptors to DPCPX and the use of this antagonist in ischemic preconditioning studies, to our knowledge this is the first study in which the beneficial effects of Cl-IB-MECA and IB-MECA have been tested in the presence of these antagonists in adult ventricular myocardium. Carr and colleagues (4), measuring contractile function in human atrial trabeculae submitted to simulated ischemia, concluded a role for A1 and A3 receptors based on results obtained with a low concentration of DPCPX (200 nM). However, DPCPX did partially block the beneficial effects of IB-MECA preconditioning. Stambaugh and co-workers (28) have also reported that DPCPX did not block A3 agonist preconditioning in fetal chick ventricular myocytes. However, this latter observation has not been reported in adult mammalian ventricular myocardium.
To exclude the possibility that our initial observations were due to a
unique property of DPCPX, additional rabbits were treated with IB-MECA
in the presence of another methylxanthine (8-SPT). Although the initial
pharmacological evidence for A3 receptors in rat
cardiovascular effects was based on observations with 8-SPT (6) and 8-SPT has been used in ischemic
preconditioning studies, there appear to be no A3 agonist
cardioprotection studies that use this antagonist. Because the
Ki of 8-SPT for cloned-rabbit A3
receptors is 38 µM (9), we used a 20-fold lower dose
(5 µM) than has been typically used in preconditioning studies. This lower dose of 8-SPT completely blocked IB-MECA protection in the rabbit, which is similar to the results obtained with DPCPX. This finding further supports the hypothesis that the cardioprotective effects of the A3 agonist IB-MECA (at least in rabbit
myocardium) are mediated via A1 receptor activation.
Although our present results with DPCPX and 8-SPT raise questions regarding the role of A3 receptor-mediated myocardial protection, these findings differ with other studies where different antagonists were used. Thourani and colleagues (30) reported that KW-3902 was ineffective at blocking Cl-IB-MECA cardioprotection in the isolated rat heart. Because KW-3902 has been reported to be a potent A1 receptor antagonist (25), the authors concluded that Cl-IB-MECA exerted its effects via A3 receptor activation. We do not have a definitive explanation for this difference between the results obtained with these two antagonists, because there has been limited use of KW-3902 in myocardial ischemia preparations. However, we used a 50-fold lower dose of DPCPX, and we demonstrated that this dose of DPCPX completely blocked the cardioprotective effects of adenosine, which was not reported by Thourani and colleagues (30).
Our findings with DPCPX and 8-SPT also differ with those obtained with
the adenosine-receptor antagonist
8(4-carboxyethenylphenyl)xanthine (BWA-1433, a
paraphenyl carboxyl-substituted derivative of
1,3-dipropyl-8-phenylxanthine). Several investigators have
reported that low doses (50 nM) of BWA-1433, which appears to be
selective for the A1 receptor, do not block
ischemic preconditioning or A3 agonist protection;
however, higher doses (1 µM) are effective (1, 31, 32,
34). These results are consistent with the reported affinity of
this antagonist for rabbit-cloned A3 receptors. Although
high doses of BWA-1433 may block receptor binding,
adenosine-receptor-independent effects may also be exerted. It has been
reported (24) that BWA-1433 but not DPCPX significantly
reduces glucose uptake and phosphorylation in nonischemic
hearts and prevents the decrease in intracellular pH during global
ischemia. The authors of this study concluded that the ability
of this antagonist to block ischemic preconditioning may be not
be due to adenosine-receptor antagonism. We have previously reported
that BWA-1433 dramatically reduced lactate release during low-flow
ischemia and accelerated the onset of ischemic
contracture (17), whereas DPCPX has been reported to have
no effect on the latter (8). Given these effects of
BWA-1433 and the extensive literature on the use of nanomolar doses of
DPCPX to block adenosine A1 receptor-mediated effects and
radioligand binding, we elected to use this antagonist in the present
study. Furthermore, it has been reported that DPCPX exhibits an
A1/A3 selectivity for rabbit-cloned adenosine
receptors of 1,120-fold compared with 249-fold for BWA-1433 (9).
In addition to the above dissimilarities between these two antagonists, there are several protocol differences between the studies by Tracey and colleagues (31, 32) and the present study that could have influenced the findings. The primary difference appears to be how the adenosine agonists and antagonists were administered before ischemia. We used a pretreatment protocol in which the drugs were administered until the onset of global ischemia, whereas these other studies employed a preconditioning protocol in which both agonists and antagonists were washed out before the onset of regional ischemia. Differences in the lipid solubilities for IB-MECA, CB-MECA, and BWA-1433 could affect how rapidly these agents cross cell membranes and are washed out of the heart. Differences in the affinities of these agents for the A1 receptor would also be expected to influence how rapidly the A1 effects terminate. Whether due to these effects or not, there are acknowledged differences between effects of ischemic and adenosine-agonist preconditioning and adenosine pretreatment. Because adenosine A1 agonist preconditioning does not improve postischemic function, we elected to use a pretreatment protocol.
Our results suggesting that A3 agonists can exert effects independent of A3-receptor activation or binding are consistent with several other reports (7, 11, 26, 27, 33). It has been reported that the binding of N6-(4-amino-3-[125I]iodobenzyl)adenosine ([125I]ABA) to IB-MECA and CB-MECA blocks binding to cloned-rabbit A1 receptors; Ki values were 30 and 105 nM, respectively (9, 32). Receptor-labeling studies in the rat brain showed that A1 receptor labeling by [125I]AB-MECA (400 pM) was blocked by Cl-IB-MECA (100 nM) (26). In the same study, the Ki values for the inhibition of [3H]DPCPX binding (2 nM) in rat brain membranes by CCPA and Cl-IB-MECA were 430 and 960 nM, respectively. We have previously reported (18) that IB-MECA- and Cl-IB-MECA-induced coronary vasodilatation in rat hearts was blocked by an A2a receptor antagonist. These results clearly indicate that IB-MECA and Cl-IB-MECA can exert effects independent of A3 receptor activation.
These findings suggest that the A3 agonists may not be acting selectively; however, it is also likely that CCPA and DPCPX, at the doses used in the present study, were not only occupying A1 receptors. Although binding studies indicate that rat- and rabbit-cloned A3 receptors are relatively insensitive to DPCPX, it is possible that DPCPX partially antagonized the A2a receptor based on the Ki value of DPCPX for the A2a receptor (470 nM) (12). It has also been reported that the Ki value of DPCPX for the human A2b receptor is ~50 nM (21). Our doses of CCPA (100 and 200 nM) could have also activated coronary vasculature A2a receptors. However, there are several studies showing that treatment with an A2a agonist before ischemia does not protect the ischemic heart (5, 16, 35). There is also no evidence that adenosine A2b receptors participate in the cardioprotective effects of adenosine. Finally, it is possible that CCPA could activate A3 receptors, because it has been reported that the A1 agonist cyclopentyladenosine competes with [125I]ABA binding to rabbit-cloned A3 receptors with a Ki value of ~50 nM (9). However, CCPA protection was completely blocked by 100 nM DPCPX, which renders it unlikely that CCPA exerted its effects via A3 receptor activation.
In conclusion, the blockade of IB-MECA and Cl-IB-MECA cardioprotection in rat and rabbit hearts with DPCPX and 8-SPT suggests that these A3 agonist effects are mediated by activation of the A1 and not the A3 receptors. It would appear that until the A3 receptor is identified in cardiac myocytes and more selective A3 agonists and antagonists become available, the exact role (if any) that A3 receptors play in adenosine cardioprotection remains to be determined.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. M. Salik Jahania and Elizabeth Partin for technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-34579 (to R. M. Mentzer, Jr.) and a National American Heart Association Grant-in-Aid (to R. D. Lasley).
Address for reprint requests and other correspondence: R. D. Lasley, Dept. of Surgery, MN 276, U.K. Medical Center, 800 Rose St., Lexington, KY 40536 (E-mail: rlasley{at}pop.uky.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 1 September 2000; accepted in final form 19 February 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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