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Ann Thorac Surg 1996;62:1364-1372
© 1996 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery Research Laboratory, Bowman Gray School of Medicine, Winston-Salem, North Carolina
Accepted for publication May 29, 1996.
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Abstract |
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Methods. Polyadenylic acid (molecular weight, 230,000 daltons) was used as an intravascularly confined adenosine mimetic. In anesthetized New Zealand white rabbits, the left coronary artery was occluded for 30 minutes and reperfused for 120 minutes.
Results. Polyadenylic acid (1 mg/kg bolus, 0.5 mg • kg-1 • h-1) given 5 minutes before reperfusion significantly (p < 0.05) reduced infarct size compared with vehicle (23% ± 2% versus 37% ± 2% area at risk). The A1-antagonist KW-3902 had no effect on this polyadenylic acid-induced protection (17% ± 3%), whereas the A1-A2 antagonist sulfophenytheophylline blocked this infarct size reduction (41% ± 2%). In vitro adherence of platelet-activating factor-activated neutrophils to thoracic aortic endothelium was significantly diminished by polyadenylic acid (185 ± 12 neutrophils/mm2 versus 36 ± 4 neutrophils/mm2 endothelial surface). Sulfophenytheophylline inhibited this effect (280 ± 6 neutrophils/mm2), whereas KW-3902 did not (31 ± 7 neutrophils/mm2).
Conclusions. An intravascular adenosine mimetic agent exerts cardioprotection during reperfusion by targeting receptor-mediated mechanisms in the intravascular compartment, possibly involving inhibition of neutrophil-related processes.
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Introduction |
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This study tests the hypothesis that ADO exerts its cardiac protection during reperfusion by activating receptors within the intravascular compartment, resulting in an attenuation of polymorphonuclear leukocyte (PMN) adherence and diminished myocardial necrosis in an ischemia/reperfusion model. Polyadenylic acid (Poly-A) was used in this study as a high molecular weight ADO mimetic that was confined to the intravascular space.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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FEMORAL ARTERY RINGS.
The direct vascular responses to Poly-A in comparison with ADO were determined in rabbit-isolated femoral artery rings using the organ bath technique. Rabbit femoral artery segments were carefully isolated, trimmed of adipose tissue, cut into 2-mm rings, and mounted on stainless steel hooks in a temperature-regulated organ chamber containing 37°C Krebs-Henseleit solution with the following composition (in mmol/L): NaCl, 118; KCl, 4.7; KH2PO4, 1.2; MgSO4, 1.2; CaCl2, 2.5; NaHCO3, 12.5; and glucose, 10. The Krebs-Henseleit solution was bubbled with 95% O2–5% CO2 and pH was adjusted to 7.4. The vascular rings were connected to isometric force transducers, and changes in isometric force were digitized at 2 Hz using an analog to digital converter (Data Translation, Marlboro, MA). The rings were equilibrated for 1 hour at an optimal tension of 2 g, and precontracted with the thromboxane A2mimetic U46619 (Upjohn Pharmaceuticals, Inc, Kalamazoo, MI). Once a stable contraction was observed, cumulative concentration–relaxation responses to ADO and Poly-A were obtained in the presence and the absence of the A1-A2 antagonist sulfophenyltheophylline (SPT, 500 µmol/L) and the specific A1-receptor antagonist KW-3902 (50 µmol/L) [15]. The in vitro concentrations spanned the range of calculated plasma concentrations of the respective drugs as described previously [15]. Cumulative drug concentrations refer to final organ chamber concentrations. Responses to ADO and Poly-A are calculated as percent cumulative relaxation from the precontraction level.
NEUTROPHIL ISOLATION.
Twenty-milliliter samples of peripheral blood collected from donor rabbits were mixed with 3.0 mL of anticoagulating agents, which included 1.6% citric acid and 2.5% sodium citrate at pH 5.4, and 17 mL of 6% Hespan solution. Neutrophils were isolated as described previously [16]. Using this procedure, final suspensions contained more than 98% neutrophils (hematoxylin/eosin staining) and cell viability was more than 99% as determined by trypan blue exclusion.
NEUTROPHIL ADHERENCE ASSAY.
Alterations in the endothelial cell adherence component of neutrophil activity by Poly-A were assessed using neutrophils labeled with Zynaxis PKH-26 vital fluorescent dye (Zynaxis Cell Science, Inc, Malvern, PA) as described previously [17] for canine neutrophils. The labeling procedure yields cells possessing normal viability and function. Thoracic aorta rings 2 to 3 mm in length were carefully opened without disturbing the endothelium, and placed in 5-mL round cell culture dishes containing 3 mL of Krebs-Henseleit buffer at 37°C. The labeled PMNs (4x106 cells/mL) were randomly divided into the following groups: (1) unstimulated neutrophils (PMNs) alone; (2) PMNs stimulated with platelet-activating factor (PAF, 100 nmol; Biomol, Plymouth Meeting, PA); (3) PMNs, PAF (100 nmol), and Poly-A (1 nmol, 10 nmol, 100 nmol, and 1 µmol in separate groups); (4) PMNs, PAF (100 nmol), Poly-A (100 nmol), and A1-A2 antagonist SPT (100 µmol/L, 200 µmol/L, 500 µmol/L, and 1 mmol/L in separate groups); and (5) PMNs, PAF (100 nmol), Poly-A (100 nmol), and KW-3902 (1 µmol/L, 5 µmol/L, 10 µmol/L, 50 µmol/L). The PMNs were then allowed to incubate for 20 minutes. After incubation, coronary segments were removed and dipped in fresh Krebs-Henseleit solution three times with the endothelium side up to wash off nonadherent PMNs. Adherence was determined by the number of PMNs adhering to the endothelial surface in six separate fields of each arterial segment under epifluorescence microscopy (490 nm excitation, 504 nm emission) using a calibrated grid to measure surface area of the field. The adherent PMNs were summed for each segment and are expressed as numbers of PMN/mm2 of segment.
In Vivo Studies
SURGICAL PREPARATION OF ANIMALS.
Male New Zealand White rabbits weighing 4 to 5 kg were anesthetized with an intramuscular injection of ketamine HCl (35 mg/kg) and xylazine (6 mg/kg). The right femoral artery and vein were cannulated for intravenous administration and arterial pressure monitoring. A continuous infusion of anesthesia (25 mg/mL of ketamine and 25 mg/mL of xylazine) was administered throughout the experiment by a Harvard infusion pump at 1.0 mL/h through a double-lumen femoral vein catheter. The trachea was exposed through a midline incision in the ventral neck and intubated. The rabbit was ventilated with oxygen-enriched room air to maintain arterial oxygen tension more than 100 mm Hg. Arterial carbon dioxide tension was maintained near 35 mm Hg, and acidemia was corrected with sodium bicarbonate as needed. The heart was exposed through a median sternotomy, and the pericardium was opened. A 4-0 Prolene suture with a tapered needle (Ethicon Somerville, NJ) was passed around a branch of the left coronary artery, and the ends of the sutures were passed through a short polyvinyl (PE90) tube to form a snare. A bolus of sodium heparin (300 U/kg) was given intravenously and the rabbit was allowed to stabilize hemodynamically for 10 to 20 minutes.
PREPARATION AND DOSAGE OF DRUGS.
The ADO A1-A2-receptor antagonist 8-p-sulfophenyltheophylline (SPT; Research Biochemical, Inc, Natick, MA) and the large ADO moiety, Poly-A (molecular weight >200,000 [average for lot used = 230,000] Sigma, St. Louis, MO) were prepared by mixing the powder with 5 mL of 0.9% saline solution at 37°C just before injection. Each Poly-A molecule has one ADO moiety that can interact with ADO receptors. Poly-A was given as an initial bolus of 1 mg/kg over 5 minutes followed by an infusion of 0.5 mg • kg-1 • h-1. To select a dosage of Poly-A, we compared its effects with ADO on segments of vascular rings as well as the in vivo hemodynamic changes induced in the dose–response study. A dose of 20 mg/kg body weight SPT was used to block ADO receptors. This dose of SPT was sufficient to completely abolish the in vivo hypotensive effects of Poly-A. The A1 selective ADO receptor antagonist, 8-(3-noradamantyl)-1,3-dipropylxanthine (KW-3902, Kyowa Hakko Kogyo, Japan), was dissolved in 100 µL of ethyl alcohol and 50 µL of 1.0 N NaOH, and then diluted with 2 mL of 0.9% saline solution at 37°C to achieve a final concentration of 2 mg/mL. The amount of KW-3902 used (50 µmol/L, approximating the in vivo plasma concentration of 1 mg/kg) was selected from an earlier study where this amount completely blocked the negative inotropic effects of R-PIA (a predominately A1 agonist) up to concentrations of 100 µmol/L in both an in vivo and in vitro model [15]. The ethyl alcohol–NaOH vehicle used with KW-3902 had no effect on infarct size compared with saline solution.
Experimental Protocol
After a 10- to 20-minute postsurgical stabilization period, animals were randomized to one of four groups: (1) saline vehicle (n = 14): rabbits received saline infusion 5 minutes before reperfusion; (2) Poly-A treatment (n = 15): a subhypotensive dose of Poly-A (1 mg/kg bolus over 5 minutes, then 0.5 mg • kg-1 • h-1) was infused intravenously 5 minutes before coronary reperfusion and discontinued 60 minutes after initiation of reperfusion; (3) Poly-A treatment plus SPT blockade (SPTPA, n = 10): SPT (20 mg/kg bolus) was infused 2 minutes before initiation of Poly-A treatment; (4) Poly-A treatment plus A1-receptor blockade (KWPA, n = 8): KW-3902 (1 mg/kg bolus) was infused 2 minutes before initiation of Poly-A treatment. A subhypotensive dose of Poly-A was determined in a pilot study using mean arterial pressure as the primary end-point.
In all groups, steady-state hemodynamic data were acquired at baseline as well as before and after infusion of SPT and Poly-A to determine any drug effects on hemodynamic variables (heart rate [HR], mean arterial pressure [MAP], and systolic blood pressure). The left coronary artery was then reversibly occluded by tightening the snare to produce a zone of regional ischemia in the left ventricle. Ischemia was confirmed visually by cyanosis and dyskinesis in the area at risk. Previous blood flow analysis with radiolabeled microspheres showed that regional coronary artery occlusion produced a 98% reduction in blood flow to the area at risk in the rabbit [8]. Hemodynamic data were again collected after 25 (predrug) and 30 minutes (postdrug) of ischemia. After 30 minutes of coronary occlusion, the left coronary artery snare was released to allow reperfusion for a total of 120 minutes. Hemodynamic data were measured at 15, 30, 60, and 120 minutes of reperfusion.
Determination of Area at Risk and Infarct Size
Upon completion of 120 minutes of reperfusion, the coronary artery snare was retightened and 4 to 6 mL of 20% Unisperse Blue dye (Ciba-Geigy, Summit, NJ) was injected into the left main atrium through a 25-gauge needle. This procedure stained the normally perfused area and thereby demarcated the area at risk by dye exclusion. After the blue dye had circulated sufficiently to stain the perfused myocardium homogeneously, 2 mg of sodium pentobarbital was injected into the left atrium and allowed to circulate briefly, and the heart was rapidly excised. The left ventricle was isolated from the rest of the heart and was cut into transverse slices approximately 2 mm thick. The normal area (stained blue) was separated from the area at risk. The area at risk was then placed in a 37°C solution of 1% triphenyltetrazolium chloride (Sigma Chemical, St. Louis, MO) for 10 minutes. The triphenyltetrazolium chloride-stained (noninfarcted) tissue was separated from the pale (necrotic) tissue and each respective area was weighed. The area at risk was calculated as the sum of the noninfarcted and necrotic weight of the tissue perfused by the occluded vessel, divided by the weight of the left ventricle and expressed as a percentage. The area of necrosis was calculated as the weight of necrotic tissue divided by the weight of the left ventricle and expressed as a percentage. Area of necrosis/area at risk was calculated by dividing the weight of the necrotic tissue by the weight of the total area at risk.
Data Acquisition
Femoral arterial pressures were digitized at 250 Hz using a 12-bit analog to digital converter (Data Translation, Marlboro, MA) and stored on hard disk using a videographics program developed in our laboratory. Pressure waveforms were visually displayed, and dysrhythmic beats were excluded. The HR, peak systolic pressure, end-diastolic pressure, and MAP were averaged from no less than 15 beats. Pressure–rate product, used as an index of myocardial oxygen demand, was calculated as the product of HR and peak systolic pressure.
Microdialysis Studies
Interstitial purines were measured in a separate series of experiments by microdialysis [18] as described previously [19]. The microdialysis probe was implanted into the myocardial area at risk to a midmyocardial depth and immediately connected to a gas-tight glass syringe mounted on a microprocessor-controlled precision syringe pump (Pump 22; Harvard Apparatus, South Natick, MA). The dialysis cannula was continuously perfused with deaerated Krebs-Henseleit buffer at a rate of 2.0 µL/min. An additional dialysis catheter was placed so that the dialysis membrane was positioned in the cavity of the right ventricle to simultaneously compare right ventricular chamber (mixed venous) blood purine levels, including the return from the coronary sinus. The dialysis catheters were allowed to stabilize for 70 minutes before the experimental protocol was begun. At the end of the experiment, the heart was dissected to verify the position of the dialysis probes. Purine levels were measured in three of the groups as previously defined: saline solution (n = 6), Poly-A (n = 6), and SPTPA (n = 6) where n = rabbit used in these microdialysis experiments.
Dialysate samples were assayed for ADO, inosine, hypoxanthine, and xanthine by high performance liquid chromatography, using a Supelcosil LC-18S column (Supelcosil, Inc., Bellefonte, PA) and a 1% (pH 5.3) to 25% (pH 5.58) methanol in 100 mmol/L KH2PO4 gradient. Purine nucleosides were determined using external standards to quantify the compounds of interest. Assays were performed by Dr Van Wylen at the Department of Biology, St. Olaf College, Northfield, Minnesota.
Criteria for Exclusion
Standard exclusion criteria were (1) poor ischemia observed as lack of cyanosis and dyskinesia and/or poor reperfusion by lack of hyperemia or appearance of cyanotic banding, (2) poor demarcation of the area at risk during Unisperse blue staining, (3) ventricular fibrillation that did not convert spontaneously within 30 seconds or after three cardioversion shocks, (4) failure to complete the entire protocol, (5) extremely large (more than 50% area at risk producing hemodynamic instability) or small (less than 15% area at risk) areas at risk, and (6) misplacement of the microdialysis catheter in the left ventricular free wall or cavity of the right ventricle in the microdialysis studies.
Statistical Analysis
Analysis of variance for repeated measures was used to determine if time- and group-related differences occurred in the hemodynamic and purine data. If significant group/time interactions were found, Duncan's multiple range test was applied to locate the sources of differences. One-way analysis of variance was used to analyze overall group differences in infarct size variables followed by Duncan's post hoc test to determine group differences. A p value of less than 0.05 was accepted as statistically different. Results are reported as mean and standard error of the mean.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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. Poly-A relaxed the vascular rings in a cumulative concentration-dependent manner. Complete relaxation was achieved at 1.11 µmol/L Poly-A and the concentration of Poly-A required to achieve 50% of maximal relaxation (EC50) was 0.11 µmol/L. Maximum relaxation was achieved at lower doses of Poly-A compared with ADO, the latter of which showed a right shift in the concentration–response curve relative to Poly-A. SPT (approximating the in vivo concentrations used in the study) significantly inhibited the maximum vasodilator response of Poly-A, with the maximum relaxation averaging 39% ± 5% at 1.1 µmol/L Poly-A (p < 0.05% versus ADO). KW-3902 at a concentration that also approximated the calculated plasma concentration (50 µmol/L), did not antagonize the vasodilator effect of Poly-A, thereby inferring an A2-mediated vasodilator response to Poly-A.
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). However, stimulation of the PMNs with PAF resulted in a significant fourfold increase in adherence. Poly-A treatment resulted in a dose-dependent attenuation of PMN adherence to the endothelium although even the lowest dose (1 nmol/L) resulted in 80% attenuation of adherence of PAF-stimulated PMNs relative to the PMN + PAF group (Fig 2, top). A1 antagonism with KW-3902 had no effect on the attenuated PMN adherence in Poly-A-treated segments (Fig 2, middle). SPT reversed the inhibitory effect of Poly-A in a dose-dependent manner up to 500 µmol/L (Fig 2, bottom). Concentration of SPT (1 mmol/L) did not result in any further increase in adherence compared with 500 µmol/L. Both the 500 µmol/L and the 1 mmol/L SPTPA groups showed a significant increase not only over unstimulated PMNs but also over PAF-stimulated PMNs (PMN + PAF), suggesting inhibition of basally released endogenous ADO.
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Hemodynamic data in all groups are summarized in Table 1. Hemodynamic variables were comparable among the groups at baseline and at 25 minutes of ischemia before any drugs were administered. However, in all groups HR significantly increased during this time (p < 0.05). The HR remained relatively constant during reperfusion in all groups. There was a tendency for HR to decrease (p > 0.05) after 15 minutes of reperfusion. After 120 minutes of reperfusion, HR was significantly lower in the Poly-A group compared with the SPTPA group. There were no differences at any time period in the other groups. There were no differences in the MAP among groups at baseline or through the end of ischemia. The bolus of Poly-A just before reperfusion significantly lowered MAP, which remained at this lower level for the remainder of the experiment, whereas the MAP of the remaining groups showed more of a gradual decline during reperfusion. By the end of reperfusion, MAP was comparable among groups. The pressure–rate product at baseline and during ischemia was similar among the groups. Poly-A infusion resulted in a significantly lower pressure–rate product than SPTPA, but not when compared with any of the other groups. This difference was no longer present by the end of reperfusion as the pressure–rate product of the SPTPA group progressively diminished. No significant difference existed between Poly-A and the vehicle group at any time point, although pressure–rate product in the Poly-A group tended to be lower. Changes in hemodynamic parameters were not predictive of group differences in infarct size.
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. Left ventricular mass was similar in all groups with the exception of the KWPA group in which the mass was slightly, but significantly, less than in the other groups. The area placed at risk by coronary occlusion ranged between 36.4% ± 3.1% and 29.4% ± 2.0% of the left ventricular mass; there was no statistical difference among groups in the area at risk whether expressed as absolute mass (Table 2) or as a percentage of the left ventricular mass (Fig 3, top). When necrosis was expressed as absolute mass, infarct size was significantly lower in the Poly-A and KWPA groups compared with vehicle, whereas SPT reversed the infarct size reduction observed in either group receiving Poly-A (Fig 3, middle). Although the SPT-treated group tended to have a higher area of necrosis than the vehicle, this did not reach significance.
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, bottom. Poly-A treatment significantly reduced infarct size compared with vehicle. This reduction in myocardial necrosis with Poly-A was unaffected by A1-receptor blockade. SPT treatment completely reversed the observed protection with Poly-A. Although the area of necrosis/area at risk was slightly higher for the SPT group compared with control, this did not reach significance.
Microdialysis Data
Dialysate values reported are absolute concentrations in the dialysate not corrected for efficiency of recovery. Previous work in our laboratory using a flow rate of 2 µL/min demonstrated a 28.6% recovery of ADO, 26.6% recovery of inosine, 42.3% recovery of hypoxanthine, and 36.8% recovery of xanthine. Transmural placement of the microdialysis probe was consistent among the three groups in which the technique was used (vehicle, Poly-A, and SPTPA), averaging 47.5% ± 4.8% of epicardial-to-endocardial distance for Poly-A, 49.0% ± 6.0% for vehicle, and 51.0% ± 4.0% for SPTPA. Figure 4 shows purine concentrations in the interstitium of the area at risk during baseline, ischemia, and reperfusion periods for the three groups. In the vehicle group interstitial ADO levels significantly increased from baseline during ischemia, and by 30 minutes of reperfusion had returned to baseline values. There were no significant group differences during ischemia as drugs were not given until reperfusion. Poly-A infusion at reperfusion did not significantly alter the ADO recovered from the interstitium at any time point compared with vehicle. Although the SPTPA group had a somewhat lower total amount of dialysate ADO, this was never significantly different from either of the other two groups. Similar temporal and group profiles were observed for hypoxanthine, inosine, and total purines. Time-related changes were not observed for xanthine or uric acid. The purine concentrations measured in the plasma (Fig 5) were generally lower than those seen in the interstitium at baseline and end of reperfusion (Fig 4), especially for ADO, hypoxanthine, inosine, and total purines. Although the plasma ADO concentrations remained relatively stable throughout ischemia and reperfusion, there was a significant elevation in the plasma concentration measured at 120 minutes of reperfusion in each group (Fig 5). However, neither Poly-A infusion nor SPT treatment altered the plasma ADO concentrations compared with vehicle. Group or time-related differences were not observed in the other variables.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Poly-A has a molecular weight of more than 230,000 daltons, and contains a single vasoactive moiety at its 3` end. Using a macromolecular ADO congener avoids the spillover of ADO into the interstitial compartment. The ADO mimetic actions of Poly-A were confirmed in the present study by dose-dependent relaxation of femoral artery in agreement with a study by Schrader and colleagues [20]. This vasodilation was antagonized by SPT, but not by the A1-specific antagonist KW-3902, consistent with the known A2-mediated vasodilation by ADO. The interstitial and plasma microdialysis data from the present study confirm that Poly-A was not degraded to ADO in vivo, and did not alter the release pattern of ADO during ischemia and reperfusion, and is consistent with earlier reports demonstrating that Poly-A remains in the vascular space. However, the large molecular weight of Poly-A prevented sampling of the macromolecule by dialysis, particularly in the area at risk, to rule out transendothelial migration in this area of microvascular damage. In addition, the probe measuring mixed venous plasma purines may have underestimated ADO levels in the coronary microcirculation because of rapid deamination.
Infusion of Poly-A 5 minutes before reperfusion caused a small but significant decrease in mean arterial pressure (approximately 10 mm Hg), which was not seen in the group cotreated with Poly-A and the antagonist SPT. However, hemodynamic variables, including the pressure–rate product were comparable in all groups during ischemia. This suggests that the severity of ischemia may have been similar among groups, barring differences in collateral blood flow. However, our previous studies demonstrate little variability in collateral blood flow in rabbits, and collateral blood flow shows an insensitivity to antagonists of endogenously released ADO (ie, SPT) [8, 15, 21]. Although the pressure–rate product was significantly less in the Poly-A-treated group at 15 minutes of reperfusion, there has been no correlation between levels of pressure–rate product or its components during reperfusion and infarct size as there has been for these variables during ischemia. Therefore, it is highly unlikely that a decrease in the pressure–rate product during reperfusion would contribute to infarct size reduction in the Poly-A group.
Neutrophils play an important role in ischemic reperfusion injury in the myocardium [22]. Adenosine inhibits superoxide anion production directly by activated neutrophils [12, 23, 24], and inhibits both adherence to endothelium [11, 24] and endothelial adherence-dependent superoxide anion production [24]. This inhibition of neutrophil function has been attributed to ADO A2-receptor-mediated processes [24]. In agreement with these observations, Poly-A reduced PAF-stimulated adherence to coronary artery endothelium by receptor-mediated processes. The lack of antagonism to ADO's inhibition of PMN adherence by a specific A1-antagonist (at doses that inhibited catecholamine-stimulated positive inotropy in papillary muscle preparations [15]) suggests principally an A2-mediated effect. Therefore, Poly-A had properties similar to those of ADO regarding inhibition of neutrophil adherence to coronary vascular.
In summary, in light of the confinement of Poly-A to the intravascular compartment, and the lack of change in interstitial ADO concentrations accompanying treatment with Poly-A, the data suggest that the reduction of infarct size by the macromolecular ADO congener may be due to its effects in the intravascular compartment. Furthermore, blockade of this protection by SPT suggests receptor-mediated effects, specifically of the A2 subtype. Direct confirmation of this inference is hampered by the lack of a water-soluble A2-antagonist suitable for in vivo use. This study adds further support to the concept that ADO exerts infarct size-reducing effects by inhibition of receptor-mediated events during the early reperfusion period. This cardioprotection may involve inhibition of neutrophils and possibly the vascular endothelium. Furthermore, this study highlights the vascular compartment as a primary site of these cardioprotective mechanisms of ADO. In vivo, the vascular endothelium is uniquely positioned to play a pivotal role in this protection in the vascular compartment by being a significant source of ADO [25], as well as being an efficient barrier in the transport of ADO between vascular and interstitial compartments. The concentration of ADO achieved at the margins of the blood laminar flow pattern (ie, the unstirred layer) or in the microenvironment created by closely juxtaposed neutrophils and endothelial cells is unknown, but may exceed measured plasma or interstitial values. More important, pharmacologic augmentation of endothelially derived ADO by regulating agents or other modulators of ADO concentrations may represent an important therapeutic approach in targeting nonsurgical and surgical reperfusion injury in a compartment that participates dramatically in its genesis and perpetration. The direct clinical application of Poly-A may be limited by its relatively potent vasodilator effect and its prolonged half-life compared with ADO.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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G.-L. Liu, T. A. Christopher, B. L. Lopez, F. Gao, Y. Guo, E. Gao, K. Knuettel, M. Feelisch, and X. L. Ma SP/W-5186, A Cysteine-Containing Nitric Oxide Donor, Attenuates Postischemic Myocardial Injury J. Pharmacol. Exp. Ther., November 1, 1998; 287(2): 527 - 537. [Abstract] [Full Text]
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p <0.05 versus control.)
