Am J Physiol Heart Circ Physiol 288: H2763-H2769, 2005.
First published January 21, 2005; doi:10.1152/ajpheart.00657.2004
0363-6135/05 $8.00
Preconditioning of salvaged myocardium in conscious rabbits with postinfarction dysfunction
Karim Aouam,1,2,3,5,*
Renaud Tissier,1,2,3,*
Patrick Bruneval,4
Chantal Mandet,4
Alain Berdeaux,1,2,3 and
Bijan Ghaleh1,2,3
1Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 660, Créteil; 2Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort; 3Fédération de Cardiologie de l'hôpital Henri Mondor, Créteil; and 4INSERM, Unité 652, Institut des Cordeliers, Paris, France; and 5Laboratoire de Pharmacologie, Faculté de Médecine de Monastir, Tunisia
Submitted 2 July 2004
; accepted in final form 11 January 2005
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ABSTRACT
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Protection against postinfarction myocardial dysfunction is modest with classic preconditioning (PC). We investigated whether multiple cycles of PC could improve this protection and whether postinfarction dysfunction only depends on the amount of viable tissue. Eighteen rabbits were chronically instrumented with coronary occluders and ultrasonic crystals (segment shortening, SH) in the ischemic zone. A control group underwent 30-min coronary artery occlusion (CAO) with 72-h reperfusion (CAR). In two other groups, PC was induced by six 4-min CAO/4-min CAR cycles (PCx6) or one 5-min CAO/10-min CAR cycle (PCx1). After 72-h CAR, depression in SH was reduced in PCx1 (–68 ± 7% from baseline) and to a greater extent in PCx6 (–18 ± 10%) vs. control (–99 ± 7%; all P < 0.05). Infarct sizes were reduced in PCx1 (15 ± 2%) and to a greater extent in PCx6 (3 ± 1%) vs. control (46 ± 5%; P < 0.05). Contractility of salvaged myocardium was evaluated by calculating the ratio between SH at 72-h CAR and the amount of viable tissue. This index was enhanced in PCx1 (0.39 ± 0.07, P < 0.05) and to a greater extent in PCx6 (0.82 ± 0.09) vs. control (0.0 ± 0.10). This differential effect of PC was not related to changes in apoptosis, endothelial nitric oxide synthase (NOS) expression, or macrophages infiltration but, rather, to blunted inducible NOS expression in PCx6 vs. control and PCx1. Thus multiple cycles of PC induced an almost complete protection against postinfarction dysfunction, potentially involving beneficial effects on salvaged myocardium.
contractility; ischemia; cardioprotection; nitric oxide synthase
ALTHOUGH IT IS WELL DOCUMENTED that early ischemic preconditioning strongly reduces myocardial infarct size induced by long periods of coronary artery occlusion (8), several studies have demonstrated that this effect is not associated with a concomitant improvement in regional contractile function during the first hours of reperfusion (6, 10). With longer periods of reperfusion, the recovery of myocardial function is enhanced in conscious preconditioned rabbits, but this recovery is disproportionately small compared with the degree of corresponding tissue salvage (3, 10). Because these reports investigated only one type of ischemic preconditioning, we hypothesized that different preconditioning protocols might induce differential functional recovery. Indeed, the critical effect of the number of occlusion-reperfusion cycle is widely recognized.
Accordingly, chronically instrumented conscious rabbits were subjected to a 30-min coronary artery occlusion (CAO) followed by 3 days of reperfusion (CAR) (13). Using this model, we compared the infarct-sparing and functional effects of two ischemic preconditioning stimuli, i.e., 1) one cycle of 5-min CAO and 10-min CAR and 2) six cycles of 4-min CAO and 4-min CAR. The functional measurements were performed using sonomicrometry. Finally, macrophage infiltration, apoptosis, and endothelial and inducible isoforms of nitric oxide synthase (eNOS and iNOS, respectively) expression were investigated using immunohistochemistry.
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METHODS
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The animal instrumentation and the ensuing experiments were performed in accordance with French official regulations.
Animal surgery.
Male New Zealand White rabbits (2–2.5 kg) were anesthetized with a mixture of tiletamine (25 mg/kg iv) and zolazepam (25 mg/kg iv), intubated, and mechanically ventilated. Subsequent anesthesia was maintained with 2% isoflurane. An external electrocardiogram (ECG) was recorded during the surgery. A left thoracotomy was performed under sterile conditions at the fourth intercostal space. A pneumatic occluder manufactured from 18-gauge Tygon tubing was implanted around a major branch of the left coronary artery as previously described (13). A pair of 1-mm ultrasonic piezoelectric crystals (Sonometrics, London, ON, Canada) was inserted in the ventricular wall that would become ischemic with balloon inflation. The chest was closed in layers, and a small tube was left in the thorax to evacuate the air and fluids after surgery. Internal ECG leads were attached to the intercostal muscles. The occluder, internal ECG, and crystal wires were exteriorized between the scapulae. During the postoperative period, rabbits received buprenorphine (0.02 mg·kg–1·day–1 sc) and flunixine meglumate (1 mg·kg–1·day–1 im) for analgesia as well as gentamicin (0.5 mg·kg–1·day–1 im). Rabbits were allowed to recover for a minimum of 10 days after surgery.
Hemodynamic measurements.
Data were digitized on a computer and analyzed using the data acquisition software HEM (v3.4; Notocord Systems, Croissy-sur-Seine, France). Heart rate was determined from the ECG recording. Regional segment length was measured by connecting the crystal wires to a sonomicrometer (TRX-4; Sonometrics). Percent segment shortening was calculated from the segment length recordings and defined as end-diastolic minus end-systolic segment lengths divided by end-diastolic segment length, multiplied by 100.
Experimental protocol.
After recovery from surgery, rabbits were randomized into three groups: control, PCx6, and PCx1 (Fig. 1). The PCx6 group underwent a sequence of six successive 4-min CAO/4-min CAR cycles, and the PCx1 group was subjected to a single cycle of 5-min CAO/10-min CAR. CAO and CAR were induced by manually inflating and deflating the balloon occluder, respectively. After completion of the preconditioning stimuli, the animals underwent a 30-min CAO followed by 72-h CAR. ECG and segment length were recorded before (baseline) and throughout the preconditioning protocol as well as during the 30-min CAO and the first 3 h of subsequent reperfusion. Additional recordings were performed at 24, 48, and 72 h of reperfusion.
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Fig. 1. Experimental protocols. PCx6, preconditioning with 6 cycles of 4-min coronary artery occlusion (CAO) and 4-min coronary artery reperfusion; PCx1, preconditioning with 1 cycle of 5-min CAO and 10-min coronary artery reperfusion.
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Determination of myocardial area at risk and infarct size.
After completion of reperfusion, the animals received an injection of heparin and were anesthetized with pentobarbital sodium (50 mg/kg iv). Potassium chloride was administered intravenously to induce cardiac arrest. The hearts were excised, and the previously occluded coronary artery was ligated. The ascending aorta was cannulated and perfused (120 mmHg) retrogradely with saline followed by Evans blue (1%). The right ventricle was then removed, and the left ventricle was cut into thin slices that were weighed and incubated in 1% triphenyltetrazolium chloride (TTC) in a pH 7.4 buffer for 15 min at 37°C to identify the infarcted myocardium. Slices were fixed overnight in 10% formaldehyde and then photographed with a digital camera. Using a computerized planimetric program (Scion Image; Scion, Frederick, MD), the area at risk and the infarcted zones were quantified. The area at risk was identified as the non-blue region and was expressed as a percentage of the left ventricle weight. Infarcted area was identified as the TTC negative zone and was expressed either as a percentage of the area at risk or as a percentage of the left ventricle weight.
Histological studies.
To determine myocardial infarction between the crystals, we analyzed the formalin-fixed samples between the crystals using histology. As previously described (13), histological sections were cut from each slice and stained with hematoxylin-eosin. For morphometry, all stained sections were observed with a microscope at a x2 magnification. Successive digital photographs of the adjacent microscopic fields encompassing the whole sample were recorded. A computerized reconstruction (Photoline; Computerinsel, Bad Gögging, Germany) of the complete section at a x2 magnification was made by adequate juxtaposition of the different and complementary digital photographs. Infarct was delimited from this photographic reconstitution by drawing its contours with a computer mouse. Simultaneous observation of the histological section on a microscope at x4 or x10 magnification allowed an accurate detection of the infarcted area, yielding high sensitivity in delimiting the infarcted area. Myocardial infarction was considered a central region of coagulation necrosis with a border of myocytolysis and inflammatory infiltration in a granulation tissue. It was adjacent to myocardium exhibiting a normal appearance and was considered living myocardium. Finally, planimetry was performed, and infarct sizes between crystals were measured.
TdT-mediated dUTP nick end labeling and immunohistochemistry.
Detection of apoptosis using the TdT-mediated dUTP nick end labeling (TUNEL) technique and of macrophages as well as eNOS and iNOS expressions using immunohistochemistry was performed on paraffin tissue sections from all rabbits that completed the experimental protocol. TUNEL ApopTag kit (Q. Biogene, Carlsbad, CA), RAM11 antibody against rabbit macrophages diluted at 1:30 (Dako, Trappes, France), and anti-eNOS and anti-iNOS antibodies diluted at 1:50 (Becton Dickinson Biosciences PharMingen, San Diego, CA) were used in accordance with TUNEL or immunohistochemical procedures as previously described (1, 12).
Combined immunofluorescence for confocal laser microscopy.
To assess the precise type of iNOS-expressing cells, we performed double labeling of tissue sections as previously described (1, 2). Briefly, anti-iNOS antibody was revealed in a first step by using anti-rabbit biotinylated antibody and streptavidin-cyanin-2 (Amersham, Les Ulis, France). In a second step, either anti-desmine (cardiomyocyte marker) or anti-CD31 (endothelial cell marker) monoclonal antibodies (Dako) were used and revealed using anti-mouse antibody labeled with cyanin-3 (Amersham). The sections were observed with a confocal microscope Leica TCS SP (Leica Microsystems, Heidelberg, Germany). These experiments were performed in sections from rabbits of the control and PCx1 groups, because no iNOS expression was observed in the PCx6 group.
Data analysis.
Values are expressed as means ± SE. Infarct sizes, areas at risk, and ventricular weights were compared using one-way ANOVA followed, if necessary, by a Student's t-test with Bonferroni correction. Heart rate and segment shortening values were compared using two-way ANOVA with repeated measures followed, if necessary, by Student's t-test with Bonferroni correction. Significant differences were determined as P < 0.05.
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RESULTS
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Thirty chronically instrumented conscious rabbits were subjected to CAO. Ten were excluded after ventricular fibrillation, i.e., three control, four PCx6, and three PCx1 rabbits. Two other rabbits, i.e., one control and one PCx1 rabbit, also were excluded for technical reasons (lost of sonomicrometric contractility signals). Finally, 18 rabbits successfully completed the protocol: 6 control, 6 PCx1, and 6 PCx6 rabbits.
Hemodynamics.
There were no significant differences in heart rate values among the three groups of rabbits at baseline (209 ± 10, 207 ± 8, and 213 ± 13 beats/min for control, PCx1, and PCx6 groups, respectively) and during CAO and CAR.
Area at risk and infarct size.
Left ventricle weights were not different among control, PCx6, and PCx1 groups (4.3 ± 0.4, 4.2 ± 0.3, and 4.7 ± 0.2 g, respectively). Sizes of areas at risk also were similar among the three groups of rabbits (29 ± 4, 33 ± 5, and 38 ± 4% for control, PCx6, and PCx1 groups, respectively). As shown in Fig. 2A, infarct sizes were significantly reduced in the PCx6 and PCx1 groups compared with the control group. Furthermore, infarct size was significantly lower in the PCx6 compared with the PCx1 group.
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Fig. 2. A: infarct sizes (expressed as %area at risk) measured after 72 h of coronary artery reperfusion using the triphenyltetrazolium chloride technique. Open and filled circles indicate individual and average values, respectively. B: scatterplots of the relationship between infarct sizes and areas at risk (both expressed as %left ventricular weight). Regression lines are represented for each group. *P < 0.05 vs. control.  P < 0.05 vs. PCx1.
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Because infarct size depends on the size of the area at risk, the effects of the two preconditioning protocols also were investigated by plotting these two parameters expressed as percentages of the left ventricle (15). As shown in Fig. 2B, regression lines between infarct size and the size of the area at risk were shifted downward in both the PCx6 and PCx1 groups compared with the control group. Moreover, the downward shift was significantly greater for the PCx6 compared with the PCx1 group.
Regional contractility.
The baseline values of segment shortening were not significantly different among the three groups of rabbits (12.5 ± 3.0, 12.7 ± 0.7, and 14.3 ± 2.0% for control, PCx6, and PCx1 groups, respectively). As shown in Fig. 3, segment shortening was strongly and similarly depressed in the three groups throughout CAO and during the first 3 h of reperfusion, except at 5 min of CAR, when it was significantly greater in the PCx6 compared with the control group. From 24 to 72 h of CAR, segment shortening values were significantly enhanced in the PCx6 and PCx1 groups compared with the control group. At 48 and 72 h, the depression of segment shortening was significantly lower in the PCx6 (–42 ± 9 and –18 ± 10% from baseline, respectively) compared with the PCx1 group (–73 ± 4 and –68 ± 7% from baseline, respectively).
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Fig. 3. Evolution of segment shortening expressed as the percent change from baseline for control and preconditioned groups. PC, preconditioning. *P < 0.05 vs. control. P < 0.05 vs. PCx1.
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Histology.
The overall histological pattern of the intercrystal myocardium sections was similar for all rabbits among the three groups. Indeed, all infarcts consisted of a core of patent myocyte coagulation necrosis with some residual hemorrhage and edema. They were limited by a clear-cut border of detersion with granulation tissue and inflammation. Finally, no alteration was observed in the salvaged tissue. Individual infarct sizes between the crystals were plotted against the segment shortening recovery as shown in Fig. 4. A significant nonlinear inverse relationship was demonstrated between these two parameters (y = –106 + 88e–17/x; r = 0.87, P < 0.05).
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Fig. 4. Relationship between segment shortening measured at 72 h of coronary artery reperfusion (expressed as %variation from preischemic value) and infarct size (measured between crystals by histology).
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Infarct sizes also were specifically quantified in the subendocardium and in the subepicardium. Compared with those in control rabbits, subendocardial infarct sizes were significantly decreased in the PCx1 group (52 ± 8 vs. 28 ± 7%, respectively, P < 0.05) and, to a greater extent, in the PCx6 group (1 ± 1%, P < 0.05). However, subepicardial infarct sizes were similarly decreased in the PCx1 (4 ± 2%) and PCx6 groups (2 ± 1%) compared with the control group (24 ± 8%, P < 0.05).
TUNEL and immunohistochemistry.
As shown in Fig. 5, the overall pattern regarding RAM11- and TUNEL-positive cells was similar in all myocardial intercrystal sections provided by the three groups. Macrophages defined as RAM11-positive cells and apoptotic cells defined as TUNEL-positive cells mainly were observed in the detersion border zone of infarction. In contrast, neither RAM11- nor TUNEL-positive cells were observed in the salvaged tissue.
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Fig. 5. TdT-mediated dUTP nick end labeling (TUNEL) and immunohistochemical labeling patterns in the 3 groups for detection of apoptosis, macrophage infiltration, and inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression. Top row: with TUNEL, apoptosis was not detected in the living myocardium surrounding the infarcted area in any group. In the granulation tissue (arrows) and the necrotic core (star), brown labeling was observed, consistent with background or necrosis in the infarcted area and occasional apoptosis of inflammatory cells in the granulation tissue (arrowheads). Bars = 40 µm. 2nd row: with RAM11 immunohistochemistry, the macrophagic inflammatory infiltration (red spots) was mainly detected in the granulation tissue (arrows) surrounding the infarcted area (star). Few macrophages were present in the infarcted necrotic area, but macrophagic infiltration was not observed in the adjacent living myocardium. Bars = 80 µm. 3rd row: use of immunohistochemistry showed that iNOS was expressed in the endothelium (arrows) of large subepicardial coronary arteries in the control and PCx1 groups but not in the PCx6 group. Bars = 80 µm. 4th row: iNOS was detected in the microvessels of the living myocardium, including arterioles and capillaries (arrows), in the control and PCx1 groups but not in the PCx6 group. Bars = 20 µm. Bottom row: use of immunochemistry showed that eNOS was equally expressed among groups in the endothelium (arrows) within the microcirculation and the macrocirculation in small- or large-sized coronary arteries. Accordingly, only 1 representative image is shown for each kind of vessel among the 3 groups, i.e., microcirculation for control group (left; bar = 30 µm), small-sized coronary artery for PCx1 (middle; bar = 30 µm), and large-sized coronary artery for PCx6 (right; bar = 15 µm).
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Inducible NOS was differentially expressed among the three experimental groups. First, iNOS-positive cells were observed in the detersion border of infarction in macrophagic cells in the three groups. Second, intensive iNOS expression was observed in salvaged tissue in both the control and PCx1 groups but was almost absent in the PCx6 group. This expression was observed in the endothelium of large vessels and in the interstitium. This interstitial expression of iNOS appeared to be related to the microvascular endothelium, because no macrophage infiltration was observed in the salvaged tissue. In the three groups, no iNOS immunostaining was observed in the cytoplasm of salvaged cardiomyocytes. Finally, eNOS expression was similarly observed among groups in the endothelium of micro- and macrovessels.
Combined immunofluorescence.
No colocalization was observed between cardiomyocytes and iNOS expression (Fig. 6A), with iNOS expressed only in the interstitium adjacent to cardiomyocytes. Conversely, a colocalization was observed between iNOS expression and endothelial cells, in both large (Fig. 6B) and small coronary arteries (Fig. 6C) and in the microcirculation (Fig. 6D). This pattern was similarly observed in both the control and PCx1 groups. However, one cannot rule out iNOS synthesis in cardiomyocytes at very low levels, i.e., below the threshold of detection of immunochemistry.
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Fig. 6. Combined immunofluorescence. iNOS expression (left) was matched to cell markers to determine precisely which cell type actually produced iNOS. Detection of iNOS is indicated in green (cyanin-2). Detection of desmine and CD31 is indicated in red (cyanin-3). No colocalization was observed with the cardiomyocyte marker desmine (A). A colocalization was observed with the endothelial cell marker CD31 in large-sized coronary arteries (B), in small-sized coronary arteries (C), and in microcirculation (D). Bars = 50 µm in A and B; bars = 25 µm in C and D. Images were taken from a control rabbit heart. The observed pattern was similar in PCx1 hearts.
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DISCUSSION
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The present study demonstrates that early ischemic preconditioning based on multiple brief ischemic episodes can induce an almost complete protection against postinfarction myocardial dysfunction in chronically instrumented conscious rabbits.
Although it is widely recognized that early preconditioning strongly reduces infarct size after an ischemic insult, several studies have reported that this protective effect is not always associated with an improvement in postinfarction myocardial contractility (6, 10). These studies were limited, however, to the investigation of regional function within the first hours of reperfusion. In another study, Cohen et al. (3) reported in conscious rabbits that the functional protective effect of ischemic preconditioning could be revealed when reperfusion was extended to 72 h, i.e., segment shortening reached 44% of its baseline value with an infarct size averaging 10.2 ± 1.4%. Using the same preconditioning protocol (i.e., PCx1) in the present study, we confirmed this pattern, because segment shortening averaged 32 ± 7% of its baseline value with an infarct size reaching 15 ± 2%. Regarding these results, it could be hypothesized that preconditioning does not afford a strong and rapid protection against postinfarction dysfunction. One also could argue that the preconditioning protocol was not optimal. Indeed, by using six cycles of brief ischemia-reperfusion for preconditioning, our study demonstrates that an almost complete recovery in regional contractility can be achieved within 3 days of CAR. Under these conditions, segment shortening recovered up to 82 ± 9% of its respective baseline value and infarct size averaged 3 ± 1% of the area at risk. Although the difference in infarct sizes was rather modest between the two preconditioning protocols, the functional gain appeared dramatically potentiated with the use of multiple ischemia-reperfusion cycles. An additional 12% of viable tissue in PCx6 vs. PCx1 was indeed associated with an almost 50% gain in functional recovery at 72-h CAR compared with PCx1. One might argue that this could be explained by differences in the kinetics of functional recovery and prolonged stunning. This is unlikely, because with 21 days of CAR, Cohen et al. (4) reported a plateau in segment shortening recovery with PCx1 (64.7 ± 9.8% of baseline value), i.e., a value lower than that observed with PCx6 in the present study with 72-h CAR (82 ± 9% of baseline value). Therefore, compared with the preconditioning protocol with a single occlusion-reperfusion cycle, our results show that the use of six cycles allows us to reach both a more rapid and a greater contractile recovery of the postinfarcted zone despite modest differences in corresponding ultimate infarct sizes.
To further investigate whether this functional recovery was due to different infarct-sparing properties of the preconditioning sequences, we calculated an index corresponding to the ratio between segment shortening measured after 72-h CAR (percentage of baseline) and the amount of salvaged tissue (percentage of the intercrystal area). Such an index allows us to approximate the regional function of the sole salvaged tissue independently, theoretically, from the infarct size. For example, an index value of 1 indicates a complete recovery. In the control group, this index averaged 0.00 ± 0.10, indicating akinesis of salvaged cardiomyocytes. As expected, this index was greater with PCx1 (0.39 ± 0.07), demonstrating that, in agreement with previous results (4), preconditioning is able to induce a modest functional protection of the salvaged tissue along with its infarct-limiting effect. However, this functional protection can be further potentiated, because the index value was increased to 0.82 ± 0.09 by PCx6. Although the main determinant of postinfarction dysfunction remains infarct size, the use of such an index allows us to postulate that the two preconditioning protocols exert differential functional effects on salvaged tissue, i.e., independently of their infarct-sparing effects (9, 11).
Several hypotheses might be raised to explain this apparent differential effect of these preconditioning protocols. Tissue loss due to infarction is known to have differential consequences when localized in the subendocardium vs. subepicardium. Indeed, infarct size in the subendocardium was dramatically reduced in the PCx6 vs. the PCx1 group, a result that confirms that localization and geometry of infarction may induce a nonlinear relationship between infarct size and postinfarction dysfunction. Another consequence of infarction on the peri-infarct viable tissue is a paradoxical lengthening in the early systole, i.e., mechanical tethering (7). In the present study, a potent tethering was indeed observed in both the control and PCx1 groups but not in the PCx6 group (1.8 ± 0.8, 1.4 ± 0.6, and 0 ± 0% of the telediastolic length, respectively). However, other factors not directly dependent on infarct size are also probably involved in postinfarction regional dysfunction. For example, our immunohistochemistry and colabeling immunofluorescence experiments demonstrated that iNOS is highly expressed in the endothelium of the coronary vessels of both the control and PCx1 groups but not in the PCx6 group. This clearly shows that biochemical changes occur within the salvaged tissue that may partly explain the difference between preconditioning protocols. Indeed, it is known that activation of iNOS during reperfusion may contribute to myocardial dysfunction through a negative inotropic effect (5, 14) and that inhibition of iNOS improves the functional recovery of postinfarcted myocardium in rabbits (14). One can therefore speculate that PCx6 allows, at least in part, a greater functional recovery of salvaged tissue by preventing iNOS expression and upregulation during the postinfarction period. It also should be acknowledged that differences in the kinetic of iNOS expression during reperfusion could also explain part of our results. Finally, we can rule out changes in apoptosis, macrophage infiltration, and eNOS expression in the salvaged tissue because they were not observed in all rabbits in the salvaged tissue.
In conclusion, this study demonstrates for the first time to our knowledge that early ischemic preconditioning can confer a rapid and almost complete protection against postinfarction dysfunction when it is induced by multiple vs. unique ischemia-reperfusion cycles. This protection not only involves an increase of the amount of viable tissue but also exerts a beneficial effect on the functional recovery of the salvaged myocardium. Inhibition of iNOS might represent a potential target for protecting the salvaged reperfused myocardium against postinfarction dysfunction. Further specific experiments with iNOS inhibitors are required to strengthen this conclusion. This work, however, was beyond the scope of the present study, which was not designed to perform such investigations.
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GRANTS
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This study was supported by Fondation de l'Avenir Grants ET2-293 and BQR 2001 (Faculté de Médecine Paris-Sud).
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ACKNOWLEDGMENTS
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We are greatly indebted to Alain Bizé, Stéphane Bloquet, and Georges Zadigue for excellent technical support. We are also greatly indebted to Martine Douheret for techniques of histological analysis.
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FOOTNOTES
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Address for reprint requests and other correspondence: A. Berdeaux, INSERM, U660, Faculté de Médecine de Créteil, Université Paris XII, 8 rue du Général Sarrail, 94000 Créteil, France (E-mail: berdeaux{at}im3.inserm.fr)
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.
* K. Aouam and R. Tissier contributed equally to this work. 
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Copyright © 2005 by the American Physiological Society.
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ABSTRACT
METHODS
