© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Left ventricular regional systolic and diastolic function in conscious sheep undergoing ischemic preconditioning
Basic Sciences Research Institute, The René G. Favaloro University Foundation, Buenos Aires, Argentina
* Corresponding author. Tel.: +54-1-378-1187; fax: +54-1-381-0323; e-mail: lascano@favaloro.edu.ar
Received 13 January 1998; accepted 26 May 1998
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Abstract |
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Objective: Late preconditioning diastolic protection and cardiac function optimization by the combined effects of late and early preconditioning have not been studied in conscious animals. This study assessed in fully conscious sheep: (1) whether 24 h after a reversible ischemia, a new ischemic episode results in lesser systo–diastolic dysfunction (late preconditioning protection) and (2) whether the addition of early preconditioning (brief episodes of ischemia–reperfusion before the subsequent sustained ischemia) on the second day of late preconditioning optimized the second window of protection. Methods: Three protocols were assessed: (a) late preconditioning, 9 min ischemia and 2 h reperfusion was done on two consecutive days; (b) early plus late preconditioning, as in protocol (a) except that on day 2 the heart underwent three periods of 3 min ischemia–6 min reperfusion prior to the sustained 9 min ischemia; (c) early preconditioning, the same protocol as in (b) except that day 2 was separated 1 week from day 1. Results: Late preconditioning decreased regional radial diastolic stiffness from 147±26% (day 1) to 96±14% (day 2), at 2 h of reperfusion (mean±SEM, p<0.05), but did not protect against systolic stunning (thickening fraction and regional stroke work). Early plus late preconditioning did not improve late preconditioning findings. Early preconditioning alone did not protect either systolic or diastolic functions. Conclusion: In conscious sheep, there is diastolic but not systolic mechanical protection with late preconditioning. Diastolic protection is not enhanced by the addition of early preconditioning.
KEYWORDS Ischemia; Preconditioning; Reperfusion; Stunning; Ventricular function, sheep
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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In 1986, Murry et al. showed in dogs that brief repetitive episodes of myocardial ischemia reduced infarct size following sustained coronary occlusion, and termed this phenomenon ischemic preconditioning [1]. According to recent studies, the time course of myocardial preconditioning comprises two phases: early preconditioning, which lasts up to 2 h after the last preconditioning ischemia [1–5], and late preconditioning (also referred to as "second window of protection"), which appears approximately 12 h later and extends over 24 to 72 h [6–9].
The effects of early or late preconditioning on systolic function following totally or partially reversible ischemia have been studied in isolated hearts [4, 5], open-chest animals [2, 3], sedated pigs [6, 8, 9]and conscious rabbits [10]with controversial results. No clearly established origin of protection against systolic stunning by early or late preconditioning has been shown after a sustained ischemic insult resulting in a certain proportion of myocardial necrosis, ventricular functional improvement being associated with reduction of stunning, infarct size or both [2, 9, 11]. Furthermore, early preconditioning did not afford protection against stunning following reversible ischemia in open-chest dogs [3]. A different response has been found in recent studies of late preconditioning protection following reversible ischemia in sedated pigs and conscious rabbits, where brief periods of ischemia–reperfusion performed on two consecutive days produced a faster recovery of regional systolic thickening after the last reperfusion of the second day [6, 8–10]. Fewer studies have analyzed the diastolic response to preconditioning. Protection of isovolumic developed and end-diastolic pressures with early ischemic preconditioning has been reported in isolated rat and rabbit hearts subjected to 25–30 min of global ischemia [4, 5]. Moreover, pharmacologically induced early and late preconditioning have been found to preserve developed and end-diastolic pressures in isolated rat hearts undergoing 20 min of global ischemia [12]. Even though these studies indicate a trend of diastolic function to improve with preconditioning, they are not conclusive since they were performed at the limit or exceeding the time of reversible ischemia and might be ascribed in part to reduction of necrotic tissue. Thus, it remains to be seen if a similar diastolic protection occurs following reversible ischemia, particularly in response to late preconditioning in conscious animals where systolic preservation has already been found.
Consequently, in the present study our objectives were: (1) to corroborate late preconditioning protection of systolic function after a reversible ischemia in fully conscious sheep; (2) to assess in the same experimental conditions the diastolic response to late preconditioning; (3) to establish in conscious animals, if it is possible to improve systo–diastolic recovery by addition of early preconditioning to the second window of protection.
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2 Methods |
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2.1 Surgical preparation
Forty-two Hampshire Down sheep of either sex aged 7 to 9 months, weighing 30 to 41 kg (35±3) were operated. On arrival to the animal house, they were deparazited with ivermectine, and vaccinated against tetanus, anthrax, gas gangrene and clostridial enterotoxemia. Adequate health condition was assessed by professional veterinary staff through clinical examination and laboratory tests. During 10 days before surgery, the animals were familiarized with the laboratory personnel and environment. After sedation with acepromazine maleate 0.3 mg/kg, anesthesia was induced with thiopental sodium 20 mg/kg. Following intubation and connection to mechanical ventilation (Neumovent 910, Córdoba, Argentina), anesthesia was maintained with 3% enflurane carried in oxygen and fentanyl citrate 0.1 mg. A sterile thoracotomy was performed at the left fifth intercostal space. The heart was suspended in a pericardial cradle, and a solid-state pressure (P) microtransducer (Konigsberg P7, Pasadena, CA, USA) was inserted in the left ventricular cavity through a stab wound at the apical dimple. Tygon fluid-filled catheters were inserted in the right atrium (for drug infusion) and in the left ventricle (for later calibration of the pressure microtransducer). The left anterior descending artery was dissected free from adjacent tissue just distal to the second diagonal branch, and a pneumatic cuff occluder was positioned around it. Using the technique described by Sasayama et al. [13]one pair of piezoelectric crystals (5 Mhz) measuring left ventricular wall thickness (WTH) was placed well within the zone to be rendered ischemic. For appropriate placement of the crystals, the ischemic zone was visually assessed by transitory inflation of the coronary cuff. In five sheep, another pair was placed in a remote, control zone. This step was later discontinued, since it was observed that the experiments did not induce any significant regional changes in the normoperfused area. A third pair of crystals (3 Mhz) was used to measure left ventricular internal diameter (D) at the level of the ischemic zone. This was achieved by inserting one of the crystals of the pair on the endocardium of the wall to be rendered ischemic, close to the wall thickness pair, and the other one on the endocardium of the opposite wall. All wires and catheters were tunnelled subcutaneously to emerge between the scapulae, and the thoracotomy was closed without pericardial closure. The right atrial and left ventricular catheters were flushed daily with heparinized saline until the day of the experiment. Cephalomycin, 1 g i.v., was given immediately after surgery and continued during 3 days at a dose of 1 g/day i.m. The present investigation conformed with the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
2.2 Experimental protocol
Seven to 10 days after surgery, the animals were studied in the conscious, unsedated state, standing in a cage. The fluid filled catheter was connected to a pressure transducer (DT-XX, Viggo-Spectramed, Oxnard, CA, USA) previously calibrated using a transducer calibration system (Xcaliber, Viggo-Spectramed). The zero pressure point was set approximately at the level of the right atrium, and the signal generated by the Konigsberg transducer was adjusted to match that of the external transducer. The three pairs of ultrasonic crystals were connected to a sonomicrometer (Triton, San Diego, CA, USA) and calibrated in mm using the internal calibration. Throughout the experiment, all signals were recorded on paper at low speed (Gould Brush 2600S polygraph, Cleveland, OH, USA). During the experimental steps established in the protocol, all signals were digitized at 4 ms intervals over 12 s using a personal computer equipped with an A/D converter (National Instruments Lab-PC, Austin, TX, USA) and software developed in our laboratory. In order to reduce the incidence of ventricular arrhythmias, lidocaine (1 mg/kg) was given as a bolus injection through the right atrial catheter before basal recordings, and thereafter infused in saline at a rate of 1.5 mg/min until 10 min after reperfusion.
Late, early plus late and early preconditioning were assessed (Fig. 1).
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2.2.1 Late preconditioning
The animal was subjected to two experimental sessions separated by 24 h. Each session consisted of a 9 min period of regional ischemia followed by reperfusion.
2.2.2 Early plus late preconditioning
On day 1, after 27 min of control recordings, the animal was subjected to 9 min of regional ischemia followed by reperfusion. Twenty four hours later, three 3 min periods of regional ischemia followed by three 6 min reperfusion periods preceded the 9 min ischemia.
2.2.3 Early preconditioning
An early preconditioning protocol was done to confirm results of early plus late preconditioning. This consisted in repeating the scheme of early plus late preconditioning, except that the two experimental sessions were separated by 7 to 8 days to avoid the effect of late preconditioning on the early preconditioning window.
The duration of the prolonged ischemia (9 min) was decided on the basis of the results of pilot experiments. These experiments, done in four additional sheep, showed that longer ischemic periods (up to 15 min) resulted in a high incidence of ventricular fibrillation during ischemia and reperfusion despite protection with lidocaine infusion. We thus shortened the duration of the prolonged ischemia to 9 min, with which the incidence of ventricular fibrillation decreased, still allowing for a significant degree of myocardial stunning during reperfusion, with no anatomopathological evidence of myocardial necrosis.
The signals of nine to 18 consecutive steady beats were recorded in each acquisition time. For the late preconditioning protocol, on days 1 and 2, basal values were taken after stabilization of left ventricular pressure and dimensions prior to ischemia. Then, measurements were acquired at 2, 4, 6 and 9 min of the prolonged ischemia, and at 2, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 105 and 120 min of reperfusion. For the early and early plus late preconditioning protocols, on day 2, measurements were taken at baseline, at the end of each ischemic preconditioning period, and at the end of each reperfusion following the ischemic preconditioning periods (seven recordings during 27 min). On day 1, control measurements were taken at the times corresponding to the preconditioning periods of day 2. Thereafter, the same schedule as for late preconditioning was followed during the rest of the experimental session for days 1 and 2.
2.3 Data analysis
End-diastole was defined to occur at the onset of the rapid upstroke of the digitally obtained time derivative of left ventricular pressure (dP/dt). End-systole was defined as the time point where the P/D ratio reached its maximum, and end-ejection as the instant of minimal diameter between end-systole and peak negative dP/dt. Percent regional wall thickening (%WTH) was calculated as
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T) was obtained from P, D and WTH, according to the equation
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T–ln(1/WTH) loop [14], according to the following equation:
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 | (2) |
End-diastolic tangential stiffness (ET) was defined as [14]:
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T vs. ln(1/WTH) relationship, using the same data points. Signal processing and parameter calculation consisted of: at each time of data acquisition, end-systolic pressure, end-diastolic pressure, WTHd,%WTH, RWM, ER and ET were calculated from each recorded beat and the average of processed beats was the value assigned to the corresponding acquisition time (nine to 18 beats). Units used were mmHg for P and cm for dimensions.
2.4 Statistical analysis
Results are expressed as mean±SEM. Since the same animal was used for nonpreconditioned and preconditioning conditions in the three protocols, a two-tailed paired Student's t-test was used to compare data of day 1 vs. day 2 at the corresponding time points. Differences were considered to be significant when p<0.05.
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3 Results |
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3.1 Animal loss
Of 42 operated sheep, three died at surgery or during the early post-operative period, nine developed irreversible ventricular fibrillation either during the prolonged ischemia or during early reperfusion, two were discarded because of poor signal quality or signal loss, two because of inadequate crystal positioning, two because of failure of the coronary cuff occluder and nine because on the day of the experiment they exhibited a wall thickness tracing compatible with myocardial infarction. Results from 15 animals are thus reported. Of these, five underwent all three protocols, four underwent two protocols and six one protocol.
3.2 Hemodynamic data
Table 1 lists the values for global and regional hemodynamic variables during control conditions at day 1 and day 2 of the three protocols. Small though significant differences were found in heart rate between day 1 and day 2 for the early plus late preconditioning protocol. No differences between days 1 and 2 were found for the other variables in any of the protocols. The validity of reusing some of the animals in more than one protocol was tested through the basal values of systolic and regional variables involved in the preconditioning response. Table 2 shows that basal thickening fraction and radial stiffness of the five animals that underwent the three protocols evidenced no significant differences either between protocols or between the experimental sessions in each protocol (days 1 and 2).
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3.3 Systolic and diastolic function
Figs. 2–4
show the time course of systolic pressure, diastolic pressure, thickening fraction, regional stroke work, and regional radial and tangential diastolic stiffness for the late, early plus late and early preconditioning protocols, respectively. In the three figures, it is seen that the prolonged ischemia induced significant, long-lasting regional stunning during ischemia and reperfusion. However, end-systolic pressure remained stable over the whole experiment, indicating that the ischemic region was small enough to be well compensated by the normoperfused myocardium. Furthermore, in the five sheep in which control wall thickness was measured, percent thickening fraction did not show any significant changes over the whole experiment.
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p<0.01 (paired t-test, day 1 vs. day 2).
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Late preconditioning induced a selective improvement of regional diastolic function, evidenced by a significant and sustained decrease in regional diastolic radial stiffness, with no effect on wall thickening fraction (Fig. 2). Regional diastolic tangential stiffness tended to decrease without achieving statistical significance, probably because the inclusion of diameter in its calculation increased the final random error and the error due to the use of a not purely regional dimension (diameter was subtended between the ischemic and the normoperfused walls). The addition of early preconditioning to late preconditioning (Fig. 3) did not provoke modifications of the results of radial stiffness observed in late preconditioning; the difference between the temporal values of days 1 and 2 for late preconditioning was not significantly different from the same calculation for early plus late preconditioning at any time (unpaired t-test between differences). In this last protocol there was a tendency for regional stroke work to improve during reperfusion. Early preconditioning alone did not improve either systolic or diastolic regional function during reperfusion (Fig. 4).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The purpose of this study was to examine the regional systo–diastolic mechanical response to ischemic preconditioning in conscious sheep subjected to a nonlethal ischemia of 9 min duration. The effect of preconditioning on systolic function has been studied in isolated heart, open-chest and intact, sedated animals. Conversely, diastolic response to preconditioning has only been examined in isolated heart experiments. This is the first report that, to our knowledge, has addressed the effects of early and late preconditioning on diastolic function in fully conscious animals. The main findings of this study can be summarized as follows: (a) early and late ischemic preconditioning do not protect against regional systolic stunning; (b) late preconditioning but not early preconditioning preserves diastolic function; (c) the combined effects of early and late preconditioning do not improve the observed diastolic protection.
4.1 Animal model and experimental protocol
Young adult sheep were chosen for several reasons to perform this study. First, sheep develop no collateral circulation with coronary occlusion, as observed with gradual progressive stenosis by the Ameroid technique [16]. In the present protocol, the coronary occlusions were repeated in the same animal on different days. Thus, absence of collateral vessel development was necessary to obtain the same degree of regional ischemia in all the experiments. Second, the coronary circulation of the sheep is similar to that of humans [17]. Third, sheep are very docile animals, which can remain conscious and calm, standing in a cage, throughout the whole experiment. Even though in these conditions the animals exhibited some uncontrolled fluctuation in the hemodynamic variables during the experimental session, no sedation was administered to reproduce as closely as possible the normal physiological setting. Lidocaine was used to reduce arrhythmias because its intrinsic cardioprotective action does not inhibit preconditioning induced contractility protection, as shown in globally ischemic isolated rat hearts [5]. Moreover, since the same lidocaine doses was administered to all the animals in control and preconditioned situations, the comparative responses to ischemia could not have been affected by treatment with this antiarrhythmic drug. The 9 min period of prolonged ischemia was short enough to avoid necrosis but elicited ventricular fibrillation and death in nine animals despite administration of lidocaine. Thus, the duration of ischemia could not be extended to induce more severe stunning in the conscious sheep. In addition, ischemia could not be prolonged because it was necessary to have at 24 h a complete recovery of ischemic wall parameters in early and early plus late preconditioning protocols. Even though radial and tangential stiffness were still increased at the end of the experiment in day 1, the nonsignificant differences between basal measurements of both days indicated that there had been a full recovery of these parameters.
It is known that late preconditioning protection begins to appear 12 h after the ischemic insult, significantly reduces infarct size at 24 h [18]and disappears within 10 days [6]. Consequently, in the cases where the same animal was subjected to more than one preconditioning protocol, each protocol was separated by at least 1 week from the next one to avoid interference of a late preconditioning effect, as corroborated by results shown in Table 2. Moreover, any remaining action of late preconditioning between protocols was avoided by having a proper control (day 1) for each of them. The same consideration was applied to the early preconditioning protocol, a lapse of 1 week separating day 1 from day 2.
Basal percent thickening fraction (26.1±11.7%, mean pooled data in control, N=29) was similar to that recorded for the pig [6, 9, 19]and dog [20], suggesting that the sheep is an adequate species to study regional mechanics. Basal diastolic wall thickness (0.65±0.15 cm, N=29) was less than that reported for other species because the microcrystals were placed near the apex of the heart where the ventricular wall is thinner. Results showing comparable basal hemodynamic results in days 1 and 2 indicated that the preparation was stable in consecutive days.
4.2 Protection against stunning
Systolic mechanical function has been analyzed both in early and late preconditioning experiments with conflicting results on the degree of protection against stunning, depending on the experimental model (isolated heart, open-chest or conscious animals) and on the duration of sustained ischemia, producing or not necrosis [2–5, 11]. Recent studies of preconditioning and systolic function have been done in sedated pigs and lately in conscious rabbits subjected to several brief periods of ischemia–reperfusion [6, 8–10]. However, diastolic function has only been evaluated in isolated heart experiments through the behavior of end-diastolic pressure as a stiffness index. We thus addressed the problem of analyzing, in fully conscious sheep, the effect of preconditioning on regional diastolic function, assessing regional radial and tangential myocardial stiffness following a transient nonlethal sustained ischemia. In general, stiffness is defined as the derivative of stress with respect to strain [14, 15]. Fujii et al. estimated radial stiffness from the exponential fit of pressure vs. the natural logarithm of thickness from minimum pressure to end-diastole, the resulting exponential parameter representing myocardial stiffness [21]. On the other hand, Bourdillon et al. [22]plotted residual pressure vs. the natural logarithm of wall thickness and measured myocardial radial stiffness from the slope of this relationship at a defined residual pressure of 4 mmHg. In the present work we could not use the entire diastole to calculate radial stiffness, because during stunning the presence of post-ejective wall thickening indicated the possibility of active myocardium, preventing stiffness calculation until it had ended. In addition, in the conscious animal, the variability between subsequent data points did not show an exponential trend. These considerations prompted us to assess radial stiffness as the slope of the linear fit of pressure vs. the natural logarithm of wall thickness relationship towards end-diastole, after post-ejective wall thickening had finished, during a period that comprised the last 50 to 100 ms depending on heart rate. Regional systolic tangential stiffness was calculated by Nakano et al. [14]as the derivative of regional systolic tangential stress with respect to strain. Moreover, he proposed that the integral of regional tangential stress–strain for the whole cardiac cycle represented regional stroke work. Thus, because no restrictions were imposed in the use of regional stress–strain to the entire beat, we applied the same equation of regional systolic stiffness postulated by Nakano to estimate diastolic myocardial tangential stiffness, during the same period in which radial stiffness was calculated.
Because the sustained ischemic insult was brief enough to be completely reversible, the control and preconditioning sessions were performed in the same animal in each of the three protocols. This experimental design allowed for a paired statistical analysis of results that reduced the variability in the response to ischemia arising from differences between animals, microcrystals placement and surgical damage.
The magnitude of the area to be rendered ischemic resulted in marked regional mechanical deterioration during total occlusion, evidenced by pronounced decreases in systolic wall thickness and regional stroke work. Conversely, ischemia did not affect global pump function as shown by a stable systolic pressure close to basal values, indicating that ischemia induced regional contractile dysfunction was well compensated for by the increase in end-diastolic pressure. Thus, the response of the ischemic area to any of the preconditioning protocols occurred under a normal global systolic behavior.
Diastolic pressure increased during ischemia concomitantly with the augmented regional radial stiffness of the occluded region in control and preconditioning sessions. During reperfusion, even though diastolic pressure decreased, it tended to be higher in day 1 with respect to day 2 in late and early plus late preconditioning. Consequently, the significant difference of stiffness between days 1 and 2 in these two protocols could be in part attributed to an increase in end-diastolic pressure.
4.3 Late preconditioning
Late preconditioning did not significantly improve systolic function during reperfusion after sustained ischemia. Recently, sedated pigs have been used to analyze the myocardial resistance to stunning following late preconditioning. In the first of these studies, a late preconditioning protocol of ten 2 min episodes of ischemia–reperfusion applied on three consecutive days was shown to improve wall thickening on the second and third days [6]. Conversely, in the same animal model, late preconditioning did not reduce infarct size and failed to preserve contractile function after a sustained 40 min ischemic period [9]. The accordance of our results with this last study indicates that a sustained ischemia even if it is short enough to be nonlethal, fails to induce any relevant systolic protection. As to the effect of preconditioning on diastolic function, we found that on day 2 radial stiffness decreased with respect to day 1, whereas a trend of improvement was observed for tangential stiffness. This last nonsignificant result could be due to the fluctuating behavior observed in day 1 and the greater data dispersion resulting from the calculation of stress through three signals (Eq. (1)) instead of only one as in radial stress (Eq. (2)). The present findings showing diastolic protection in the absence of systolic recovery are similar to results in isolated rat hearts where the early preconditioning effects were to decrease diastolic pressure with unchanged systolic pressure [5].
4.4 Combined effect of early and late preconditioning
A recent study [12]showed an optimized systolic but not diastolic pressure protection by the additive effects of pharmacologically induced early and late preconditioning in isolated rat hearts. Our study was in accordance with the lack of additive effect on diastolic function. This result was expected since regional radial stiffness had already returned to basal values in day 2 of late preconditioning. However, the incipient systolic wall thickening protection found in day 2 of late preconditioning was not improved by the addition of the early preconditioning, a discrepant result which might be attributed to the different animal species, conscious vs. isolated heart and ischemic vs. pharmacological preconditioning.
4.5 Early preconditioning
In these experimental conditions early preconditioning does not protect against regional systolic nor diastolic function following a 9 min ischemic insult. These results show that the lack of functional improvement to the combined effects of early and late preconditioning was due solely to the nonresponsiveness of systo–diastolic mechanics to early preconditioning. In this respect, the deficient response of regional wall thickening and stroke work to preconditioning confirmed observations of segment length behavior in open-chest dogs undergoing a 2.5 or 5 min occlusion–5 min reperfusion episode before a nonlethal ischemia of 15 min duration [3], but differed from the improved wall thickening and reduced infarct size observed by Qiu et al. [9]with ten 2 min occlusions–2 min reperfusion periods followed 25 min later by a partially reversible 40 min occlusion in sedated pigs. The controversial results between Qiu's experiments and our work could be ascribed to the different animal species (sheep vs. pig), the experimental conditions (conscious vs. sedated), the preconditioning cycles or the duration of sustained ischemia. Whereas in our study, ischemia was short enough to produce no irreversible cellular damage, in their study the mechanical recovery could be due both to reduced stunning and decreased necrosis, similarly to results reported in open-chest rabbits, where improved segment shortening and reduced infarct size was observed following 20 min of ischemia [2]. No beneficial effect of early preconditioning on diastolic function was found in our study, contrary to results of end-diastolic pressure preservation with preconditioning in isolated rat hearts subjected to 30 min of global ischemia [5]and isolated rabbit hearts undergoing 20 min of global ischemia [4]. Again, the duration of ischemia in these studies was long enough to produce some cellular damage, it not being completely clear if recovery of diastolic pressure was due to decreased stunning or reduced infarct size.
Recent reports of late preconditioning protection against systolic stunning have pointed to the role of reactive oxygen species and nitric oxide as the possible stimulus of selected genes resulting in the synthesis of cardioprotective proteins [9, 23]. In spite of these findings, the exact mechanisms underlying the cytoprotective effect of late preconditioning on systolic function and, as from the present results on diastolic function, still remain to be elucidated. However, it could be hypothesized that similarly to the systolic function protection theory, cardioprotective proteins could preserve sarcolemmal and sarcoplasmic reticulum membranes preventing Ca2+ overload which has been postulated as one of the major determinants of diastolic stunning. These speculative remarks need, however, experimental confirmation.
In conclusion, the present results of preconditioning protection against nonlethal ischemia in fully conscious sheep show: (1) diastolic but not systolic protection with late preconditioning, (2) no additive action of the combined effects of early plus late preconditioning and (3) no systo–diastolic protection during early preconditioning.
Time for primary review 35 days.
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Acknowledgements |
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The authors wish to thank Dr. R. Levy for help in the surgeries, J. Mart
énez for microcrystals preparation and surgical assistance, Drs. M.I. Besansón, P. Iguaén and M. Tealdo and the personnel of the animal house for veterinary support and F. Gauna for technical assistance during the experiments. |
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