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Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432 - 1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The contribution of heat shock protein 72 (HSP72) to the protection of cardiac function was examined in rats with chronic heat failure (CHF) following coronary artery ligation (CAL). The CAL animals revealed functional deterioration without low cardiac output 2 wk after CAL and with low cardiac output 8 wk after CAL, suggesting that CHF had developed by 8 wk after CAL. The hearts isolated from animals 2 and 8 wk after CAL (2-wk CAL heart and 8-wk CAL heart, respectively) were subjected to hyperthermia (at 42°C) for 15 min, followed by 6-h perfusion (hyperthermia/6-h perfusion). The 2-wk CAL heart showed a 19.0 ± 3.9% decline in the rate- pressure product (RPP) after hyperthermia/6-h perfusion, similar to the nonoperated control (19.8 ± 2.9% decline). The production of myocardial HSP72 increased in the 2-wk CAL heart in response to hyperthermia (412.7 ± 29.5% of each prehyperthermia value). The 8-wk CAL heart showed a reduction in the RPP (45.2 ± 4.3% decline) after hyperthermia/6-h perfusion, associated with blunting of the production of HSP72 (68.9 ± 22.6% increase, respectively). The results suggest that functional deterioration of the isolated failing heart may be attributed to a reduction in the production of myocardial HSP72.
contractile function; coronary artery ligation; stress
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS GENERALLY RECOGNIZED that production of heat shock proteins (HSPs) is enhanced after exposure of cells, tissue, and the whole body to various kinds of stresses. The major HSPs induced by such stresses are HSP27, HSP60, HSP72, HSP90, and heat shock cognate protein 73 (HSC73). These are inducible and/or constitutive components of normal cells and function as molecular chaperons in protein folding and protein translocation (3, 7, 11, 20). Several reports (1, 15) have suggested that HSPs other than HSP72/HSC73 may contribute to cellular tolerance and protection of normal animals, tissue, and cells against stress-induced damage. The proteins are considered to exert a protective effect on some tissues, particularly the heart, against stresses such as ischemia-reperfusion, cytotoxic substances, and high temperature (8-10, 14, 16). Despite some evidence for protective effects of HSP72 on normal hearts, the role of these proteins in the protection of cardiac function of animals and humans in pathophysiological states remains elusive.
Recently, several reports have shown changes in the production of HSP72 in animals in a pathophysiological state. For example, an increased production of myocardial HSP72 in response to hyperthermia was seen in young spontaneously hypertensive rats (2, 6). HSP72 in both ventricles was increased in response to heat shock in monocrotaline-induced right ventricular failure of rats (4, 5). In the aortic-banded, hypertrophied rat heart, HSP72 induction after 5-min ischemia was blunted, whereas HSP72 production was enhanced after more severe (10-min) ischemia (18). In contrast, there were no appreciable increases in the production of HSP72/HSC73 in human failing hearts (12). Therefore, alterations in and the role of production of HSP72/HSC73 in animals and humans in the pathophysiological state remain inconclusive. The present study was undertaken to elucidate whether changes in the production of myocardial HSP72/HPC73 may occur in chronic heart failure (CHF) and to determine whether or not the production of HSP72/HSC73 may contribute to the protection of cardiac function in the failing hearts.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Male Wistar rats (SLC; Hamamatsu, Japan), weighing 210-240 g, were used in the present study. The animals were conditioned to an environment of 23 ± 1°C, a constant humidity of 55 ± 5%, a 12-h light/12-h dark cycle, and given free access to food and tap water according to the National Institutes of Health's Guide for the Care and Use of Laboratory Animals. The Committee of Animal Use and Welfare of the Tokyo University of Pharmacy and Life Science approved the study protocol.
Myocardial infarct model. Myocardial infarction was produced in 49 rats by occlusion of the left ventricular coronary artery at ~2 mm from its origin according to the method described previously (17). Rats that revealed an abnormal Q wave (>1 mV), when monitored by electrocardiography (lead I) 1 day after the operation, were considered to have developed an acute myocardial infarction and used for the following experiment (rats with coronary artery ligation; CAL rats). Among the CAL rats, 30 rats survived 1 wk after surgery (~60% of the operated animals). No rats died between 2 wk and 8 wk after surgery. Thirty sham-operated rats (sham rats) were treated in a similar manner, except that CAL was not performed.
Measurement of in vivo hemodynamic parameters. Measurements of in vivo hemodynamic parameters were performed by the method of Sanbe et al. (17). Briefly, before the operation and 2 and 8 wk after the operation, the rats were anesthetized with a gas mixture of nitrous oxide-oxygen (3:1) and 2.5% halothane. Anesthesia was continued with a gas mixture of nitrous oxide-oxygen (3:1) and 0.5% halothane. A microtip pressure transducer (SPC 320, Miller Instrument; Houston, TX) was introduced into the left ventricle through the right carotid artery to measure left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressures (LVEDP). The arterial blood pressure was measured by means of a pressure transducer attached to a cannula placed into the right femoral artery. Heart rate (HR) measurements were triggered from changes in arterial blood pressure. After equilibration for 10 min, LVSP, LVEDP, arterial blood pressure, and HR were recorded on a thermal pen recorder. The PO2, PCO2, and pH of the blood samples of the animals under the present experimental conditions ranged from 95 to 104 mmHg, from 37 to 42 mmHg, and from 7.41 to 7.45 (n = 5), respectively.
In another set of experiments, we determined the aortic flow, and then the cardiac output and stroke volume indices were determined by the method described previously (17). The rats were inhaled with a gas mixture of nitrous oxide-oxygen and halothane as described above, intubated, and artificially respirated with air. After the right thorax was dissected, an electromagnetic flowmeter with a diameter of 2 to 2.5 mm (model MFV-3100, Nihonkohden; Tokyo, Japan) was placed around the thoracic aorta, and then the blood flow was measured. The systemic blood pressure was monitored through a cannula inserted into the femoral artery, and the HR was measured based on changes in the systemic blood pressure in the manner described above. Cardiac output and stroke volume indices were calculated by dividing aortic flow by body weight and by dividing cardiac output index by HR, respectively. The PO2, PCO2, and pH of the blood sample of the animals under the present experimental conditions ranged from 92 to 101 mmHg, 35 to 40 mmHg, and 7.35 to 7.42 (n = 5), respectively.Perfusion of hearts. After the in vivo hemodynamic parameters were measured, the hearts were rapidly isolated from animals 2 and 8 wk after CAL (n = 10 for each time point). The hearts were perfused in the Langendorff manner at 37°C at a constant flow rate of 9.0 ml/min with Krebs-Henseleit bicarbonate buffer (KH solution) composed of (in mM) 120 NaCl, 4.8 KCl, 1.2 KH2PO4, 1.2 MgSO4, 1.25 CaCl2, 25 NaHCO3, and 11 glucose (19). The perfusion buffer was equilibrated with a gas mixture of 95% O2-5% CO2 (pH 7.4). A latex balloon with an uninflated diameter of 3.7 mm, connected to a pressure transducer, was inserted into the left ventricular cavity through the mitral opening. The initial LVEDP of the perfused heart was adjusted to 5 mmHg. Changes in LVDP, LVEDP, and HR that was triggered from LVDP were measured by means of a pressure transducer and a HR counter. The rate-pressure product (RPP) was calculated by multiplying LVDP by HR. After the hearts were equilibrated for 20 min, the hearts were perfused for 15 min at 42°C (hyperthermia) or 37°C (normothermia). Thereafter, the perfusion was continued for 6 h at 37°C with a mixture (3:1) of KH solution and medium 199 (KHM buffer), a culture medium for cardiomyocytes that contains amino acids, vitamins, nucleosides, and nucleotides, to support protein synthesis after the hyperthermia. These procedures were referred to as "hyperthermia/6-h perfusion" and "normothermia/6-h perfusion," respectively. The KHM buffer was equilibrated with a gas mixture of 95% O2-5% CO2 (pH 7.4). The osmolarity of the KHM buffer was 286 osmol/l when determined by an osmometer (model OM801, Vogel; Giessen, Germany), whose value was almost the same as that of the KH solution. After the 6-h perfusion, the function of the perfused heart was determined. Nonoperated rats subjected to the same procedure as above served as the control.
Determination of infarct size. After aortic flow was measured, the left ventricle of rats with CAL or sham-operated rats was isolated and sectioned into seven slices, each 1 mm thick (n = 5), from the base of the heart to the apex in a plane parallel to the atrioventricular groove. The slices were stained at 37°C for 10 min with 1% triphenyltetrazolium chloride (TTC) in saline. After the slices were stained, TTC-unstained areas (i.e., infarct areas) were determined according to a planimetric method based on determination of the epi- and endocircumference of the infarcted myocardium (17).
Determination of HSPs by Western blot analysis.
After hyperthermia/6-h perfusion or normothermia/6-h perfusion was
performed, hearts were quickly removed from the Langendorff apparatus. The viable left ventricle, including the septum, was then
separated from the heart, frozen, and stored in a container cooled at
85°C until assayed for HSPs. The tissue was homogenized in buffer
(pH 7.40) containing 320 mM sucrose, 0.1 mM disodium EDTA, 0.1 mM
phenylmethylsulfonyl fluoride, and 10 mM Tris · HCl. After
homogenate was centrifuged at 1,000 g for 20 min at 4°C, the supernatant fluid was employed as a sample for determination of
myocardial HSPs such as HSP27, HSP60, HSP72, HSC73, and HSP90. The
samples were applied to an 8% sodium dodecyl sulfate-polyacrylamide gel (SDS-PAGE, 10 cm × 10 cm) according to the method of Laemmli (13) with the buffer containing (in mM) 49.7 Tris, 384 glycine, and 3.47 SDS and were separated in the gel at the constant
current of 30 mA/gel for 2 h.
Statistics. Results were expressed as means ± SE. Statistical significance was estimated by analysis of variance, followed by Fisher's multiple comparison. The relationship between two parameters was calculated by the least squares method. Differences with a probability of <5% were considered to be statistically significant (P < 0.05).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamics of the CAL rat in vivo and infarct size.
Hemodynamic parameters of CAL and sham rats in vivo were measured 2 and
8 wk after the operation (Table 1). The
mean arterial pressure and LVSP of the CAL rat were decreased 2 and 8 wk after surgery, whereas HR was not altered at these times
(experiment A in Table 1). In contrast, the LVEDP of the CAL
rats increased 2 wk and then further increased 8 wk after CAL. There
were no changes in these hemodynamic parameters of the sham rats
throughout the experiment. In another set of experiments, aortic flow
of the animals was measured, and their cardiac output and stroke volume
indices were determined 2 and 8 wk after the operation (experiment B in Table 1). Cardiac output and stroke volume
indices decreased only 8 wk after CAL.
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Induction of HSP72/HSC73 in control rat hearts.
To elucidate the optimal conditions for induction of HSP72/HSC73, we
subjected the hearts isolated from nonoperated rats (control rats) to
15-min hyperthermia at a temperature of 42°C, followed by different
periods of normothermic perfusion ranging from 0 to 8 h. In the
present study, we primarily examined the optimal conditions for
production of HSP72/HSC73, because several reports suggest an important
role for these proteins, among HSPs, in the cardioprotection against
various stresses. Figure 1 shows the time
course of the production of HSP72/HSC73 detected by Western blot
analysis (see Fig. 1, top) and their densitometric
quantification (Fig. 1, bottom). The peak level of
HSP72/HSC73 in the perfused hearts was seen 6 h after
hyperthermia. Thus we used 6-h perfusion with KHM solution following
hyperthermia to induce the peak levels of HSP72/HSC73.
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Function of perfused hearts. Hearts perfused in the Langendorff mode can maintain their function for a limited time only. Thus we examined how long the isolated heart was able to maintain cardiac function under perfusion with normal KH solution. LVDP and HR in hearts that were perfused for 6 h with the normal KH solution were <35% and ~50% of each initial value, respectively. To improve this decline in cardiac function, we changed the perfusion solution to the KHM buffer. In this case, the LVDP and HR in hearts perfused for 6 h were 83 and 90% of their initial values, respectively. We considered that such a small decline in cardiac function would allow us to evaluate pathophysiological alterations in the function of perfused hearts after a 6-h perfusion.
Figure 2 shows LVDP, HR, and RPP of perfused hearts from CAL and control rats before hyperthermia, which may represent the baseline cardiac function of animals (n = 10 each). Hearts isolated from the CAL rats 2 and 8 wk after the operation, termed "2-wk CAL heart" and "8-wk CAL heart," respectively, generated LVDPs of ~78 and 50% of the control value, respectively. The HR of the 2-wk CAL heart was similar to that of the control heart, whereas the HR of the 8-wk CAL heart was significantly lower than that of control heart or the 2-wk CAL heart. The RPP of the 2-wk CAL heart decreased to ~80% of the control value, whereas the value for the 8-wk CAL heart was <50% of the control one.
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Myocardial HSP72/HSC73 of sham and CAL rats 8 wk after the
operation.
Figure 4 shows changes in HSP72/HSC73
content of the left ventricle of control, sham, and CAL rats 8 wk after
surgery. The myocardial HSP72/HSC73 content of control and sham rats
after hyperthermia/6-h perfusion increased to ~400% of the value for the corresponding normothermic groups. In contrast, the increase in
myocardial HSP72/HSC73 content of CAL rats on hyperthermia/6-h perfusion was markedly blunted. Myocardial HSP72/HSC73 content of CAL
rats on normothermia/6-h perfusion was similar to that of the
corresponding control or sham rats.
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Production of myocardial HSP72 and HSC73 in sham and CAL rats.
Myocardial HSP72 and HSC73 contents of control, sham, and CAL rats 2 and 8 wk after surgery were examined after the normothermia/6-h perfusion and hyperthermia/6-h perfusion (n = 5 each).
Figure 5, A and B,
shows the time course of changes in HSP72 and HSC73 contents of the
left ventricle of sham and CAL rats. In the sham rat heart after the
hyperthermia/6-h perfusion, the HSP72 content increased to 602 ± 24% and the HSC73 content increased to 246 ± 6% of the
corresponding values for normothermic animals (n = 5).
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Relationships between induction of HSP72 or HSC73 and changes in
function of perfused hearts after hyperthermia.
To elucidate the possible relationship between an increase in the
production of HSP72 or HSC73 and functional alterations in the failing
rat heart, we plotted the increase in HSP72 and HSC73 contents against
the alterations in RPP and LVEDP of the respective rat hearts subjected
to the hyperthermia/6-h perfusion. We examined this relationship in all
hearts of animals with CAL, i.e., the 2-wk CAL heart and the 8-wk CAL
heart because the hearts isolated from the CAL rats exhibited a general
reduction in the hyperthermia-induced production of HSP72/HSC73
(n = 10). As shown in Fig.
6, left, hyperthermia-induced
increase in the production of HSP72 was inversely related to the
decrease in RPP (r = 0.948, P < 0.0001) and to the increase in LVEDP (r = 0.891,
P < 0.003). As shown in Fig. 6, right, the
increase in HSC73 after hyperthermia/6-h perfusion was also inversely
related to the decrease in RPP (r = 0.746,
P < 0.02) and to the increase in LVEDP of the perfused hearts (r = 0.681, P < 0.03).
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Other myocardial HSPs of sham and CAL rats 8 wk after the
operation.
To examine the possible contribution of other HSPs to the alteration in
cardiac function of the CAL rat heart, myocardial HSP27, HSP60, and
HSP90 contents of control, sham, and CAL rats 8 wk after surgery were
also examined after the normothermia/6-h perfusion or hyperthermia/6-h
perfusion (n = 5 each). Figure
7A shows changes in HSP27
content of the left ventricle of control, sham, and CAL rats. The
myocardial HSP27 content of the control and sham rats were not altered
6 h after the 15-min hyperthermia. The HSP27 content of the 8-wk
CAL heart tended to be higher than that of the control hearts, but the
difference was not statistically significant (P > 0.05). There was no difference in HSP27 content of the 8-wk CAL heart
irrespective of treatment with hyperthermia or not.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we first assessed the in vivo hemodynamic parameters of the animals before CAL and 2 and 8 wk after CAL to examine the effects of the infarct in these animals in two different series of experiments. Mean arterial pressure and LVSP were decreased 2 and 8 wk after the operation, whereas LVEDP was increased with time after the operation. The HR was not altered significantly during these experimental periods. The findings indicate that contractile dysfunction developed with time after CAL. We also observed a significant reduction in cardiac output and stroke volume indices 8 wk after the operation. These results are similar to those reported previously from our laboratory (17). From these observations, we can conclude that CHF with low cardiac output developed by 8 wk after the induction of the infarct in this model. Because LVSP was appreciably decreased without any change in cardiac output and stroke volume indices 2 wk after the operation, we considered that the animals at this period were in a compensatory state before the development of severe cardiac dysfunction.
To examine cardiac function of animals with CAL without the influence of the systemic circulation, we determined the time course of changes in cardiac parameters using isolated heart preparations. At baseline, LVDP and RPP of the CAL rat hearts were significantly decreased at both 2 and 8 wk post CAL, whereas HR was significantly decreased only in the 8-wk CAL heart. These results suggest that the function of the 8-wk CAL heart, i.e., failing heart, may be reduced when compared with those of the control and sham rat hearts.
We also examined the effects of hyperthermia on the function of perfused control hearts of the control rat at the initial stage and after the hyperthermia/6 h-perfusion. As was shown in Fig. 3, only a slight decrease in LVDP was seen after the hyperthermia/6-h perfusion. This decline was observed irrespective of treatment with normothermia or hyperthermia. Thus, although the process of hyperthermia itself slightly decreased cardiac contractile function, it is unlikely that it caused significant functional deterioration of the perfused hearts.
Finally, we examined the effects on the function of the isolated perfused hearts of the combination of CAL with hyperthermia, followed by the 6-h period of perfusion. Although function of the 2-wk CAL hearts was decreased after the hyperthermia/6-h perfusion, the pattern of changes was similar to that of the control, as shown in Table 2. In contrast, to the normothermic condition, the hyperthermia/6-h perfusion resulted in a significant reduction in LVDP and RPP and in a significant increase in LVEDP in the 8-wk CAL heart. This alteration in these parameters was further confirmed by the findings that the percent decreases in LVDP, HR, and RPP and the percent increase in LVEDP were greater in the 8-wk CAL heart with hyperthermia than in any of the other three groups, i.e., sham, sham + hyperthermia, and CHF groups. These findings suggest that CHF may cause deterioration of function in perfused hearts and that the hyperthermia/6-h perfusion heightens this deterioration.
We then determined HSP72/HSC73 production under the present experimental conditions. The hyperthermia/6-h perfusion was capable of producing HSP72/HSC73 in control and sham rat hearts (Figs. 1 and 4). In contrast, the 8-wk CAL heart did not reveal a significant increase in the production, suggesting the inability of the failing heart to produce HSP72/HSC73. As described above, it was only the cardiac function of the 8-wk CAL heart, i.e., function of the failing heart, that was significantly deteriorated by hyperthermia/6-h perfusion among the experimental groups. This finding implies that the reduction in hyperthermia-induced HSP72/HSC73 production appears to be correlated with functional deterioration of the failing heart. This observation agrees with those reported previously (2, 4-6).
To elucidate the relationship between HSP72 or HSC73 production and functional deterioration of the failing heart isolated from the animals with CAL in more detail, we plotted changes in parameters for cardiac function against the increase in HSP72 and HSC73 of each heart (see Fig. 6). The decrease in RPP and the increase in LVEDP were inversely related to the increase in the production of HSP72. Although the production of both HSP72 and HSC73 was inversely related to changes in the functional parameters, HSP72 appeared to be more closely related to the parameters of cardiac function than HSC73. The results in the present study therefore allow us to conclude that the capacity of the myocardium to produce HSP72 plays an important role in protecting the failing heart from functional deterioration. Our findings suggest that the ability of the failing heart to tolerate this stress may decrease if HSP72 content is reduced.
As described in the introduction, Knowlton et al. (12) examined the production of various HSPs in failing human hearts with ischemic or dilated cardiomyopathy. They found an increase in HSP60 of the heart with ischemic cardiomyopathy and increases in HSP27 and HSP60 of the heart with dilated cardiomyopathy. In their study, normal human hearts were isolated from those of humans after accidents (i.e., gunshot and traffic accident fatalities). One of advantages of using experimental animals is that the sham rat heart does not exhibit any pathophysiological alterations. Despite differences in the specimens, our findings of the production of HSPs in this model without hyperthermia were comparable to theirs. Furthermore, we observed the enlargement of viable cardiomyocytes and dilated left ventricular cavity in this model. Thus this experimental model appears to mimic the pathophysiological state of the human dilated cardiomyopathy.
To determine whether production of HSPs other than HSP72 and HSC73 may contribute to preserve cardiac function of the failing heart, we examined the effects of hyperthermia/6-h perfusion on production of several other HSPs. Hyperthermia/6-h perfusion did not increase the HSP27 content in the failing heart or in the sham-operated rat heart. Production of HSP60 was increased by the hyperthermia to a small degree, both in the failing heart and in the corresponding sham-operated rat heart. Because we found functional deterioration only in the failing heart, but not in the sham-operated rat heart, HSP27 and HSP60 would unlikely contribute to the preservation of cardiac function during the hyperthermia/6-h perfusion. An increase in HSP90 production was caused by the hyperthermia both in the failing hearts and in the corresponding sham-operated rat heart, whereas only the failing heart revealed a significant deterioration of cardiac function. This would imply that the production of HSP90 would be unrelated to functional deterioration of the isolated perfused heart. These results have shown that responses of these HSPs to stresses are different from those of HSP72 and HSC73, respectively. Obviously, it would be premature to conclude that HSPs other than HSP72/HSC73 do not contribute to the maintenance of cardiac function of the isolated perfused heart of the animals with CAL after hyperthermia, because we focused on an induction of HSP72/HSC73 in the failing heart and employed experimental conditions of heat stress as inducers of HSP72 and HSC73. Thus we cannot rule out the possibility that a greater degree of HSP27, HSP60, or HSP90 might be produced when hearts are subjected to hyperthermia, followed by perfusion, which is different from the present experimental conditions.
In conclusion, we have shown that failing hearts after a myocardial infarction revealed a decreased ability to produce hyperthermia-induced HSP72/HSC73 and that the amount of HSP72/HSC73, particularly HSP72, produced in the myocardium was closely related to the loss in function of the perfused heart during hyperthermia, followed by the 6-h perfusion. These results provide evidence for a possible involvement of HSP72/HSC73 in the preservation of cardiac function of the CHF animal.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. Grant N. Pierce, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada, for editing this manuscript.
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FOOTNOTES |
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This work was supported by Grant-in-Aid 10771304 for Encouragement of Young Scientists of The Ministry of Education, Science, Sports, and Culture of Japan.
Address for reprint requests and other correspondence: S. Takeo, Dept. of Pharmacology, Tokyo Univ. of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan (E-mail: takeos{at}ps.toyaku.ac.jp).
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 22 December 1999; accepted in final form 7 March 2001.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Adv Exp Med Biol
225:
287-304,
1987[Medline].
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) or
normothermia (
), followed by different perfusion
periods ranging from 0 to 8 h. Production of HSP72/HSC73 is shown
as the percent change from the control value for hearts without
hyperthermia/6-h perfusion. Each value represents means ± SE of 3 to 5 experiments.
) rat heart perfused for 6 h after 15-min
normothermia or 15-min hyperthermia [sham rats (
)]. Hearts were isolated from the CAL and
sham rats 2 and 8 wk after the operation. Each value represents the
mean ± SE of 5 experiments. *P < 0.05, significantly different from the corresponding group without
hyperthermia. #Significantly different from the sham group with
hyperthermia.
