| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Departments of Pharmacology and Pediatrics and 2 Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Belke, Darrell D., Lawrence C. H. Wang, and Gary D. Lopaschuk. Effects of hypothermia on energy metabolism in rat and Richardson's ground squirrel hearts. J. Appl.
Physiol. 82(4): 1210-1218, 1997.
Glycolysis,
glucose oxidation, palmitate oxidation, and cardiac function were
measured in isolated working hearts from ground squirrels and rats
subjected to a hypothermia-rewarming protocol. Hearts were
perfused initially for 30 min at 37°C, followed by 2 h of
hypothermic perfusion at 15°C, after which hearts were rewarmed to
37°C and further perfused for 30 min. Functional recovery in ground
squirrel hearts was greater than in rat hearts after rewarming.
Hypothermia-rewarming had a similar general effect on the various
metabolic pathways in both species. Despite these similarities, total
energy substrate metabolic rates were greater in rat than ground
squirrel hearts during hypothermia despite a lower level of work being
performed by the rat hearts, indicating that rat hearts are less
efficient than ground squirrel hearts during hypothermia.
After rewarming, energy substrate metabolism recovered completely in
both species, although cardiac work remained depressed in rat hearts.
The difference in functional recovery between rat and ground squirrel
hearts after rewarming cannot be explained by general differences in
energy substrate metabolism during hypothermia or after rewarming.
glucose oxidation; glycolysis; fatty acid oxidation; cardiac
efficiency
INTRODUCTION HYPOTHERMIA IS ROUTINELY USED during heart surgery and
transplantation as a means of reducing metabolic demand to protect the
heart from the damaging effects of prolonged exposure to
ischemia. Although considerable attention has been focused
on delaying or avoiding the damaging effects of ischemia, the
detrimental effects of hypothermia alone have received little
attention. Prolonged exposure of whole animals to hypothermia results
in a poor recovery of heart function on rewarming, eventually leading
to circulatory collapse (29). Under these conditions, the recovery of
function during rewarming is depressed to a greater extent than the
recovery of oxidative metabolism, suggesting a decreased efficiency in translating energy metabolism into work. In isolated working hearts, exposure to high levels of fatty acids during hypothermia and rewarming
leads to a greater depression in functional recovery after rewarming
(20, 26). This effect is analogous to that observed after
ischemia-reperfusion where high fatty acid concentrations can depress
the recovery of function after reperfusion (15, 16). Under these
conditions, fatty acids depress glucose oxidation, leading to a greater
dissociation between glycolysis and glucose oxidation and a greater
production of H+ (16). While most
aspects of energy metabolism during hypothermia deal with the
preservation of ATP and creatine phosphate (see Ref. 27 for example),
or the addition of substrates such as glucose and oxygen to
cardioplegic solutions to enhance ATP production (5, 28), little is
known about the potential effects of hypothermia and rewarming on
energy substrate metabolism and energy utilization in relation to work.
Although exposure to hypothermia is deleterious to many mammalian
species, a few species have evolved the means of safely utilizing low
body temperatures to survive in cold environments. Heart function in
these animals is maintained at temperatures approaching 0°C (3, 4,
17), and they are capable of recovering normal heart function on
rewarming despite spending days to weeks at temperatures just above
freezing (31). Although the nature of this cold tolerance is not
completely understood, it appears to be an innate property of hearts
from hibernating species regardless of season and physiological state
within the annual hibernation cycle (3, 4). Furthermore, these animals
are capable of adapting to a heavy reliance on fat metabolism as a
source of energy during hibernation (7). Little is known about energy substrate metabolism and energy utilization in hibernating species under conditions of hypothermia and rewarming. Whether cardiac function
in these animals is affected by the presence of high concentrations of
fatty acids after rewarming from hypothermia, and whether myocardial
energy substrate metabolism differs from that of species more sensitive
to low temperatures, remains to be examined.
This study examined cardiac function and energy substrate metabolism in
both rat hearts (cold-sensitive species) and Richardson's ground
squirrel hearts (cold-tolerant species) during hypothermia and
rewarming in the presence of high levels of fatty acids. We tested the
hypothesis that, unlike rat hearts (20, 26), the recovery of cardiac
function after rewarming in Richardson's ground squirrel hearts is not
depressed by the presence of high concentrations of fatty acids in the
perfusion medium. In addition, we compared energy
substrate metabolism in the two species to determine whether differences in substrate metabolism could aid in understanding how
hypothermia-rewarming affects myocardial performance.
METHODS
Measurement of glycolysis, glucose oxidation, and palmitate oxidation. Glycolysis and glucose oxidation were measured simultaneously in the working heart by perfusing with a solution containing [5-3H-U-14C]glucose [specific activity equaled 200,000 disintegrations/min (dpm)/ml of 3H and 200,000 dpm/ml of 14C]. Glycolysis was measured by quantitatively collecting the 3H2O liberated from [5-3H]glucose at the triose phosphate isomerase step of the glycolytic flux pathway (9), as outlined by Saddik and Lopaschuk (25). Glucose oxidation was measured by quantitative collection of 14CO2 produced by dehydrogenases within heart mitochondria (16). This included 14CO2 released as a gas from the sealed system and [14C]bicarbonate retained in the solution. Palmitate oxidation was measured in a separate series of hearts, in which the solution contained [9,10-3H]palmitate (specific activity equaled 80,000 dpm/ml of 3H). Palmitate oxidation was measured as the amount of 3H2O liberated from [3H]palmitate (measured separately from glycolysis), as outlined by Saddik and Lopaschuk. Perfusate samples for substrate utilization were collected every 10 min during the normothermic control and rewarmed periods, and every 30 min during hypothermia. Acetyl-CoA production from the various metabolic pathways was calculated by using molar ratios of 2 mol acetylCoA produced/mol of glucose oxidized and 8 mol acetyl-CoA produced/mol of palmitate oxidized. The efficiency of converting substrate oxidation into cardiac work was calculated by using total acetyl-CoA production from glucose and palmitate metabolism and the values of cardiac work obtained during the control, hypothermia, and rewarmed periods. H+ production from the imbalance between glycolysis and glucose oxidation was calculated as described previously (16). H+ production was calculated for both species for the control, hypothermia, and rewarmed periods and during the period of rewarming from 15 to 37°C (the period between 160 and 170 min). O2 consumption and cardiac work were measured at 37 and 15°C in a separate series of hearts to determine whether cardiac efficiency calculated from acetyl-CoA production at these temperatures reflect true changes in cardiac efficiency. This was done to ensure that cardiac efficiency values calculated from acetyl-CoA production are not influenced by the preferential utilization of unlabeled endogenous substrates by any of the groups. In these hearts, the pulmonary artery was cannulated, and O2 consumption was measured in the effluent from the pulmonary artery by using an O2-sensing electrode. After the measurement of O2 consumption at 37°C, hearts were cooled to 15°C and O2 consumption was measured. The O2 electrode was calibrated at each temperature to avoid artifacts induced by the changes in electrode performance and solution O2 solubility. Determination of glycogen and triacylglycerol levels. Glycogen was extracted from hearts frozen at the end of the control, hypothermia, and rewarmed periods, according to the method of Bergmeyer and Grassl (2). Glucose released from the acid hydrolysis of glycogen was measured by using a glucose determination kit from Sigma Chemical (St. Louis, MO). Tissue lipids were extracted and separated as described previously (14). After separation of neutral lipids from phospholipids on the silicic acid column, the neutral lipid fraction was dried for the determination of triacylglycerol content by using a triacylglycerol kit from Wako (Osaka, Japan). Values for triacylglycerol are expressed as micromoles per gram of dry weight after conversion by using the molecular weight of triolein (885 g/mol). Statistical analysis. A two-way analysis of variance followed by a Student-Newman-Keuls multiple-comparisons test was used to test for differences between the species and the effects of hypothermia and rewarming. A paired t-test was used to test for significance in O2 consumption within species for hearts perfused at 37 and at 15°C. A value of P < 0.05 was considered to be significant. All values presented represent means ± SE. The values presented in Tables 1, 2, 3, and 7 as the average for the control, hypothermia, and rewarmed periods represent values obtained by first averaging the data collected over that time period for the individual animals before compilation of the data for individual animals.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||
RESULTS
) and rats (
). Values represent means ± SE
for 16 ground squirrel hearts and 17 rat hearts. * Significantly
different between species at same time point.
Hypothermia caused a significant depression in all functional parameters measured in both ground squirrel and rat hearts. Coronary flow and cardiac output were significantly higher in ground squirrel hearts compared with rat hearts, and cardiac work was over twofold higher in ground squirrel hearts during hypothermia (Table 1). Despite being depressed as a result of hypothermia, the level of cardiac work being performed by the hearts of both species was stable over the course of the 2-h hypothermia period. Similarly, although coronary flow was significantly lower in both species, coronary flow normalized for cardiac work actually increased as a result of hypothermia, suggesting that the supply of substrates and O2 was adequate. Whereas cardiac work (and all other functional parameters) recovered to prehypothermic levels in ground squirrel hearts (Table 1), it was significantly depressed in rat hearts, recovering only to a maximum of 62% of prehypothermia values immediately after rewarming and slowly decreasing over the remainder of the rewarmed period (Fig. 2). All functional parameters, with the exception of HR and PSP, were significantly lower in the rat hearts compared with ground squirrel hearts during the rewarmed period. PSP, cardiac output, and cardiac work were all significantly lower than the prehypothermia control period values in rat hearts. Although coronary flow rates were slightly depressed in rat hearts during rewarming, the level of coronary flow was not depressed relative to the level of cardiac work obtained from these hearts, suggesting that perfusion was adequate for the level of work being obtained from these hearts. This observation is supported by the failure to see a significant increase in glycolysis in these hearts during the rewarmed period (see Energy substrate metabolism). Energy substrate metabolism. The average rates for glycolysis, glucose oxidation, and palmitate oxidation over the different phases of the experiment are shown in Table 2. During the initial control perfusion, glucose metabolism was similar between the two species. Although glycolytic rates tended to be higher in rat hearts, this difference was not statistically significant. The only major species difference was observed in palmitate oxidation, where rates were significantly higher in rat hearts. Cooling hearts to 15°C did not affect the two pathways of glucose metabolism equally. Hypothermia resulted in a severe reduction in the rate of glucose passing through glycolysis in both species, whereas glucose oxidation was largely unaffected. The rate of glucose oxidation remained unchanged from control period values in rat hearts but decreased slightly in ground squirrel hearts so that glucose oxidation rates were significantly lower in ground squirrel hearts than in rat hearts during the hypothermic period. Palmitate oxidation was significantly depressed in ground squirrel and rats, being decreased to 19% of control period values in both species. Despite the decrease as a result of hypothermia, the rate of palmitate oxidation remained significantly higher in rat than ground squirrel hearts. After rewarming, rates of substrate metabolism recovered to, or exceeded, values obtained during the prehypothermic control period, with the rate of glucose oxidation being significantly increased in both species after rewarming. Glycolysis was slightly (although not significantly) increased in both species despite the fact that function and coronary flow were only depressed in rat hearts, suggesting that this increase does not occur as a result of ischemia. Because changes in temperature may affect energy substrate metabolism either by acting directly to slow the enzymes involved in the metabolic pathway or by reducing metabolic demand by decreasing the level of work being performed by the heart, substrate metabolism through the individual pathways during the various phases of the protocol was also normalized for cardiac work (Table 3). When glycolysis is normalized for cardiac work, no significant species differences are observed, and whereas glycolysis tends to increase during rewarming, the values are not significantly different from the control period. Glucose oxidation normalized for cardiac work was significantly higher than control period values during hypothermia and rewarming in both species. In contrast, palmitate oxidation normalized for cardiac work increased slightly (although not significantly) in rats during hypothermia but decreased significantly in ground squirrels. This suggests that the increased reliance on glucose oxidation in rat hearts during hypothermia is not accompanied by a reduction in palmitate oxidation. After rewarming, palmitate oxidation returns to control period values in ground squirrel hearts but is significantly elevated in rat hearts. These results suggest that substrate metabolism, especially oxidative metabolism, is not solely affected by the changes in cardiac work that occur as a result of hypothermia and rewarming. Acetyl-CoA production from substrate metabolism. The contribution of glucose and palmitate to acetyl-CoA production for oxidative metabolism is shown in Table 4. In both species, palmitate provides the bulk of acetyl-CoA for oxidative metabolism, and while the contribution from glucose is increased three- to fourfold during hypothermia, palmitate still supplies over 87%. The two species show similar changes in the contribution of substrates to overall metabolism, despite the significantly higher level of total acetyl-CoA production in rat hearts during the control and hypothermic periods. During the rewarmed period, the total acetyl-CoA derived from substrates was similar between the species despite differences in the recovery of cardiac work, suggesting a species difference in converting acetyl-CoA into ATP or an increased expenditure in converting ATP into mechanical work developed as a result of hypothermia-rewarming.
|
|||||||||||||||||||||||||||||||||||||||||||
Significantly different from initial control values. * Significantly different between species under same state.
To determine whether the changes in cardiac efficiency observed during hypothermia, and calculated by using acetyl-CoA production, accurately reflect the response of metabolism and cardiac work in the two species, a series of hearts was perfused at 37 and 15°C for measurment of cardiac work and O2 consumption as an index of oxidative metabolism (Table 5). Under hypothermic conditions, cardiac work was decreased to 26% of euthermic values in ground squirrel hearts while O2 consumption decreased to 18% of euthermic values. In contrast, cardiac work decreased to 16% in rat hearts while O2 consumption only decreased to 24%. This indicates that a disparity between cardiac work and metabolism occurs in these species during hypothermia. Under these conditions, cardiac efficiency was observed to increase in ground squirrel hearts and to decrease in rat hearts as a result of cooling to 15°C. This suggests that the changes in cardiac efficiency calculated from substrate metabolism accurately reflect changes in the relationship between cardiac work and metabolism between the species at 15°C.
|
||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
1 · g
dry wt1, rat vs. ground
squirrel) and glucose oxidation (254 ± 59 vs. 204 ± 58 nmol · min1 · g
dry wt1, rat vs. ground
squirrel) observed during this transition period. The values for this
time period are presented as a rate for comparison with the other
periods of the experiment despite the fact that both temperature and
cardiac work increase during rewarming so that the values do not
represent a true steady-state rate. Although H+ production tended to be higher
in rat hearts, the differences were only significant during the
rewarming period (160-170 min). This effect was primarily due to a
faster recovery of glycolysis in rat than ground squirrel hearts during
this period.
DISCUSSION
Although hypothermia is widely used during surgery as a means of reducing metabolic demand during ischemia, the effects of hypothermia itself on heart function and energy metabolism have received little attention. Previous studies have suggested that cold cardioplegia is less favorable than warm cardioplegia in preserving heart function (18). Similarly, whole animal hypothermia leads to a depression in heart function during rewarming (29), and substrates such as fatty acids are capable of exacerbating the depression of function after hypothermia and rewarming (20, 26). The potential interactions of hypothermia and rewarming with energy substrate metabolism and mechanical function have not been examined despite interest in stimulating oxidative metabolism to improve ATP production through the addition of substrates and O2 to the cardioplegic medium (5, 28) or the use of blood cardioplegia to provide additional O2-carrying capacity (30). Because plasma fatty acid levels can rise dramatically during surgery, the practice of using blood cardioplegia may expose the hypothermic heart to high concentrations of fatty acids. Thus an understanding of the interaction of hypothermia with metabolism and function would be beneficial in developing strategies for maximizing energy production and help to improve the recovery of function after rewarming.
Energy substrate preference during hypothermia and rewarming. In the present study, the recovery of function in ground squirrel hearts after rewarming was significantly better than that observed in rat hearts despite the presence of high concentrations of fatty acids in the perfusion medium. A general overview of metabolism revealed that hypothermia had a similar effect on metabolism in both species, with glycolysis being depressed to a greater extent than oxidative metabolism and palmitate oxidation being depressed to a greater extent than glucose oxidation. Because we only measured the fate of exogenously added energy substrates, the changes in substrate utilization that occur during hypothermia and rewarming could be due to the preferential utilization of endogenous substrates (glycogen and triacylglycerol). However, analysis of glycogen and triacylglycerol levels did not indicate preferential utilization of these substrates during hypothermia or after rewarming in both species. Similarly, the estimated changes in cardiac efficiency in both species as a result of hypothermia were similar whether substrate oxidation or O2 consumption was used as an index of metabolism, supporting the observation that endogenous substrate mobilization did not contribute significantly to energy metabolism during the experiment. Previous estimates of hypothermia effects on glycolysis, determined by examining lactate production and glycogen depletion, have also suggested that glycolysis is greatly suppressed by hypothermia (24). By perfusing hearts with [3H]glucose and relevant concentrations of fatty acids, we were able to confirm these results by directly measuring the flux of glucose through the glycolytic pathway. Our observation that glycogen content was not significantly reduced as a result of hypothermia (Table 6) confirms previous findings that hypothermia itself does not increase glycogen utilization in the heart (23, 26). Although glycolytically derived ATP is thought to be preferentially used in the maintenance of transmembrane ionic gradients (8, 22), it is unlikely that the dramatic reduction in glycolysis plays a role in mediating the decreased cardiac efficiency or the poor recovery of function in rat hearts after rewarming, because glycolytic flux is similarly depressed in ground squirrels with none of the adverse effects. However, this observation assumes that glycolytically derived ATP plays an equally important role in both species, and a previous report has suggested that under hypothermic conditions (15°C) rat and ground squirrel hearts behave differently when glycolysis is inhibited by iodoacetate (6). This suggests that glycolytically derived ATP may be more important for myocyte physiology in rat than ground squirrel hearts. However, this study did not attempt to compensate for the depression in glucose oxidation that would result from the inhibition of glycolysis, making these results difficult to interpret. Clearly, any role that a depression in glycolysis may play in affecting heart function in hypothermic rat hearts requires further study. The increase in glucose oxidation relative to the other pathways during hypothermia may be due to a rise in intracellular and intramitochondrial Ca2+ (12), leading to activation of the pyruvate dehydrogenase complex through Ca2+-mediated activation of pyruvate dehydrogenase phosphatase (19). Regardless of how glucose oxidation is stimulated by hypothermia, the fact that it is significantly increased relative to cardiac work in both species suggests that this is a feature common to cold-sensitive and cold-tolerant species. Similarly, the fact that glucose oxidation is not depressed to the same degree as glycolysis may explain the beneficial effects of adding lactate to cardioplegic solutions under clinical conditions to improve the recovery of function (28). The conversion of lactate to pyruvate provides carbohydrate for the TCA cycle, bypassing the reduced supply from glycolysis. When fatty acid oxidation rates are normalized for differences in cardiac work, the response of the two species to hypothermia differs. Under normal conditions, an increased reliance on glucose leads to a corresponding decrease in fatty acid utilization (24). In ground squirrel hearts, palmitate oxidation normalized for cardiac work decreased during hypothermia, but it is increased slightly relative to control period levels in rat hearts. Because fatty acid oxidation provides the bulk of acetyl-CoA for oxidative metabolism, this has the effect of increasing cardiac efficiency in the ground squirrel hearts and decreasing efficiency in rat hearts. Why fatty acid oxidation responds differently in the two species in relation to cardiac work during the hypothermic period is unknown, but it suggests that non-work-related energy expenditure may increase in rat hearts during hypothermia, with this effect becoming more exaggerated during rewarming when substrate metabolism becomes further uncoupled from cardiac work. After rewarming, the recovery of substrate metabolism in both species returns to prehypothermia control period values in both species, suggesting that hypothermia-rewarming does not adversely affect substrate flux through the metabolic pathways. Rather, the poor recovery of function in rat hearts appears to be related to the inability to convert energy substrate metabolism into mechanical work. Whether this is due to an inability to convert energy substrates into ATP (i.e., an uncoupling of oxidative phosphorylation) or ATP into mechanical work (i.e., more ATP is used for non-work-related reactions) cannot be distinguished in the present study. H+ production during hypothermia and rewarming. A dissociation of glycolysis from glucose oxidation leading to a greater production of H+ is thought to contribute to Ca2+ overload during reperfusion after ischemia (16). Although hypothermia has been shown to lead to an increase in intracellular Ca2+ in rat myocardial tissue (12, 26), the reduction in H+ production as a result of the closer coupling of glycolysis and glucose oxidation makes it unlikely that fatty acids contribute to the rise in intracellular Ca2+ through this mechanism during hypothermia itself (this does not exclude the possibility that other sources of H+ can affect Ca2+ overload during hypothermia). Similarly, unlike the situation of reperfusion after ischemia (16), H+ production was not markedly enhanced in rat hearts during the rewarmed period. The only species difference that may account for the effect of fatty acids occurred during rewarming itself, when increased glycolysis in rat hearts lead to a significantly higher rate of H+ production. An overproduction of H+ during this period may have prevented or slowed the reestablishment of a normal intracellular Ca2+ concentration in rat hearts during rewarming when they may be trying to unload excess Ca2+ accumulated during hypothermia. This may account for the observation by Mjos et al. (20) that fatty acids are most detrimental when present during rewarming itself and for the higher level of tissue Ca2+ observed immediately after rewarming by Steigen et al. (26) in rat hearts perfused with 1.2 mM palmitate. A lower H+ production in ground squirrels during rewarming, along with better control of intracellular Ca2+ during hypothermia (11, 12), may have contributed to the better recovery of function after rewarming in this species. Cardiac efficiency during hypothermia. The increased cardiac efficiency measured in ground squirrels by using O2 consumption as a metabolic index is similar to values reported by Burlington and Darvish (3) under similar conditions with use of a different species of ground squirrel. The effect of temperature on cardiac efficiency is variable according to the species and the extent of cooling. Some studies have shown that a mild hypothermia of only a few degrees can increase cardiac efficiency in dogs (21) and rats (3), whereas deeper hypothermia may reduce cardiac efficiency in dogs (1) and the mechanical efficiency in rat papillary muscle (13). The underlying reasons for the differences in cardiac efficiency at different temperatures and in different species remain an enigma. Differences in cardiac efficiency may result from species differences in the efficiency of oxidative phosphorylation, the expenditure of energy for noncontractile work such as ion homeostasis, changes in the sensitivity of myofibrils to activator Ca2+, or a combination of these effects. In this study, we are unable to distinguish which of these possibilities contribute to the effect of hypothermia on efficiency. The efficiency of producing energy through the various metabolic pathways may be considered as metabolic efficiency. Hypothermia can affect metabolic efficiency by altering the ratio of carbohydrates to fatty acids being oxidized (more O2 is required to obtain the same amount of ATP from fatty acids than from carbohydrates). Hypothermia can also potentially uncouple oxidative phosphorylation so that a general decrease in energy production occurs regardless of the type of energy substrate metabolized. Changes in efficiency involving the conversion of ATP into cardiac work may be considered as mechanical efficiency. Mechanical efficiency is dependent on the efficiency of ATP use by the various biochemical reactions required to maintain normal myocyte physiology, whether this is directly related to contractile force development or basal metabolism. A better distinction between the different factors affecting cardiac efficiency during hypothermia is required to gain a better understanding of the nature of the damage induced by exposure to hypothermia. The decrease in cardiac efficiency in rat hearts during hypothermia may be related to a lower endogenous level of sarcoplasmic reticulum (SR) activity and a greater thermal sensitivity of SR activity to inhibition at low temperatures in comparison with ground squirrels (10). In addition, the higher sensitivity of the SR Ca2+ release channel to stimulation by Ca2+ in rat hearts suggests that a futile cycle of SR Ca2+ uptake and release may develop in this species at low temperatures, which could account for the decreased efficiency in these hearts at low temperatures. Whether Ca2+ handling in ground squirrel hearts plays a role in increasing efficiency remains to be examined. Summary. Hypothermia is capable of reducing energy substrate metabolism in cold-sensitive and cold-tolerant species but does not affect all metabolic pathways equally. Ground squirrels are able to recover cardiac work after rewarming despite the presence of high concentrations of fatty acids, whereas work was depressed in rat hearts under similar conditions. Hypothermia induced a general change in the pattern of metabolism, which was similar for the two species. The recovery of substrate metabolism does not appear to be the cause of the poor recovery of cardiac work in rat hearts after reperfusion. The major differences between cold-sensitive and cold-insensitive species involved cardiac efficiency during hypothermia and the coupling of glycolysis and glucose oxidation during rewarming. The extent to which factors, either individually or synergystically, act to reduce the recovery of function in the hearts of cold-sensitive species requires further study and may provide insights that are beneficial in improving function recovery in the heart after the use of hypothermia in a clinical setting.ACKNOWLEDGEMENTS
This research was funded by grants from the Medical Research Council and the Natural Sciences and Engineering Research Council of Canada. G. D. Lopaschuk is a Medical Research Council of Canada Scientist and a Senior Scholar of the Alberta Heritage Foundation for Medical Research. D. D. Belke is a trainee of the Heart and Stroke Foundation of Canada.
FOOTNOTES
Address for reprint requests: G. Lopaschuk, Cardiovascular Disease Research Group, 423 Heritage Medical Research Centre, Univ. of Alberta, Edmonton, AB, Canada T6G 2S2.
Received 7 August 1996; accepted in final form 22 November 1996.
REFERENCES
| 1. | Archie, J. P., and J. W. Kirklin. Effect of hypothermic perfusion on myocardial oxygen consumption and coronary resistance. Surg. Forum 24: 186-188, 1973. [Medline] . |
| 2. | Bergmeyer, J., and M. Grassl. Poly-, oligo-, and disaccharides: glycogen. In: Methods of Enzymatic Analysis (3rd ed.). New York: Academic, 1983. , chapt. 1.2, p. 11-18. |
| 3. | Burlington, R. F., and A. Darvish. Low-temperature performance of isolated working hearts from a hibernator and a nonhibernator. Physiol. Zool. 61: 387-395, 1988. . |
| 4. | Caprette, D. R., and J. B. Senturia. Isovolumetric performance of isolated ground squirrel and rat hearts at low temperature. Am. J. Physiol. 247 (Regulatory Integrative Comp. Physiol. 16): R722-R727, 1984. . |
| 5. | Doherty, N. E., J. F. Turocy, G. A. Geffin, D. D. O'Keefe, J. S. Titus, and W. M. Daggett. Benefits of glucose and oxygen in multidose cold cardioplegia. J. Thorac. Cardiovasc. Surg. 103: 219-229, 1992. [Abstract] . |
| 6. | Erasmus, R., and D. W. Rennie. Substrate uptake and utilization in normothermic and hypothermic perfused rat and ground squirrel hearts (Abstract). Physiologist 10: 163, 1967. . |
| 7. | Galster, W. A., and P. Morrison. Seasonal changes in serum lipids and proteins in the 13-lined ground squirrel. Comp. Biochem. Physiol. 18: 489-501, 1966. [Medline] . |
| 8. | Glitsch, H. G., and A. Tappe. The Na+/K+ pump of cardiac Purkinje cells is preferentially fueled by glycolytic ATP production. Pfluegers Arch. 422: 380-385, 1993. [Medline] . |
| 9. | Hue, L., and H. Hers. On the use of [3H, 14C] labeled glucose in the study of the so-called futile cycles in liver and muscle. Biochem. Biophys. Res. Commun. 58: 532-539, 1974. [Medline] . |
| 10. |
Liu, B.,
D. D. Belke,
and
L. C. H. Wang.
Ca2+ uptake by cardiac sarcoplasmic reticulum at low temperature in rats and ground squirrels.
Am. J. Physiol.
272:
R1121-R1127,
1997.
|
| 11. | Liu, B., and L. C. H. Wang. Regulation of cardiac cytosolic free Ca2+ at low temperature in the Richardson's ground squirrel. In: Life in the Cold, edited by C. Carey, G. L. Florant, B. A. Wunder, and B. Howitz. Boulder, CO: Westview, 1993, p. 207-215. . |
| 12. | Liu, B., L. C. H. Wang, and D. D. Belke. Effect of low temperature on the cytosolic free Ca2+ in rat ventricular myocytes. Cell Calcium 12: 11-18, 1991. [Medline] . |
| 13. | Loiselle, D. S. The effects of temperature on the energetics of rat papillary muscle. Pfluegers Arch. 379: 173-180, 1979. [Medline] . |
| 14. |
Lopaschuk, G. D.,
C. A. Hansen,
and
J. R. Neely.
Fatty acid metabolism in hearts containing elevated levels of CoA.
Am. J. Physiol.
250 (Heart Circ. Physiol. 19):
H351-H359,
1986.
|
| 15. |
Lopaschuk, G. D.,
M. A. Spafford,
N. J. Davies,
and
S. R. Wall.
Glucose and palmitate oxidation in isolated working rat hearts reperfused after a period of transient global ischemia.
Circ. Res.
66:
546-553,
1990.
|
| 16. |
Lopaschuk, G. D.,
R. B. Wambolt,
and
R. L. Barr.
An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts.
J. Pharmacol. Exp. Ther.
264:
135-144,
1993.
|
| 17. | Lyman, C. P., and D. C. Blinks. The effect of temperature on the isolated hearts of closely related hibernators and nonhibernators. J. Cell Comp. Biol. 54: 53-63, 1959. . |
| 18. |
Mauney, M. C.,
and
I. L. Kron.
The physiological basis of warm cardioplegia.
Ann. Thorac. Surg.
60:
819-823,
1995.
|
| 19. | McCormack, J. G., R. L. Daniel, N. J. Osbaldeston, G. A. Rutter, and R. M. Denton. Mitochondrial Ca2+ transport and the role of matrix Ca2+ in mammalian tissues. Biochem. Soc. Trans. 20: 153-159, 1992. [Medline] . |
| 20. | Mjos, O. D., K. Ichihara, E. Fellenius, T. Myrmel, and J. R. Neely. Fatty acids suppress recovery of heart function after hypothermic perfusion. Ann. Thorac. Surg. 52: 965-970, 1991. [Abstract] . |
| 21. | Monroe, R. G., R. H. Stang, C. G. LaFarge, and J. Levy. Ventricular performance, pressure-volume relationships, and O2 consumption during hypothermia. Am. J. Physiol. 206: 67-73, 1964. . |
| 22. |
Opie, L. H.
Cardiac metabolismemergence, decline and resurgence. Part I.
Cardiovasc. Res.
26:
721-733,
1992.
|
| 23. | Orme, S. K., G. A. Kelly, K. Brendel, and R. Bressler. Glucose metabolism in the hypothermic perfused rat heart. Life Sci. 20: 597-608, 1977. [Medline] . |
| 24. | Randle, P. J., D. A. Priestman, S. Mistry, and A. Halsall. Mechanisms modifying glucose oxidation in diabetes mellitus. Diabetologica 37, Suppl. 2: S155-S161, 1994. |
| 25. |
Saddik, M.,
and
G. D. Lopaschuk.
Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts.
J. Biol. Chem.
266:
8162-8170,
1991.
|
| 26. |
Steigen, T. K.,
E. Aasum,
T. Myrmel,
and
T. S. Larsen.
Effects of fatty acids on myocardial calcium control during hypothermic perfusion.
J. Thorac. Cardiovasc. Surg.
107:
233-241,
1994.
|
| 27. | Stringham, J. C., J. H. Southard, J. Hegge, L. Triemstra, B. L. Fields, and F. O. Belzer. Limitations of heart preservation by cold storage. Transplantation 53: 287-294, 1992. [Medline] . |
| 28. | Teoh, K. H., D. A. G. Mickle, R. D. Weisel, M. M. Madonik, J. Ivanov, R. D. Harding, A. D. Romaschin, and J. C. Mullen. Improving myocardial metabolic and functional recovery after cardioplegic arrest. J. Thorac. Cardiovasc. Surg. 95: 788-798, 1988. [Abstract] . |
| 29. |
Tveita, T.,
E. Mortensen,
O. Hevroy,
H. Refsum,
and
K. Ytrehus.
Experimental hypothermia: effects of core cooling and rewarming on hemodynamics, coronary blood flow and myocardial metabolism in dogs.
Anesth. Analg.
79:
212-218,
1994.
|
| 30. | Vinten-Johansen, J., S. J. Julian, H. Yokoyama, W. E. Johnston, T. D. Smith, D. S. McGee, and A. R. Cordell. Efficacy of myocardial protection with hypothermic blood cardioplegia depends on oxygen. Ann. Thorac. Surg. 52: 9399-948, 1991. . |
| 31. | Wang, L. C. H. Ecological, physiological, and biochemical aspects of torpor in mammals and birds. In: Advances in Comparative and Environmental Physiology, edited by L. C. H. Wang. Berlin: Springer-Verlag, 1989, p. 361-401. . |
This article has been cited by other articles:
|
|
 |
|
  F. van Breukelen and S. L. Martin Molecular Biology of Thermoregulation: Invited Review: Molecular adaptations in mammalian hibernators: unique adaptations or generalized responses? J Appl Physiol, June 1, 2002; 92(6): 2640 - 2647. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
