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PubMed2002

Coronary patency and its relation to contractile reserve in hibernating myocardium.

OBJECTIVES: Recent clinical studies suggest that contractile reserve may occur in a minority of viable, chronically dysfunctional segments with reduced resting flow (hibernating myocardium). We hypothesized that epicardial artery patency might predict which segments have critically reduced subendocardial flow reserve and limited contractile reserve. METHODS: Pigs were chronically instrumented with a fixed stenosis on the left anterior descending coronary artery (LAD) to produce hibernating myocardium. At least 3 months later, flow at rest and during adenosine vasodilation (microspheres), ventricular function and contractile reserve (contrast ventriculography), and (18)F-2-deoxyglucose (FDG) deposition (ex vivo tissue counting) were quantified. RESULTS: Hibernating myocardium (regional dysfunction with reduced resting perfusion) was present in animals with an occluded (n=40) or patent (n=19) LAD. Viability was confirmed by histology and FDG deposition. In collateral-dependent hibernating myocardium, subendocardial flow did not increase above baseline levels during epinephrine or adenosine stimulation, consistent with exhausted subendocardial flow reserve at rest. This was associated with limited contractile reserve and regionally increased FDG deposition. In contrast, subendocardial flow reserve was present in hibernating myocardium distal to a patent artery. Contractile reserve during epinephrine infusion in this group was significantly greater than in animals with an occluded artery. CONCLUSIONS: The physiology and metabolism of hibernating myocardium was dependent upon stenosis severity and its effects on subendocardial flow reserve. In collateral-dependent hibernating myocardium, contractile reserve was limited in the setting of exhausted subendocardial flow reserve, thus supporting the hypothesis that metabolic imaging may be preferable for determining viability distal to a complete occlusion.

Adenosine↗
PubMed2002

Variability of contractile reserve in hibernating myocardium: dependence on the method of inotropic stimulation.

OBJECTIVE: Contractile reserve during graded beta-adrenergic stimulation identifies viability in patients with left ventricular dysfunction. Nevertheless, contractile reserve is frequently absent in viable, chronically dysfunctional myocardium with reduced resting flow (hibernating myocardium). The goal of this study was to evaluate the mechanisms responsible for limited contractile reserve in hibernating myocardium. METHODS: Pigs were chronically instrumented with a left anterior descending coronary artery (LAD) stenosis to produce hibernating myocardium; and regional flow, function and hemodynamics were assessed during graded beta-adrenergic stimulation (epinephrine). RESULTS: The chronic LAD stenosis produced a critical reduction in coronary flow reserve with regional reductions in resting subendocardial flow (0.69+/-0.05 vs. 1.03+/-0.11 ml/min/g in shams, P<0.05) and wall thickening (2.0+/-0.4 vs. 4.3+/-0.4 mm in shams, P<0.05), consistent with hibernating myocardium. In sham controls, LAD flow and function increased during graded, steady-state increases in epinephrine. Nevertheless, despite similar external determinants of demand in animals with hibernating myocardium, neither subendocardial flow (peak response: 0.66+/-0.14 and peak dose: 0.58+/-0.13 ml/min/g, respectively) nor wall thickening (3.0+/-0.5 and 2.5+/-0.6 mm, respectively) increased during graded epinephrine infusion. However, during a transient epinephrine infusion to the maximum dose used in the graded protocol, flow remained unchanged (0.80+/-0.06 to 0.85+/-0.08 ml/min/g) but wall thickening improved (2.3+/-0.4 to 4.1+/-0.6 mm, P<0.05). CONCLUSIONS: These data indicate that variability in contractile reserve in hibernating myocardium is at least partly related to the protocol used for beta-adrenergic stimulation. The blunted steady-state responses to beta-adrenergic stimulation raise the possibility that, like moderate supply-induced ischemia, an exquisite matching between flow and function develops during moderate demand-induced ischemia. This prevents metabolic deterioration in hibernating myocardium but limits contractile function during increases in the external determinants of myocardial metabolism.

Adrenergic beta-Agonists↗
PubMed1999

The carvedilol hibernation reversible ischaemia trial; marker of success (CHRISTMAS). The CHRISTMAS Study Steering Committee and Investigators.

BACKGROUND: Carvedilol improves left ventricular (LV) function when heart failure is due to LV systolic dysfunction, but the magnitude of the response is heterogeneous among patients with coronary disease, possibly reflecting the presence or volume of hibernating myocardium. AIMS: The primary objective of the study is to determine whether the presence of hibernating myocardium predicts the magnitude of improvement in LV ejection fraction in response to carvedilol among patients with heart failure and LV systolic dysfunction due to coronary disease. METHODS: The study is a prospective, randomised, parallel-group, double-blind, multi-centre study comparing carvedilol and placebo over a period of approximately 6 months in the above patient population. The primary end-point is the comparison of the mean change, from baseline to the final visit, in radionuclide-determined LV ejection fraction among patients on placebo with those on carvedilol stratified according to the presence of hibernating myocardium. Hibernating status will be determined by a combination of echocardiographic and myocardial perfusion (technetium-99m sestamibi) imaging. RESULTS: 255 patients have undergone screening tests of which 207 have been randomised so far. The study intends to randomise 400 patients and the first report of results is expected in 2000. CONCLUSIONS: As far as we are aware this is the first randomised controlled trial to investigate the effects of treatment in patients stratified according to the presence of hibernating myocardium. The study will provide insights into the prevalence of myocardial hibernation, its natural history, and its influence on prognosis as well as the interaction between the presence of hibernating myocardium and the effects of treatment with carvedilol.

Adrenergic beta-Antagonists↗
PubMed1998

The persistence of hibernating myocardium after acute myocardial infarction.

OBJECTIVE: To establish the persistence of hibernating myocardium initially detected after myocardial infarction treated with thrombolysis. METHODS AND RESULTS: Fourteen patients underwent gated positron emission tomography with 18-fluoro-deoxyglucose and N13-ammonia at a median of 8 days after first myocardial infarction. Repeat scans were performed at a median of 13 weeks post-infarction. A total of 148 (30.9%) myocardial segments showed reduced N13-ammonia uptake at the time of the first scan compared with 154.5 (32.2%) segments at the time of repeat imaging. The median change in the number of segments with reduced perfusion was -1.0. Initially 13 subjects had hibernating myocardium, seven patients had large areas and six had smaller regions. Six (46.2%) subjects had repeat scans showing unchanged areas of hibernating tissue and seven had second scans demonstrating changes in the size of the region of hibernating myocardium. One patient had no hibernating myocardium on either scan. CONCLUSIONS: Positron emission tomography performed several months after myocardial infarction demonstrates significant changes in myocardial perfusion. However, a reduction in the number of segments with reduced perfusion does not always result in an improvement in myocardial metabolism and contraction. Whilst most regions of hibernating myocardium were still present several months after infarction, in only approximately half was the size of the mismatched region unchanged. Therefore it is not possible to predict the fate of hibernating myocardium which is present after infarction.

Aged↗
PubMed1997

Myocardial hibernation. A form of endogenous protection?

The origins and mechanisms of myocardial hibernation are obscure and controversial. Indeed, there is even debate over whether the hibernating heart is 'ischaemic'. In attempting to clarify this last point, it is clear that there is no universally agreed definition of ischaemia. It is proposed that much of the confusion can be resolved distinguishing between biochemical and physiological ischaemia and ascertaining whether the tissue metabolism is in steady state equilibrium or is progressively deteriorating. On the basis of this, the hibernating heart would be designated as physiologically ischaemic but it would not exhibit the characteristics of biochemical ischaemia. This distinction also allows one to argue that hibernation is an adaptive phenomenon in which cardiac metabolism and function are down-regulated to match the available energy supply (perfusion-contraction matching). Such an adaptive response would be expected to avoid the occurrence of tissue injury but it would not be expected to prevent the occurrence of adaptive morphological changes that always occur with prolonged inactivity of muscle. However, the morphological characteristics of hibernation are controversial and, like so many other aspects of the hibernation controversy, the problem may not be resolved until an acceptable animal model of hibernation has been developed.

Acute Disease↗
PubMed1998

Hibernating myocardium.

Decreased myocardial contraction occurs as a consequence of a reduction in blood flow. The concept of hibernation implies a downregulation of contractile function as an adaptation to a reduction in myocardial blood flow that serves to maintain myocardial integrity and viability during persistent ischemia. Unequivocal evidence for this concept exists in scenarios of myocardial ischemia that lasts for several hours, and sustained perfusion-contraction matching, recovery of energy and substrate metabolism, the potential for recruitment of inotropic reserve at the expense of metabolic recovery, and lack of necrosis are established criteria of short-term hibernation. The mechanisms of short-term hibernation, apart from reduced calcium responsiveness, are not clear at present. Experimental studies with chronic coronary stenosis lasting more than several hours have failed to continuously monitor flow and function. Nevertheless, a number of studies in chronic animal models and patients have demonstrated regional myocardial dysfunction at reduced resting blood flow that recovered upon reperfusion, consistent with chronic hibernation. Further studies are required to distinguish chronic hibernation from cumulative stunning. With a better understanding of the mechanisms underlying short-term hibernation, it is hoped that these adaptive responses can be recruited and reinforced to minimize the consequences of acute myocardial ischemia and delay impending infarction. Patients with chronic hibernation must be identified and undergo adequate reperfusion therapy.

Adaptation, Physiological↗
PubMed2002

Dissociation of regional adaptations to ischemia and global myolysis in an accelerated Swine model of chronic hibernating myocardium.

We tested the hypothesis that an acute critical limitation in coronary flow reserve could rapidly recapitulate the physiological, molecular, and morphological phenotype of hibernating myocardium. Chronically instrumented swine were subjected to a partial occlusion to produce acute stunning, followed by reperfusion through a critical stenosis. Stenosis severity was adjusted serially so that hyperemic flow was severely reduced yet always higher than the preocclusion resting level. After 24 hours, resting left anterior descending coronary artery (LAD) wall thickening had decreased from 36.3+/-4.0% to 25.5+/-3.7% (P<0.05), whereas resting flow had remained normal (67+/-6 versus 67+/-8 mL/min, respectively). Although peak hyperemic flow exceeded the prestenotic value, resting flow (45+/-10 mL/min) and LAD wall thickening (17.0+/-5.0%) progressively decreased after 2 weeks, when physiological features of hibernating myocardium had developed. Regional reductions in sarcoplasmic reticulum proteins were present in hibernating myocardium but absent in stunned myocardium evaluated after 24 hours. Histological analysis showed an increase in connective tissue along with myolysis (myofibrillar loss per myocyte >10%) and increased glycogen typical of hibernating myocardium in the LAD region (33+/-3% of myocytes from animals with hibernating myocardium versus 15+/-4% of myocytes from sham-instrumented animals, P<0.05). Surprisingly, the frequency of myolysis was similar in normally perfused remote regions from animals with hibernating myocardium (32+/-7%). We conclude that the regional physiological and molecular characteristics of hibernating myocardium develop rapidly after a critical limitation in flow reserve. In contrast, the global nature of myolysis and increased glycogen content dissociate them from the intrinsic adaptations to ischemia. These may be related to chronic elevations in preload but appear unlikely to contribute to chronic contractile dysfunction.

Adaptation, Physiological↗
PubMed2004

Program of cell survival underlying human and experimental hibernating myocardium.

Hibernating myocardium refers to chronically dysfunctional myocardium in patients with coronary artery disease in which cardiac viability is maintained and whose function improves after coronary revascularization. It is our hypothesis that long-term adaptive genomic mechanisms subtend the survival capacity of this ischemic myocardium. Therefore, the goal of this study was to determine whether chronic repetitive ischemia elicits a gene program of survival protecting hibernating myocardium against cell death. Accordingly, we measured the expression of survival genes in hibernating myocardium, both in patients surgically treated for hibernation and in a chronic swine model of repetitive ischemia reproducing the features of hibernation. Human hibernating myocardium was characterized by an upregulation of genes and corresponding proteins involved in anti-apoptosis (IAP), growth (VEGF, H11 kinase), and cytoprotection (HSP70, HIF-1alpha, GLUT1). In the swine model, the same genes and proteins were upregulated after repetitive ischemia, which was accompanied by a concomitant decrease in myocyte apoptosis. These changes characterize viable tissue, because they were not found in irreversibly injured myocardium. Our report demonstrates a novel mechanism by which the activation of an endogenous gene program of cell survival underlies the sustained viability of the hibernating heart. Potentially, promoting such a program offers a novel opportunity to salvage postmitotic tissues in conditions of ischemia.

Adult↗
PubMed2002

Glial cell line-derived neurotrophic factor-supplemented hibernation of fetal ventral mesencephalic neurons for transplantation in Parkinson disease: long-term storage.

OBJECT: Investigation of fetal dopaminergic tissue transplantation is being conducted in animal models and clinical trials as a potential treatment for advanced Parkinson disease (PD). Because the availability of fetal tissue is limited, however, the duration of its storage prior to transplantation is a key practical issue. Longer storage times may enable fetal tissue obtained over several days to be pooled together for transplantation in a recipient. Glial cell line-derived neurotrophic factor (GDNF) has been shown to improve survival of stored human dopaminergic tissue prior to transplantation. The objective of this study was to evaluate GDNF-supplemented hibernation of fetal dopaminergic tissue for extended periods of 6 to 15 days. METHODS: A total of 27 rat ventral mesencephalons (VMs) were obtained in gestation Day 14 rat fetuses, and three were cultured immediately (fresh-culture control group). The remaining 24 VMs were divided sagittally along the midline to form 48 equal pieces of hemimesencephalons. Twenty-four pieces were stored with GDNF-supplemented hibernation medium for 6, 9, 12, or 15 days, and the 24 "partner" hemimesencephalons were stored in control hibernation medium for the same periods of time. Tissue was cultured for 48 hours and processed for tyrosine hydroxylase (TH) immunoreactivity and cresyl violet. Cell counts for all cultures and percentage of TH-immunoreactive cells were obtained. The percentage of TH-positive cells for the fresh control group was 6.3 +/- 0.5%; that measured in cultures derived from tissue hibernated in GDNF-supplemented medium was significantly increased at 6 and 9 days posthibernation compared with the fresh-culture control group and the partner groups stored in hibernation medium only. No significant increase in percentage of TH-immunoreactive cells was observed in the 12- and 15-day hibernation groups. CONCLUSIONS: In summary the authors found that fetal dopaminergic tissue can safely be stored up to 9 days in GDNF-supplemented hibernation medium. Furthermore the percentage of TH-immunoreactive cells is significantly increased after 6 and 9 days of storage in this medium, improving the yield of TH-positive cells prior to transplantation. These observations may have important clinical implications for collecting fetal dopaminergic cells and improving their survival after transplantation.

Animals↗
PubMed2003

Dobutamine-induced contractile reserve in stunned, hibernating, and scarred myocardium in patients with ischemic cardiomyopathy.

UNLABELLED: Because of damage to cardiomyocytes and the contractile apparatus, contractile reserve may be observed less frequently in hibernating than in stunned myocardium. The aim of this study was to assess the presence of contractile reserve in response to dobutamine infusion in a large group of patients with stunned and hibernating myocardium. METHODS: A total of 198 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fraction < or = 40%) underwent resting 2-dimensional echocardiography to assess regional contractile dysfunction. On the basis of assessment of perfusion (with (99m)Tc-tetrofosmin SPECT) and glucose use (with (18)F-FDG SPECT), dysfunctional segments were grouped. Dysfunctional segments with normal perfusion were classified as stunned. Dysfunctional segments with a perfusion defect were classified as hibernating when a perfusion-(18)F-FDG mismatch was present. Dysfunctional segments with a perfusion defect were classified as scar tissue when a perfusion-(18)F-FDG match was present; these segments were subdivided into nontransmural and transmural scars. Contractile reserve was evaluated by dobutamine stress echocardiography. RESULTS: Dobutamine-induced contractile reserve was more frequently found in stunned than in hibernating myocardium (61% vs. 51%, respectively; P < 0.01). Only 14% of the scarred segments improved in wall motion during dobutamine infusion, significantly less than stunned or hibernating myocardium (P < 0.001). Nontransmural scars exhibited contractile reserve more frequently than did transmural scars. CONCLUSION: The progressive reduction of contractile reserve in stunned, hibernating, and scarred myocardium supports the hypothesis that stunning, hibernation, and scarring are not circumscript pathophysiologic entities but represent gradual ultrastructural damage on the myocyte level.

Dobutamine↗
PubMed1991

[Down-regulation and hibernating myocardium].

Some homeothermic animals can survive adverse conditions by hibernation, i.e., by reducing their body temperature in accordance with ambient temperature, thus reducing metabolism and vital functions. Six years ago, the term hibernation was introduced to describe a particular state of the myocardium. Although the meaning is different from that used in zoology and, thus, is misleading, it is used increasingly to describe a condition induced by moderate reduction in coronary flow. Some evidence in the literature suggests that the myocardium can actively reduce its mechanical function as a consequence of reduced coronary flow in order to prevent ischemia-induced injury. It is conceivable that the hibernating myocardium is the result of such a down-regulation of function. The hibernating myocardium can be characterized by decreased function in the hypoperfused area, which still exhibits active metabolism and remains viable. This is in contrast to "stunned" myocardium, which represents dysfunction during postischemic reperfusion, i.e., with coronary blood flow being close to normal. In analogy to hibernation in its original meaning, down-regulation and hibernating myocardium are considered to represent a protective mechanism, because such myocardium can quickly regain its initial function after restoration of physiologic blood flow. Because hibernating myocardium is salvageable, it has to be distinguished from other dysfunctional tissue that has lost its function due to ischemic damage, so that appropriate clinical interventions can succeed in restoring normal coronary blood flow.

Adaptation, Physiological↗
PubMed1995

[The hibernating myocardium].

The hibernating myocardium refers to the presence of persistent myocardial and left ventricular dysfunction at rest, due to reduced coronary blood flow. This left ventricular dysfunction represents an endogenous adaptive mechanism which prevents irreversible cell damage. The dysfunction in hibernating myocardium improves following restoration of coronary blood flow. A key concept in hibernating myocardium is that the reduction in contractile function induced by ischaemia has a protective effect. By reducing oxygen demand the myocardium maintains its viability in the setting of limited oxygen supply. The hibernating myocardium is a new metabolic state that is a consequence of an ischaemic condition, but the hibernating cardiomyocytes are not necessarily ischaemic. There are no adequate animal models for chronic hibernation. However, there are models for acute hibernation both in intact beating hearts and in isolated hearts. In these models a stable reduction in mechanical function for some hours has been demonstrated, whereas metabolic indicators of ischaemia improve during sustained low-flow ischaemia.

Coronary Circulation↗
PubMed1998

Perfusion-contraction mismatch during inotropic stimulation in hibernating myocardium.

UNLABELLED: The aims of this study were to assess the value of dobutamine echocardiography in identifying myocardial hibernation versus stunning and to elucidate the underlying pathophysiological mechanism of the contractile impairment. METHODS: Twenty-one patients with isolated stenosis of the left anterior descending artery were evaluated 1 mo after thrombolysed acute anterior infarction. Regional function and blood flow were measured using echocardiography and PET at rest and during dobutamine administration (10 microg/kg/min). RESULTS: Defined by [18F]fluorodeoxyglucose uptake, 36 of 102 dyssynergic segments were necrotic, and 66 were viable. The latter segments were subdivided according to their [13N]ammonia flow distribution: 30 hibernating regions with perfusion defects (flow of <80% of maximum) and 36 stunned areas with preserved resting perfusion (flow of > or =80% of maximum). Resting flows were similar in necrosis and hibernation (0.43 +/- 0.18 versus 0.47 +/- 0.16 ml x min(-1) x g(-1); not significant), and both resting values were lower than those seen in stunning (0.79 +/- 0.24; p < 0.05). Flow response to dobutamine was markedly reduced in necrosis (dobutamine/resting flow = 1.16 +/- 0.27), whereas it was maintained in hibernation (1.65 +/- 0.54) and stunning (1.42 +/- 0.57). Dobutamine improved function in a higher number of stunned (55%) than hibernating (16%) or necrotic (11%) segments. CONCLUSION: Dobutamine improves function mainly in stunned myocardium and does not reliably identify hibernation. The lack of functional response in hibernation is not related to an exhausted vasodilating capacity.

Cardiotonic Agents↗
PubMed2000

Changes in thyroid hormones in the serum and the thyroid gland of hibernating frogs, Rana temporaria L.

The hypothalamo-pituitary-gonadal axis spontaneously activates in hibernating frogs, Rana temporaria, under constant conditions (0-4 degrees, darkness). The hypothesis that the spontaneous hibernatory activation involves other regulatory processes preparing the frogs for breeding and posthibernatory activity was tested. The serum concentrations and glandular contents of thyroid hormones (THs) were determined during hibernation. It was shown that (i) in both sexes, serum thyroxine and triiodothyronine levels significantly increased in the middle of January (week 13/14, between day 92 and 98 of hibernation); (ii) the peak of THs blood concentration was accompanied by a slow decrease of free forms of THs and the bound forms of both hormones dropped rapidly over this period; (iii) after a decrease on day 111, the low level of serum THs (but higher than before the peak) was sustained to the end of hibernation; (iv) the thyroid content of free THs significantly rose after their "surge" into the blood, reached maximal values in the middle of February, and remained at this level to the end of hibernation (last week of March); (v) in spring, after spawning, the THs levels in glands and in serum were much lower than those at the end of hibernation or were not detectable; and (vi) the results were confirmed during the second season, when the material in the period of expected elevation of serum THs was collected every other day.

Animals↗
PubMed1995

The neuroendocrine system in hibernating mammals: present knowledge and open questions.

The present review describes the distribution and the function-dependent reactivity pattern of those peptidergic and aminergic components of the neuroendocrine system of hibernating mammals that have been studied by histological, pharmacological and physiological techniques. Particular attention has been paid to the intrinsic connectivity of the peptidergic apparatus and its input systems. Since the reactivity patterns of the neuroendocrine system show remarkable fluctuations in relation to the various stages of hibernation and euthermia, these fluctuations have been analyzed with respect to (1) their causative role in the regulation of hibernation and (2) their secondary response to physiological changes during hibernation. The author's investigations described in this review have mainly been performed in European hedgehogs (Erinaceus europaeus), European and golden hamsters (Cricetus cricetus, Mesocricetus auratus), dormice (Glis glis), and in Richardson's and Columbian ground squirrels (Spermophilus richardsonii, Spermophilus columbianus), by the use of light- and electron-microscopic immunocytochemistry and histochemistry, in situ hybridization, radioimmunoassays and stereotaxically guided application techniques. These experiments were also performed in hypothermic animals. The (partially published) results obtained by the author and his associates are reviewed with reference to the body of evidence found in the recent literature. With respect to their reactivity patterns, several neuropeptide and transmitter systems can be regarded as candidates for control systems of hibernation. Neuronal complexes immunoreactive for endogenous opiates, in particular enkephalin, and also for vasopressin, somatostatin, substance P, corticotropin-releasing factor and serotonin are probably involved in the neuroendocrine control of hibernation.

Animals↗
PubMed1985

Allometries of the durations of torpid and euthermic intervals during mammalian hibernation: a test of the theory of metabolic control of the timing of changes in body temperature.

The durations of the intervals of torpor and euthermia during mammalian hibernation were found to be dependent on body mass. These relationships support the concept that the timing of body temperature changes is controlled by some metabolic process. Data were obtained from species spanning nearly three orders of magnitude in size, that were able to hibernate for over six months without food at 5 degrees C. The timing of body temperature changes was determined from the records of copper-constantan thermocouples placed directly underneath each animal. Because all species underwent seasonal changes in their patterns of hibernation, animals were compared in mid-winter when the duration of euthermic intervals was short and relatively constant and when the duration of torpid intervals was at its longest. Large hibernators remained euthermic longer than small hibernators (Fig. 2). This was true among and within species. The duration of euthermic intervals increased with mass at the same rate (mass 0.38) that mass-specific rates of euthermic metabolism decrease, suggesting that hibernators remain at high body temperatures until a fixed amount of metabolism has been completed. These data are consistent with the theory that each interval of euthermia is necessary to restore some metabolic imbalance that developed during the previous bout of torpor. In addition, small species remained torpid for longer intervals than large species (Fig. 3). The absolute differences between different-sized species were large, but, on a proportional basis, they were comparatively slight.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Effects of multiple routes of cadmium exposure on the hibernation success of the American toad (Bufo americanus).

The effects of multiple routes of cadmium exposure on juvenile American toads (Bufo americanus) were evaluated using environmentally relevant concentrations. During or after exposure, toads were individually hibernated for 172 days at approximately 4degreesC. The following experiments were conducted: (1) dermal exposure (hibernation in soil contaminated with up to 120 microg Cd/g (dry weight)); (2) injection exposure (single injection with cadmium to achieve a maximum whole-body nominal concentration of 3 microg Cd/g (wet weight) 12 days before hibernation in uncontaminated soil); and, (3) oral exposure (feeding with mealworms containing < or =16 microg Cd/g (dry weight) for 50 days before hibernation in uncontaminated soil). We hypothesized that sublethal levels of cadmium would become lethal during hibernation because of combined chemical and cold stress. No prehibernation mortality occurred in the injection and oral exposure studies. There was a significant treatment effect on whole-body cadmium concentration in toads orally or dermally exposed and on percent of cadmium retention in toads orally exposed. There was also a trend of increased time-to-burrowing and more toads partially buried with greater cadmium concentration in the dermal study, which indicated avoidance. In all 3 experiments, no significant differences were found among cadmium treatments in hibernation survival, percent of mass loss, or locomotor performance. However, toads fed mealworms averaging 4.7 microg Cd/g (dry weight) had only 56% survival compared with 100% survival for controls. Although our results suggest that environmentally relevant levels of cadmium do not pose a great risk to American toads, factors such as soil type or prey species may increase cadmium bioavailability, and other amphibian species may be more sensitive to cadmium than B. americanus.

Administration, Oral↗
PubMed2003

Hibernation induces glutathione redox imbalance in ground squirrel intestine.

Glutathione (GSH) is the major thiol-disulfide redox buffer in cells and is a critical component of antioxidant defense. Here we examined GSH redox balance in the intestinal mucosa during the annual cycle of 13-lined ground squirrels (Spermophilus tridecemlineatus). The ratio of reduced GSH to its oxidized form (glutathione disulfide, GSSG), which is an index of oxidative stress, was five-fold lower in hibernating compared with summer-active squirrels, an effect due primarily to elevated GSSG concentration in hibernators. During hibernation the total pool of GSH equivalents was lowest in squirrels undergoing arousal and highest in squirrels during interbout arousals. Hibernation decreased intestinal GSSG reductase activity by approximately 50%, but had no effect on activities of glutathione peroxidase or glucose-6-phosphate dehydrogenase. Within the hibernation season, expression of the stress protein HSP70 in intestinal mucosa was highest in squirrels entering torpor and early in a torpor bout, and lowest in squirrels arousing from torpor and during interbout euthermia. The results suggest that hibernation in ground squirrels is associated with a shift in intestinal GSH redox balance to a more oxidized state. Higher levels of HSP70 during the early phases of torpor may reflect induction of the stress response due to aberrations in protein folding or may be a mechanism to increase enterocyte tolerance to subsequent stress imposed by extended torpor or the arousal process.

Animals↗