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PubMed1995

Effects of adenosine on synaptic transmission in hippocampal slices from hibernating and warm-acclimated Turkish hamsters and rats.

The effects of adenosine on synaptic transmission were studied with extracellular recordings of stimulus-induced population action potentials in area CA1 of hippocampal slices prepared from hibernating (HH) and warm-acclimated Turkish hamsters (WH) and rats. In HH as well as WH and rat slices, adenosine generally reduced the population spike amplitude and the slope of the field EPSP. The sensitivity for adenosine was significantly lower in HH slices than in WH and rat slices. The results are discussed with regard to the involvement of endogenous adenosine in the regulation of neuronal activity during entrance into and arousal from hibernation.

Adenosine↗
PubMed1991

Effect of graded reductions of coronary pressure and flow on myocardial metabolism and performance: a model of "hibernating" myocardium.

The term "hibernating" myocardium has been applied to chronic left ventricular dysfunction without angina or ischemic electrocardiographic changes in patients with coronary artery disease that is reversed by therapy that increases myocardial blood flow. To investigate the relation between coronary blood flow and ventricular function experimentally, graded reductions in coronary artery pressure were produced in isolated perfused rat hearts as contractile performance (peak systolic pressure and its first derivative [dP/dt]) and metabolic variables were measured using phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy. As coronary pressure and flow were reduced, significant reductions in myocardial oxygen consumption and contractile performance were observed, which returned to control levels when coronary artery pressure and flow were restored to baseline values. Two phases of metabolic abnormality were observed. With modest reductions in coronary perfusion, proportionate reductions in myocardial oxygen consumption and contractile behavior were accompanied by a slight reduction in creatine phosphate but no significant lactate production. With greater reductions in coronary artery pressure and flow, creatine phosphate decreased more, adenosine triphosphate levels and myocardial pH decreased significantly and myocardial lactate production increased. The balanced reductions in myocardial contractility and oxygen consumption without metabolic abnormalities traditionally associated with "ischemia" observed in the first phase provides evidence in normal hearts for resetting of the myocardial contractile behavior and oxygen consumption in the presence of reduced coronary flow (that is, hibernating myocardium). The data suggest that reductions in adenosine diphosphate and the index of the reduced form of nicotinamide adenine dinucleotide (NADH) (lactate formation) do not explain the coupling between coronary artery pressure and flow and myocardial oxygen consumption as contractile performance decreases.

Adenosine Diphosphate↗
PubMed2006

The relation of amino-terminal propeptide of type III procollagen and severity of coronary artery disease in patients without myocardial infarction or hibernation.

OBJECTIVES: The association of cardiac fibrosis and coronary artery disease (CAD) in patients without infarction or hibernation is unclear. We investigated the relationship between serum concentrations of procollagen propeptides and severity of CAD in such patients. DESIGN AND METHODS: Forty-six patients (32 men; mean age 64 years) with chest pain were enrolled. All patients received stress thallium-201 single photon emission computed tomography (SPECT) and analysis of the serum levels of the amino-terminal propeptide of type I and III procollagen (PINP and PIIINP). RESULTS: In patients with thallium-201 perfusion defects, the number of diseased vessels was associated significantly with PIIINP (p=0.024) rather than PINP (p=0.613). Follow-up serum PINP and PIIINP levels after coronary intervention (mean 84 days) revealed no significant decrease. CONCLUSIONS: Serum PIIINP level is significantly associated with the severity of CAD in patients without myocardial infarction or hibernation.

Aged↗
PubMed2004

Factors excercising an influence on recovery of hibernating myocardium after coronary artery bypass grafting.

OBJECTIVE: Coronary artery bypass grafting (CABG) in patients with endstage coronary disease (CAD) significantly improves symptoms and prolongs life expectancy. Left ventricular function is also improved in some patients, but not in others. Factors which influence functional recovery of hibernating myocardium after revascularization are at present under investigation. METHODS: From 3/2000 to 8/2002, we analyzed 41 patients with an ejection fraction (EF) of < or =30%, who underwent CABG, prospectively. All patients received low-dose dobutamine echocardiography (DE), dobutamine myocardial scintigraphy with SPECT, dobutamine magnetic resonance tomography (MRI), contrast-enhanced MRI and, when necessary, positron emission tomography (PET). Hibernating myocardium (area of interest) was identified with these diagnostic tools preoperatively and biopsy samples were taken intraoperatively. RESULTS: All patients received complete coronary revascularization. Early mortality was 2.4%. Three patients died during follow-up. Six months after the operation DE, MRI and SPECT were repeated. EF increased in 23 patients (group I) by at least >or =5%, and in 14 patients (group II) it did not improve. The wall motion score in the area of interest had increased during preoperative DE in group I significantly. The score did not change in group II. In addition the diastolic-systolic wall thickness increase in the area of interest rose >15% during DE in group I preoperatively; the increase was < or =15% in group II. MRI hyperenhancement of the left ventricle was significantly lower in group I compared to group II preoperatively. SPECT showed myocardial viability in the area of interest in all 37 patients. There were no significant differences between group I and II seen in SPECT. When the area of interest was located in the anterior wall the patients more frequently showed ventricular improvement postoperatively than patients with an area of interest located in the inferior, lateral or posterior wall. Light microscopy showed more severe myocardial cell hypertrophy (>19 microm) and less severe destruction of myocardial cell architecture in biopsies of group I compared to group II (myocardial cell hypertrophy < or =17 microm). Electron microscopy showed mitochondrial abnormalities in size and shape, lack of contractile material and large areas containing nonspecified cytoplasm, lipid droplets, and large glycogen-filled regions, but no significant differences between the two groups. Gene expresssion of the pro-apoptotic genes BAK and BAX was lowered compared to expression in 'normal' myocardium. The anti-apoptotic gene BCL-XL was significantly more expressed in the 'area of interest' of group II patients than in group I patients. CONCLUSIONS: We conclude that in patients with endstage CAD myocardial recovery after coronary revascularization can be predicted using DE and MRI preoperatively. Myocardial regions without any potential of functional recovery show less adaptation (less pronounced myocardial cell hypertrophy), a more severe degree of myocardial architecture destruction and a higher degree of anti-apoptotic gene expression. We recommend a myocardial biopsy when DE and MRI are not favorable in a patient with end stage coronary artery disease referred to us with the option of heart transplantation or coronary bypass.

Adult↗
PubMed1996

Inotropic stimulation by dobutamine increases left ventricular regional function at the expense of metabolism in hibernating myocardium.

The mechanism by which dobutamine increases the contraction of chronically dysfunctional myocardium and its effects on metabolism are still unknown. The aim of this study was to assess regional myocardial metabolism at rest and during an intracoronary dobutamine infusion in patients with hibernating myocardium. Eleven asymptomatic patients with single proximal stenosis of the left anterior descending coronary artery and persistent left ventricular dysfunction at rest (undergoing percutaneous transluminal coronary angioplasty [PTCA]) were studied prospectively. Regional left ventricular function was assessed by two-dimensional (2D) echocardiography and regional perfusion by thallium-201 single-proton-emission computed tomography. Great cardiac vein and aortic blood samples were obtained for measurements of lactate and plasma free fatty acid (FFA) concentrations. Inotropic challenge, obtained by using intracoronary dobutamine infusion, increases regional left ventricular function. However, the arteriovenous AV lactate difference was 0.206 = 0.070 mmol/L at rest, and it decreased to 0.018 = 0.069 mmol/L (p < 0.05 vs baseline) and 0.066 = 0.068 mmol/L (p < 0.05 vs baseline) at 4 and 10 minutes of dobutamine infusion, respectively. Thus the hibernating myocardium does not produce lactate at rest. However, when regional contraction is stimulated, dobutamine-induced inotropic challenge may cause a perfusion-contraction mismatch with an activation of anaerobic glycolysis.

Aged↗
PubMed1998

Metabolic changes in hibernating myocardium after percutaneous transluminal coronary angioplasty and the relation between recovery in left ventricular function and free fatty acid metabolism.

To elucidate the changes in oxidative metabolism in hibernating myocardium after coronary revascularization, we performed myocardial single-photon emission computed tomography with a free fatty acid analog, I-123 beta-methyliodophenylpentadecanoic acid (BMIPP), and thallium-201 before and 1 month after percutaneous transluminal coronary angioplasty (PTCA) in 11 patients with angina pectoris caused by single artery stenosis. All patients had improvement in wall motion after PTCA at the region with coronary stenosis; the wall motion abnormality score evaluated by left ventriculography decreased from 5.5+/-0.8 (mean +/- SE) to 2.1+/-0.9, p <0.01) after PTCA. The defect score of I-123 BMIPP images was significantly larger than that of thallium-201 images either before (14+/-1.3 vs 8.9+/-1.1, p <0.01) or 1 month after (7.4+/-1.5 vs 3.7+/-0.8, p <0.01) PTCA. The decrease in the defect score of both images was significant (p <0.01). Changes in the wall motion abnormality score showed a significant correlation with both the change in the defect score of thallium-201 images (r = 0.58, p < 0.01) and that of I-123 BMIPP images (r = 0.75, p <0.01). These results indicate that the metabolism of free fatty acid is impaired in hibernating myocardium, and that improvement in left ventricular function after successful PTCA is strongly associated with the recovery of oxidative metabolism.

Adult↗
PubMed1995

The hibernating myocardium: implications for management of congestive heart failure.

Left ventricular (LV) function is one of the most important determinants of long-term outcome in patients with coronary artery disease (CAD). Patients with normal or near-normal LV function have an excellent prognosis, whereas patients with impaired LV function are at substantial risk of death during medical therapy. It is now apparent that LV dysfunction is not always an irreversible process and that LV function may improve considerably, and even normalize, after myocardial revascularization in a large subset of patients. The identification of such patients with "hibernating" myocardium that is underperfused and dysfunctional, yet viable, has important implications in the selection of patients with LV dysfunction for revascularization procedures. Both nuclear cardiology techniques and 2-D echocardiography can be used for this purpose. The radionuclide techniques include positron emission tomography to assess blood flow and metabolism (using agents such as [18F]fluorodeoxyglucose) and thallium-201 (and possibly technetium-99m sestamibi) to assess blood flow and cell membrane integrity. Alternatively, echocardiographic imaging during low-dose infusions of dobutamine can be used to assess inotropic reserve. The data available to date suggest that patients with CAD in whom hibernating myocardium is largely the cause of impaired LV function constitute a subgroup of patients who may achieve a substantial improvement in LV function and in outcome if identified and treated with revascularization.

Echocardiography↗
PubMed1995

From coronary artery disease to heart failure: role of the hibernating myocardium.

Hibernating myocardium is defined as persistently impaired myocardial and left ventricular (LV) function at rest resulting from reduced myocardial blood flow. It may occur in unstable angina and chronic stable angina, acute myocardial infarction, and LV dysfunction and congestive heart failure. Recovery of the hibernating myocardium has clearly been shown to occur with the establishment of successful revascularization either by coronary bypass surgery or by percutaneous transluminal coronary angioplasty. It may be possible to show recovery of the viable myocardium by reducing myocardial oxygen demand and/or by increasing coronary blood flow with pharmaceutical agents.

Chronic Disease↗
PubMed1998

Evaluation of hibernating myocardium in patients with ischemic heart disease.

Patients with ischemic heart disease and significant left ventricular dysfunction are often difficult to manage medically. Revascularization procedures may improve left ventricular function and prognosis in this population if hypocontractile yet viable myocardium (hibernating myocardium) is demonstrated. Nuclear cardiology studies (single photon and positron methods), two-dimensional echocardiography, and magnetic resonance imaging studies have been utilized to identify hibernating myocardium. If thallium-201 studies are performed, the use of reinjection of thallium and repeat imaging improves the sensitivity of these studies for the detection of viable myocardium. Dobutamine echocardiographic studies may have a higher specificity and positive predictive value for the subsequent improvement of regional systolic left ventricular function after revascularization than the nuclear techniques. However, thallium studies have an excellent negative predictive value. Positron emission tomography (PET) allows the simultaneous assessment of perfusion and metabolic activity; however, these studies are expensive and not widely available. Functional evaluation with PET is in its infancy. Functional cardiac magnetic resonance imaging (MRI), although not widely available yet, provides the most accurate evaluation of regional ventricular function. MRI spectroscopy may be utilized to assess myocardial viability. As acquisition times improve and "real-time" imaging becomes a reality, MRI and MRI spectroscopy will likely become very accurate tools for assessing functional reserve and metabolic activity. The selection of the most appropriate method for assessment of myocardial viability will include consideration of a patient's characteristics, the presence of coronary arterial tree amenable to revascularization techniques, the techniques available to the clinician to assess viability, and local revascularization experience in this population. The result of an individual patient's evaluation is relevant to the consideration of coronary revascularization, or if this is not possible, cardiac transplantation.

Echocardiography↗
PubMed2001

Revascularization of severe hibernating myocardium in the beating heart: early hemodynamic and metabolic features.

BACKGROUND: We investigated the effects of coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) in selected patients with severe hibernating myocardium. METHODS: Twelve patients (EF = 25% +/- 0.7%) with reversible ventricular dysfunction (from 2.0 +/- 0.06 to 1.6 +/- 0.05 left ventricular score index by echodobutamine, p < 0.01) in the territory of the left anterior descending artery (LAD) have been studied. Revascularization was achieved by anastomosing the left internal mammary artery to the LAD. The ischemic time of LAD was 9.0 +/- 0.4 minutes. RESULTS: Left ventricular function increased 6 hours and 48 hours after revascularization (left ventricular stroke work index from 32 +/- 1.8 to 42 +/- 1.5 and 40 +/- 0.6 gxm/m2, respectively: p = 0.0001). During the surgical procedure, the heart did not release lactate or creatine phosphokinase. There were no perioperative deaths or severe complications. CONCLUSIONS: Early hemodynamic and metabolic features of CABG without CPB in patients with hibernating myocardium suggest that this procedure is safe and results in a significant improvement of cardiac function without affecting myocardial metabolism.

Adult↗
PubMed2002

Metabolic control analysis of anaerobic glycolysis in human hibernating myocardium replaces traditional concepts of flux control.

Myocardial hibernation represents an adaptation to sustained ischemia to maintain tissue vitality during severe supply-demand imbalance which is characterized by an increased glucose uptake. To elucidate this adaptive protective mechanism, the regulation of anaerobic glycolysis was investigated using human biopsies. In hibernating myocardium showing an increase in anaerobic glycolytic flux metabolizing exogenous glucose, the adjustment of flux through this pathway was analyzed by flux:metabolite co-responses. By this means, a previously unknown pattern of regulation using multisite modulation was found which largely differs from traditional concepts of metabolic control of the Embden-Meyerhof pathway in normal and diseased myocardium.

Anaerobiosis↗
PubMed1997

Cold- and ouabain-resistance of renal Na,K-ATPase in cold-exposed and hibernating jerboas (Jaculus orientalis).

The temperature dependence and the ouabain sensitivity of Na,K-ATPase was examined in the nephron of normal, cold-exposed, and hibernating jerboas. The transport and hydrolytic activity of renal Na,K-ATPase displayed similar temperature dependence in rats and normal jerboas. Cold-resistance of Na,K-ATPase appeared in cold-exposed jerboas and further increased during hibernation. Three subpopulations of Na,K-ATPase displaying very high (Ki approximately 10(-13) M), high (Ki approximately 10(-9) M) and low sensitivity to ouabain (Ki approximately 10(-6) M) were detected in the thick ascending limb and collecting duct of jerboas. In thick ascending limbs, the subpopulation of very high sensitivity to ouabain disappeared in cold-exposed animals, which accounted for the previously reported decrease in Na,K-ATPase activity. In collecting ducts of cold-exposed animals, the subpopulation of very high sensitivity to ouabain also disappeared, but the resulting decrease in activity was overbalanced by the appearance of the subpopulation of high sensitivity.

Animals↗
PubMed2000

End-diastolic wall thickness as a predictor of recovery of function in myocardial hibernation: relation to rest-redistribution T1-201 tomography and dobutamine stress echocardiography.

OBJECTIVES: The study assessed whether end-diastolic wall thickness (EDWT), measured with echocardiography, is an important marker of myocardial viability in patients with suspected myocardial hibernation, and it compared this index to currently established diagnostic modalities of dobutamine stress echocardiography (DSE) and rest-redistribution thallium-201 (T1-201) scintigraphy. BACKGROUND: Because myocardial necrosis is associated with myocardial thinning, preserved EDWT may provide a simple index of myocardial viability that is readily available from the resting echocardiogram. METHODS: Accordingly, 45 patients with stable coronary artery disease and ventricular dysfunction underwent rest 2D echocardiograms, DSE and rest-redistribution T1-201 tomography before revascularization and a repeat resting echocardiogram > or =2 months later. RESULTS: Global wall motion score index decreased from 2.38 +/- 0.73 to 1.94 +/- 0.82 after revascularization (p < 0.001). Thirty-eight percent of severely dysfunctional segments recovered resting function. Compared to segments without recovery of resting function, those with recovery had greater EDWT (0.94 +/- 0.18 cm vs. 0.67 +/- 0.22 cm, p < or = 0.0001) and a higher T1-201 uptake (78 +/- 13% vs. 59 +/- 21%; p < 0.0001). An EDWT >0.6 cm had a sensitivity of 94% and specificity of 48% for recovery of function. Similarly, a T1-201 maximal uptake of > or =60% had a sensitivity of 91% and specificity of 50%. Receiver operating characteristic curves for prediction of recovery of regional and global function were similar for EDWT and maximum T1-201 uptake. Combination of EDWT and any contractile reserve during DSE for recovery of regional function improved the specificity to 77% without a significant loss in sensitivity (88%). CONCLUSIONS: End-diastolic wall thickness is an important marker of myocardial viability in patients with suspected hibernation, and it can predict recovery of function similar to T1-201 scintigraphy. Importantly, a simple measurement of EDWT < or =0.6 cm virtually excludes the potential for recovery of function and is a valuable adjunct to DSE in the assessment of myocardial viability.

Aged↗
PubMed2002

Severe energy deprivation of human hibernating myocardium as possible common pathomechanism of contractile dysfunction, structural degeneration and cell death.

OBJECTIVES: We tested the hypothesis that severe alterations in myocardial energy metabolism play an important role in the pathophysiology of human hibernating myocardium (HHM). BACKGROUND: It is well established that a disturbed myocardial energy metabolism results in impairments of contractile performance, structure and viability. All of these are important characteristics of HHM. METHODS: In 16 patients with documented coronary artery disease and impaired left ventricular function, HHM was preoperatively detected by thallium-201 scintigraphy, radionuclide ventriculography and low-dose dobutamine echocardiography. These regions were validated as HHM by their recovery of contractile function three months following revascularization. During open-heart surgery, transmural biopsies were removed from the hibernating areas and analyzed both biochemically and morphologically. These findings were compared to normal human myocardium. All metabolite contents given were normalized for the degree of fibrosis (control: 9.8 +/- 0.5%; HHM: 28.1 +/- 3.0%; p < 0.05), providing myocellular contents. RESULTS: In HHM, decreased contents (micromol/g wet weight) in adenosine triphosphate (ATP) (control: 4.17 +/- 0.26; HHM: 1.72 +/- 0.25; p < 0.001), creatine phosphate (5.67 +/- 0.70 vs. 0.84 +/- 0.13; p < 0.001) and creatine (27.6 +/- 3.19 vs. 11.2 +/- 1.56; p < 0.0001) were found, but contents in lactate (2.22 +/- 0.26 vs. 25.38 +/- 3.53; p < 0.001), purine bases (0.58 +/- 0.09 vs. 1.26 +/- 0.13; p < 0.001) and protons (pH units: 7.199 +/- 0.01 vs. 6.59 +/- 0.07; p < 0.001) were increased. Levels in adenosine diphosphate, adenosine monophosphate and inorganic phosphate remained unchanged. Energy depletion in HHM was reflected by decreases in the free energy of ATP hydrolysis and in energy charge. CONCLUSIONS: These data confirm our hypothesis that HHM is energy-depleted myocardium, exhibiting signs of chronic reduction in resting blood flow and a downregulation of energy turnover. The alterations in energy metabolism observed may become operative in triggering and maintaining contractile dysfunction, continuous tissue degeneration and cardiomyocyte loss.

Aged↗
PubMed1997

Serial changes in response of hibernating myocardium to inotropic stimulation after revascularization: a dobutamine echocardiographic study.

OBJECTIVES: We sought to evaluate the serial changes in the response of the hibernating myocardium to dobutamine stimulation after revascularization. BACKGROUND: An improvement in myocardial contraction during dobutamine stress echocardiography (DSE), particularly a biphasic response, predicts recovery of rest function. However, little is known about the changes in the response of the myocardium to dobutamine after revascularization. METHODS: Thirty-four patients with stable coronary artery disease and regional left ventricular dysfunction underwent DSE before, early (within 1 week) and late (>6 weeks) after coronary angioplasty. Dobutamine was given in incremental doses from 2.5 to 40 microg/kg body weight per min. RESULTS: Of 180 revascularized segments with severe rest dysfunction, recovery of rest function was seen in 56 segments (31%) late after angioplasty, 80% of which had early recovery. Ventricular function during DSE was similar early and late after revascularization. Patients who showed a biphasic response to DSE before revascularization (n = 12) had the most improvement in function at rest (mean [+/-SD] wall motion score index [WMSI] 1.98 +/- 0.75 vs. 1.35 +/- 0.54, p < 0.05) and during DSE (2.11 +/- 0.67 vs. 1.21 +/- 0.41, p < 0.05) late after revascularization. Patients with sustained improvement during DSE before revascularization had no significant change in wall motion during DSE after angioplasty. However, patients without improvement in function at low dose DSE, who demonstrated worsening of function at a high dose, had significant augmentation in wall motion during DSE after revascularization (WMSI 2.16 +/- 0.50 vs. 1.60 +/- 0.57, p < 0.05). Patients who had no recovery of rest function had significant improvement in wall motion response to DSE, particularly when ischemia was inducible before revascularization. CONCLUSIONS: In myocardial hibernation, the majority of recovery of rest function occurs early after revascularization. Although patients who recover rest function show the most marked improvement in wall motion during DSE, those without recovery of rest function also have improved function during DSE, particularly when there is evidence of ischemia before revascularization.

Aged↗
PubMedDate not supplied

Acute oral trimetazidine administration increases resting technetium 99m sestamibi uptake in hibernating myocardium.

BACKGROUND: Trimetazidine is an antiischemic drug protecting the myocardium from ischemic damage through the preservation of mitochondrial oxidative metabolism, without any hemodynamic effect. 99mTc-sestamibi is accumulated by myocytes according to mitochondrial function. As mitochondrial metabolism is thought to be present in hibernating myocardium, the aim of the study was to investigate trimetazidine effects on infarcted and eventually hibernating myocardial areas by means of 99mTc-sestamibi perfusional scintigraphy, comparing them to postoperative recovery of wall motion. METHODS AND RESULTS: Twelve patients with previous myocardial infarction underwent 2 perfusion imaging tomographic studies at rest with 99mTc-sestamibi, receiving placebo or trimetazidine (60 mg orally), and subsequently underwent revascularization procedures. An echocardiographic study was carried out before and >3 months after revascularization. At polar map analysis of placebo scan, infarcted vascular territories (wall motion score index: 2.65 +/- 0.31) showed 73.7% +/- 10.4% of the territory with activity <2.5 SD from the mean of normals, for a severity (expressed as the sum of the standard deviations below average normal values in all abnormal pixels) of 833.8 +/- 345.7. Polar map analysis of the trimetazidine scan showed tracer uptake increased significantly in 11 of them, by 8.2% +/- 3.0% (p < 0.001) and by 180.3 +/- 111.0 SD (p < 0.001), respectively. Postoperative wall motion score index improved significantly in 9 of these territories (-0.9 +/- 0.4, p < 0.001). CONCLUSIONS: Trimetazidine-associated increase in 99mTc-sestamibi uptake in infarcted but viable myocardial areas is probably related to an improvement in mitochondrial oxidative metabolism that is essential to 99mTc-sestamibi retention. Additionally, coupling trimetazidine administration to 99mTc-sestamibi perfusional scintigraphy may represent a means of detecting viable myocardium.

Administration, Oral↗
PubMed2006

Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells.

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche in a noncycling state and enter the cell cycle at long intervals. However, little is known about inter- and intracellular signaling mechanisms underlying this unique property of HSCs. Here, we show that lipid raft clustering is a key event in the regulation of HSC dormancy. Freshly isolated HSCs from the BM niche lack lipid raft clustering, exhibit repression of the AKT-FOXO signaling pathway, and express abundant p57(Kip2) cyclin-dependent kinase inhibitor. Lipid raft clustering induced by cytokines is essential for HSC re-entry into the cell cycle. Conversely, inhibition of lipid raft clustering caused sustained nuclear accumulation of FOXO transcription factors and induced HSC hibernation ex vivo. These data establish a critical role for lipid rafts in regulating the cell cycle, the survival, and the entry into apoptosis of HSCs and uncover a striking similarity in HSC hibernation and Caenorhabditis elegans dauer formation.

Animals↗
PubMed1994

ATP gated potassium channels in acute myocardial hibernation and reperfusion.

OBJECTIVE: ATP gated potassium (KATP) channels and adenosine are of crucial importance in coronary blood flow regulation and activation of KATP channels and adenosine receptor stimulation protect against infarction and development of stunning. The aim of this study was to test the hypothesis that opening of KATP channels and adenosine receptor stimulation are involved in perfusion-contraction matching, in acute hibernation, and in recovery after reperfusion. METHODS: 30 isolated piglet hearts (2-10 d old) and 20 isolated rabbit hearts were studied. The isolated piglet hearts were perfused with modified Krebs Henseleit (KH) solution enriched by washed human red blood cells; the isolated rabbit hearts were perfused with modified KH buffer. The effects of the KATP channel opener aprikalim (1 microM), the KATP channel antagonist glibenclamide (30 microM), and the adenosine receptor antagonist 8-(p-sulphophenyl)theophylline (SPT, 300 microM) on 2 h of low flow (10%) ischaemia and 1 h reperfusion were compared with saline in the piglet hearts. The effects of aprikalim (1 microM), glibenclamide (30 microM), and saline during 90 min of low flow (10%) ischaemia followed by 1 h reperfusion were also examined in the isolated rabbit hearts. RESULTS: At constant coronary flow aprikalim reduced perfusion pressure from 53(SEM 5) to 25(1) mm Hg (p < 0.001) in piglet hearts and from 55(5) to 39(5) mm Hg (p < 0.05) in rabbit hearts. Glibenclamide increased perfusion pressure from 47(5) to 61(6) mm Hg (p < 0.01) in piglet hearts and from 45(4) to 81(5) mm Hg (p < 0.001) in rabbit hearts. SPT increased perfusion pressure from 55(6) to 67(6) mm Hg (p < 0.05) in piglet hearts. Left ventricular systolic pressure remained unchanged in both models. During stepwise reductions in coronary flow a parallel stepwise reduction in left ventricular systolic pressure was observed in all groups. At 2 h of low flow ischaemia systolic pressure was 39(4)%, 37(5)%, 41(4)%, and 37(3)% of control for hearts treated with saline aprikalim, glibenclamide, and SPT, respectively. During the low flow period systolic pressure and MVO2 stabilised. An almost identical pattern occurred in rabbit hearts. After 30 min of recovery of piglet hearts left ventricular systolic pressure increased to 78(5)% (saline), 74(5)% (aprikalim), 84(5)% (glibenclamide), and 77(4)% (SPT) of control. The recovery as percentage of control in rabbit hearts was 63(11) (saline), 69(8) (aprikalim) and 56(13) (glibenclamide). CONCLUSION: Coronary vascular tone is highly responsive to KATP channel modulation and adenosine receptor blockade. KATP channels do not modulate either perfusion-contraction matching or acute hibernation and functional recovery during reperfusion in the red blood cell perfused piglet heart or the crystalloid perfused rabbit hearts. Moreover, adenosine receptor antagonism does not affect these phenomena in piglet hearts.

Adenosine Triphosphate↗