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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of ischemia duration on the functional response of mitochondria to reperfusion and its relationship with changes in mitochondrial susceptibility to oxidative stress. Mitochondria were isolated from hearts perfused by the Langendorff technique immediately after different periods of global ischemia or reperfusion following such ischemia periods. Rates of O2 consumption and H2O2 release with complex I- and complex II-linked substrates, lipid peroxidation, overall antioxidant capacity, capacity to remove H2O2, and susceptibility to oxidative stress were determined. The effects of ischemia on some parameters were time dependent so that the changes were greater after 45 than after 20 min of ischemia, or were significantly different to the nonischemic control only after 45 min of ischemia. Thus, succinate-supported state 3 respiration exhibited a significant decrease after 20 min of ischemia and a greater decrease after 45 min, while pyruvate malate-supported respiration showed a significant decrease only after 45 min of ischemia, indicating an ischemia-induced early inhibition of complex II and a late inhibition of complex I. Furthermore, both succinate and pyruvate malate-supported H2O2 release showed significant increases only after 45 min of ischemia. Similarly, whole antioxidant capacity significantly increased and susceptibility to oxidants significantly decreased after 45 min of ischemia. Such changes were likely due to the accumulation of reducing equivalents, which are able to remove peroxides and maintain thiols in a reduced state. This condition, which protects mitochondria against oxidants, increases mitochondrial production of oxyradicals and oxidative damage during reperfusion. This could explain the smaller functional recovery of the tissue and the further decline of the mitochondrial function after reperfusion following the longer period of oxygen deprivation.
Cell Mol Life Sci 2001 Sep
PMID:Effects of myocardial ischemia and reperfusion on mitochondrial function and susceptibility to oxidative stress. 1169 31

p38 Mitogen-activated protein kinase (p38 MAPK) is activated by short episodes of ischaemia-reperfusion as well as by sustained ischemia followed by reperfusion, Whether activation of this kinase is beneficial or deleterious to the ischaemic heart is still a subject of controversy. Since transient beta-adrenergic stimulation (5 min) stimulates p38 MAPK activation and mimics the cardioprotection of ischaemic preconditioning, it was used as a tool to further evaluate the role of this kinase in cardioprotection. The isolated perfused working rat heart, subjected to 25 min ischaemia and 30 min reperfusion was used as experimental model. p38 MAPK and ATF2 activation was determined using Western blots. The results showed that isoproterenol stimulated p38 MAPK in a dose- and time-dependent manner. Ischaemia-induced activation of p38 MAPK could be partially abolished by beta- and alpha1-adrenergic receptor blockade. Isoproterenol activation of the kinase could be abolished by alprenolol and verapamil, but not by 8-cyclopentyladenosine. p38 MAPK activation induced by either a multi-episode preconditioning protocol or isoproterenol (10(-7) M for 5 min) was associated with a significant reduction in p38 MAPK activation at all time intervals studied during 25 min global ischaemia and at 20 and 30 min of reperfusion, compared with the marked activation observed in untreated non-preconditioned hearts. In each case attenuation of p38 MAPK activation during ischaemia and during reperfusion was associated with improved functional recovery during reperfusion. Cyclic elevations in tissue cAMP during an ischaemic preconditioning protocol acted as trigger of cardioprotection, since pretreatment of such hearts with alprenolol abolished cardioprotection. Mechanical failure in such hearts was characterized by a significant stimulation of p38 MAPK activity during ischaemia and reperfusion. However, p38 MAPK activation during an ischaemic preconditioning protocol did not act as trigger: inhibition of p38 MAPK activation by SB 203580 during the preconditioning phase did not abolish cardioprotection. In fact, functional recovery was significantly better than that of untreated preconditioned hearts. On the other hand, SB 203580, when administered before and during the isoproterenol-preconditioning protocol abolished cardioprotection, suggesting that p38 MAPK activation by a beta -adrenergic-induced preconditioning protocol does act as trigger of cardioprotection. In addition, attenuation of p38 MAPK activity during sustained ischaemia and reperfusion as occurs in ischaemic- or isoproterenol-preconditioned hearts, is beneficial.
J Mol Cell Cardiol 2001 Dec
PMID:p38 MAPK activation triggers pharmacologically-induced beta-adrenergic preconditioning, but not ischaemic preconditioning. 1173 62

Injured dorsal root axons fail to regenerate into the adult spinal cord, leading to permanent sensory loss. We investigated the ability of intrathecal neurotrophin-3 (NT3) to promote axonal regeneration across the dorsal root entry zone (DREZ) and functional recovery in adult rats. Quantitative electron microscopy showed robust penetration of CNS tissue by regenerating sensory axons treated with NT3 at 1 and 2 weeks postrhizotomy. Light and electron microscopical anterograde tracing experiments showed that these axons reentered appropriate and ectopic laminae of the dorsal horn, where they formed vesicle-filled synaptic buttons. Cord dorsum potential recordings confirmed that these were functional. In behavioral studies, NT3-treated (but not untreated or vehicle-treated) rats regained proprioception. Recovery depended on NT3-mediated sensory regeneration: preventing regeneration by root excision prevented recovery. NT3 treatment allows sensory axons to overcome inhibition present at the DREZ and may thus serve to promote functional recovery following dorsal root avulsions in humans.
Mol Cell Neurosci 2002 Feb
PMID:Neurotrophin-3-mediated regeneration and recovery of proprioception following dorsal rhizotomy. 1186 Feb 76

By evaluating concordant or discordant perfusion and systolic wall thickening patterns, resting quantitative electrocardiographic (ECG) gated single-photon emission tomography (SPET) can identify various myocardial pathological conditions with different functional recovery after revascularisation therapy. However, no data are available on the ability of this methodology to predict regional functional recovery after primary percutaneous transluminal coronary angioplasty (PTCA). This study evaluated whether single-injection ECG gated SPET imaging performed at rest with 99mTc-tetrofosmin early after successful PTCA can predict recovery of regional wall motion. ECG gated SPET was performed 3 days and 3 weeks after successful PTCA in 26 patients. Regional functional parameters were automatically calculated with a 20-segment model on the day 3 image, and segments with perfusion/thickening mismatch were defined as showing preserved perfusion (>55% uptake on the end-diastolic image: mean-standard deviation of the normal value) without systolic wall thickening (mean-standard deviation of the normal value). On the third day, the regional wall motion score of 37 mismatched segments (3.8+/-2.1) was significantly lower than that of 41 matched normal segments (6.0+/-2.9), but was significantly higher than that of 108 matched abnormal segments (1.4+/-1.9, both P<0.01). At 3 weeks after acute MI, the regional wall motion score of mismatched segments (6.4+/-3.9) improved to the level of matched normal segments (7.1+/-3.0) and was significantly higher than that of matched abnormal segments (2.5+/-3.0, P<0.01). Absolute change in the regional wall motion score (3 days to 3 weeks) of mismatched segments (2.6+/-3.5) was significantly greater than that in the regional wall motion score of matched normal segments and matched abnormal segments (1.1+/-1.3 and 1.2+/-2.6, respectively, both P<0.05). Twenty-seven of 37 segments (73%) with perfusion/thickening mismatch showed significant improvement in regional wall motion, whereas improvement in regional wall motion was observed in 22 of 108 segments (20%) with matched abnormal segments and 6 of 41 segments (15%) with matched normal segments. Segments with perfusion/thickening mismatch had a significantly higher incidence of regional functional improvement than did matched abnormal or matched normal segments (chi2=42.3, P<0.01). Thus, by estimating both perfusion and wall thickening, single-injection resting ECG gated SPET imaging with 99mTc-tetrofosmin early after primary PTCA can predict recovery of regional wall motion after successful reperfusion.
Eur J Nucl Med Mol Imaging 2002 Apr
PMID:Early prediction of regional functional recovery in reperfused myocardium using single-injection resting quantitative electrocardiographic gated SPET. 1191 82

Effects of ischemia time and treatment interventions upon troponin I (TnI) proteolysis and function of reperfused myocardium were examined in isolated, perfused rabbit hearts. Hearts were randomized to 90 min aerobic perfusion, 15 min low-flow (1 ml/min) ischemia (I) and 60 min reperfusion (R) or 60 min low-flow I and 60 min R. Hearts subject to 60 min I and 60 min R received either no treatment, l -arginine treatment, or treatment with oxygen free radical (OFR) scavengers (mercapto-proponyl-glycine, catalase and superoxide dismutase). Hearts from cholesterol-fed rabbits were also studied after 60 min I and R. Isovolumic LV pressure and heart rate were recorded throughout and Western analysis of ventricular myocardium, using 3 specific antibodies, detected intact TnI (29 kDa) and TnI fragment (25 kDa). Hearts subject to 15 min I had minimal irreversible injury (TTC negative region=0.6+/-0.4% LV) but hearts subject to 60 min I had more extensive injury (TTC negative=40.7+/-5.8% LV). Recovery of rate-pressure product after 15 min I and 60 min R (56+/-9% of baseline) was better than after 60 min I and 60 min R (23+/-9%, P<0.01). Both l -arginine and OFR scavengers were associated with better recovery of function after 60 min I, (66+/-7% and 72+/-3% of baseline respectively, P<0.01 v no treatment) but cholesterol hearts had poor recovery after 60 min I (37+/-8%). The 25 kDa TnI (% total TnI immunoreactivity) was 8.7+/-0.9% in controls, 10.0+/-1.6% after 15 min I and 60 min R, and 17.4+/-2.4% after 60 min I and 60 min R (P<0.01 v controls and 15 min I). The proportion of 25 kDa TnI was increased in all hearts after 60 min I and did not change with treatment (l -arginine 16.8+/-1.8%, OFR scavengers 16.0+/-3.2%, cholesterol 14.0+/-1.9%). There was no relation between proportion of 25 kDa TnI and recovery of function. Samples from freshly excised rabbit hearts and human right atria also had 25 kDa TnI (relative intensities 8.5+/-2.3% and 5.1+/-2.6% respectively). Although TnI fragmentation increases after prolonged ischemia and reperfusion, the functional recovery of stunned myocardium is independent of degree of TnI fragmentation.
J Mol Cell Cardiol 2002 Apr
PMID:Effect of treatment on ventricular function and troponin I proteolysis in reperfused myocardium. 1199 27

Accurate prediction of improvement in left ventricular ejection fraction (LVEF) after revascularisation is critical in the therapeutic decision-making process in patients with chronic ischaemic dysfunction. Positron emission tomography (PET) allows non-invasive evaluation of myocardial blood flow (MBF), metabolic rate of glucose (MRG, absolute and relative) and the water-perfusable tissue fraction (PTF). Each of these indices has been proposed for the prediction of functional recovery. Their relative merits, however, are unknown, because a direct head-to-head comparison of their predictive accuracy in the same patients has not been performed. In this study, MBF, MRG (absolute and relative) and PTF were evaluated in 34 patients with severe ischaemic LV dysfunction (LVEF 32%+/-9%). MBF and PTF were determined by oxygen-15 labelled water PET, and MRG (absolute and relative) was determined by fluorine-18 fluorodeoxyglucose (FDG) PET during hyperinsulinaemic euglycaemic clamp. LVEF was measured by radionuclide ventriculography before and 4-6 months after surgery. Sensitivities of MBF, PTF, absolute MRG and relative MRG in predicting improvement in LVEF were 80%, 80%, 90% and 100%, respectively. Their specificities were 54%, 67%, 71% and 71%, respectively. The lowest specificity was obtained for MBF, an intermediate specificity was obtained for PTF and the highest specificities were obtained with FDG PET using absolute and relative MRG. It is concluded that metabolic imaging is superior to perfusion-based indexes for assessment of the potential for functional recovery after revascularisation.
Eur J Nucl Med Mol Imaging 2002 Jun
PMID:Accuracy of PET in predicting functional recovery after revascularisation in patients with chronic ischaemic dysfunction: head-to-head comparison between blood flow, glucose utilisation and water-perfusable tissue fraction. 1202 44

The detection of viable myocardium is important for the prediction of functional recovery after revascularisation. However, a fixed perfusion defect often includes viable myocardium, and perfusion imaging then underestimates myocardial viability. We previously reported that low-dose dobutamine stress gated single-photon emission tomography (SPET) provides similar findings to dobutamine stress echocardiography in the assessment of myocardial viability. The present study investigated whether low-dose dobutamine stress gated SPET is of additional value as compared with stress-rest technetium-99m tetrofosmin SPET for the detection of myocardial viability. Standard stress-rest perfusion SPET, low-dose dobutamine stress gated SPET and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) were studied in 23 patients (mean age 67+/-7.6 years) with previous myocardial infarction. Twenty-one of them were successfully studied with each technique. FDG PET viability (FDG uptake >/=50%) was employed as the gold standard. One-day stress-rest (99m)Tc-tetrofosmin myocardial SPET was performed. After the resting study, gated SPET was acquired following infusion of 7.5 microg kg(-1) min(-1) of dobutamine. Left ventricular wall motion in 16 segments was assessed by cine mode display using a four-point scale. Myocardial viability was considered present when there was improvement by one point. Of a total of 336 segments analysed, 53 had persistent defects on stress-rest perfusion SPET. FDG viability was seen in 16 of 17 dobutamine-responsive segments, but in only 11 of 36 dobutamine non-responsive segments ( P<0.01). Thus, in the segments with persistent defects, viability findings on low-dose dobutamine stress gated SPET were concordant with those on FDG PET in 77% of segments (kappa value =0.55). For the detection of FDG-viable myocardium, the combination of stress-rest perfusion SPET and low-dose dobutamine stress gated SPET achieved a better sensitivity than stress-rest perfusion SPET alone (35/46, 76% vs 19/46, 41.3%, P<0.001), with a similar specificity (25/29, 86% vs 26/29, 90%, P=NS). We conclude that in the identification of viable myocardium, low-dose dobutamine stress gated SPET may provide additional information missed on a routine stress-rest perfusion scan. Dobutamine stress gated SPET may provide new insights into myocardial viability on the basis of ischaemia and contractile reserve.
Eur J Nucl Med Mol Imaging 2002 Jul
PMID:Low-dose dobutamine stress gated SPET for identification of viable myocardium: comparison with stress-rest perfusion SPET and PET. 1211 Nov 28

Dendritic cell (DC) counts and function were assayed in peripheral blood of lymphoma and solid tumor patients before and after chemotherapy. The DC counts declined significantly within the first week from the start of chemotherapy, recovered in the second week, and exceeded the baseline values in the third week. DC recovery was usually similar after the first and after the last cycle of chemotherapy. DC1 and DC2 subsets followed the pattern of reconstitution found for the DC population as a whole. Monocytes and granulocytes recovered 1-2 weeks later than DC. The primary proliferative response to keyhole lympet hemocyanin (KLH), totally DC-dependent, declined within the first week from the start of chemotherapy, and in the majority of patients (including those initially unresponsive) recovered along with DC counts. The recovered responsiveness to KLH, but not to anti-CD3 antibody, disappeared at the end of chemotherapy in lymphoma and some solid tumor patients. Prolonged depletion of CD4+ T cells could contribute to the loss of responsiveness in lymphoma patients receiving multiple cycles of chemotherapy. However, in some solid tumor patients, the reactivity to KLH was absent, despite the reconstitution of both DC and CD4+ T-cell counts. Our data show that numerical reconstitution of DC is not necessarily accompanied by functional recovery. The early recovery of DC should be considered while designing protocols for DC collection for immunotherapy.
Cytokines Cell Mol Ther 2002 Mar
PMID:Recovery of dendritic cell counts and function in peripheral blood of cancer patients after chemotherapy. 1217 Dec 47

Action potential duration (APD) shortening due to opening of sarcolemmal ATP-dependent potassium (KATP) channels has been postulated to protect the myocardium against postischemic damage by reducing Ca2+ influx. This hypothesis was assessed, assuming that increased postischemic stunning due to KATP channel inhibition with glibenclamide could be reverted by the addition of the Ca2+ channel blocker diltiazem. Percent wall thickening fraction (%WTh, conscious sheep) and APD (open-chest sheep) were obtained from the following groups: control: 12 min ischemia by anterior descending coronary artery occlusion followed by 2 h reperfusion; glibenclamide: same as control, with glibenclamide (0.4 mg/kg) infused 30 min before ischemia; diltiazem: same as control, with diltiazem (100 microg/kg) administered prior to ischemia; glibenclamide+diltiazem: both drugs infused as in glibenclamide and diltiazem groups. APD was reduced in control ischemia. Conversely, KATP-channel blockade by glibenclamide lengthened APD and increased postischemic stunning (p < 0.01 vs. control); glibenclamide+diltiazem did not shorten APD but enhanced functional recovery (p < 0.01 vs. glibenclamide). Ca2+ channel blockade improvement of increased stunning provoked by KATP channel inhibition supports the hypothesis that APD shortening due to opening of KATP channels protects against postischemic stunning by limiting Ca2+ influx.
Mol Cell Biochem 2002 Jul
PMID:Ischemic shortening of action potential duration as a result of KATP channel opening attenuates myocardial stunning by reducing calcium influx. 1219 Jan 21

This work investigates whether purine metabolism and release is related to cardioprotection with hyperkalemia and hypothermia. Langendorff guinea-pig hearts were used to either monitor metabolism during ischemia or to measure functional recovery, myocardial injury and release of purine during reperfusion. Hearts underwent 30 min ischemia using one of the following protocols: control (normothermic buffer), hyperkalaemia (high-potassium buffer), hypothermia (20 degrees C) and hyperkalemia + hypothermia. At the end of 30 min ischemia, hyperkalemia was associated with similar metabolic changes (rise in purine and lactate and fall in adenine nucleotides) to control group. Accumulation of purine was due to a rise in inosine, xanthine and hypoxanthine and was largely prevented by hypothermia and hyperkalemia + hypothermia. Upon reperfusion, there was a time-dependent release of all purine, lactate and AMP. A fast (peak in less than 20 sec) release of inosine, xanthine, hypoxanthine and lactate was highest in control followed by hyperkalemia then hypothermia and little release in hyperkalemia + hypothermia. Adenosine and AMP release was slow (peak at 3 min), only significant in control and was likely to be due to sarcolemmal disruption as the profile followed lactate dehydrogenase release. Recovery (left ventricular developed pressure) was 63% control, 82% hyperkalemia, 77% hypothermia and 98% for hyperkalemia + hypothermia. The loss of purine during reperfusion but not their production during ischemia is related to cardioprotection with hyperkalemia. The possibility that the consequences of hyperkalemia modulate a sodium-dependent purine efflux, is discussed. The reduced loss of purine in hypothermia or in hyperkalemia + hypothermia is likely to be due to a lower metabolic activity during ischemia.
Mol Cell Biochem 2002 Aug
PMID:Purine metabolism and release during cardioprotection with hyperkalemia and hypothermia. 1223 79


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