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

Although isoflurane protects the myocardium and facilitates functional recovery after ischemia and reperfusion, its mechanism of action is still unclear. We hypothesized that isoflurane maintains intracellular Ca2+ homeostasis, thus attenuating epinephrine-induced arrhythmogenicity in in vivo models of myocardial ischemia and reperfusion. Adult mongrel dogs, anesthetized with urethane and chloralose, underwent 15 minutes of left anterior descending coronary artery occlusion followed by reperfusion. In addition to a sham group (without occlusion, n = 5) and a control group (with occlusion, n = 7), a third group (n = 5) received 1.5% isoflurane before ischemia was induced; a fourth (n = 7), isoflurane after reperfusion; and a fifth (n = 5), isoflurane and verapamil (100 micrograms/kg) after reperfusion. Isoflurane administered before ischemia increased the arrhythmogenic dose of epinephrine (ADE), but had no effect on ADE when administered after reperfusion. The addition of verapamil further increased the ADE. These results indicate that isoflurane has a cardioprotective effect during ischemia and reperfusion by, at least in part, the reduction of Ca2+ influx.
Res Commun Mol Pathol Pharmacol 1998 May
PMID:Effect of isoflurane on epinephrine-induced arrhythmias in ischemic-reperfused dog hearts. 966 72

The study aims to determine a possible relationship between intracellular water, energy metabolism, functional recovery and membrane permeability, during and after hypothermic cardiac preservation. Isolated rat hearts were stored for 12 h at 4 degrees C with University of Wisconsin (UW), St Thomas Hospital (ST) and Krebs-Henseleit (KH) solutions, and were reperfused for 1 h. Cellular volumes were measured by 1H NMR of water and 59Co NMR of the extracellular marker cobalticyanide, and energetic profiles by 31P NMR spectroscopy. Storage in ST solution reduced ischemic swelling from 2.50 +/- 0.06 to 2.73 +/- 0.09 (P < 0.001 v 3.56 +/- 0.10 ml/g dry weight in KH), while UW solution caused cellular shrinkage to 2.12 +/- 0.08 ml/g dry weight. Intracellular ATP concentrations and pH values were higher in UW as compared to ST solution. At reperfusion, hearts stored in ST shrank while those stored in UW expanded, resulting in similar intracellular volumes. Storage with UW was superior to ST in post-ischemic function 65 +/- 5% (P < 0.01 v 49 +/- 4% with ST) and in recovery of ATP 46 +/- 3% (P < 0.001 v 25 +/- 4% with ST). Storage with both ST and UW solutions did not prevent interstitial edema. Sarcolemmal membrane integrity, as assessed by cellular swelling in response to a hypo-osmotic shock (210 mmol/l), was significantly improved by ST and UW solutions as compared to KH (P < 0.05). Creatine kinase efflux was reduced by ST and UW as compared to KH (P < 0.05), and by UW as compared to ST (P < 0.05). Coronary flow was higher following storage with UW than ST solutions. 66 +/- 6 and 45 +/- 4%, respectively (P < 0.01). According to these data, the beneficial effects of UW and ST solutions on hypothermic ischemic storage of rat hearts included prevention of cellular edema and preservation of sarcolemmal membrane integrity. It is concluded: (a) UW and ST solutions reduce ischemic and reperfusion cellular volumes: (b) both solutions, and UW in particular were efficient in preservation of membrane integrity: (c) prevention of cellular edema is not the single or main mechanism responsible for the improved preservation with UW and ST solutions.
J Mol Cell Cardiol 1998 Jul
PMID:Intracellular volumes and membrane permeability in rat hearts during prolonged hypothermic preservation with St Thomas and University of Wisconsin solutions. 971 Aug 1

Post-ischemic reperfusion causes cardiac dysfunction and radical-induced lipid peroxidation (LPO) detectable by ESR spin trapping. This study deals with the applicability of the spin trapping technique to pharmacological investigations during myocardial reperfusion injury. The use of the spin trap phenylbutylnitrone (PBN, 3 mM) in isolated rat hearts demonstrated the release of alkoxyl radicals (aN = 1.39 mT, aHbeta = 0.19 mT) formed particularly within the first 15 min of reperfusion following 30 min of ischemia. The decline of radicals, after 10 min of reperfusion, was accompanied by recovery of function in 80% of the hearts. The radical concentration in the coronary effluent (maximum after 7.5 min) was reduced by the infusion of 1 mM mercaptopropionylglycine (MPG, 2.7+/-0.5 U/ml, p < 0.001) or 5 microM vitamin E (11.7+/-0.8 U/ml, p < 0.001), compared to the (PBN-containing) control (29.7+/-4.3 U/ml). Moreover, functional recovery (left ventricular developed pressure, LVDP 91.6 +/-20% of pre-ischemic level, p < 0.05) was improved by the hydrophilic radical scavenger MPG, compared to the (PBN-containing) control (LVDP 50.5+/-15.7% of baseline). PBN alone led to higher functional recovery (p < 0.05) and reduced VF (duration of ventricular fibrillation; 7.10+/-0.36 min/30 min, p < 0.05), compared to the untreated (PBN-free) control (LVDP 26.6+/-11.8%; VF 19.42+/-3.64 min/30 min). The Ca antagonist verapamil (0.1 microM), MPG, and the lipophilic vitamin E showed cardioprotection in the absence of PBN: post-ischemic recovery of LVDP was 25.4+/-6.8% (p < 0.05), 39.6+/-12.7% (p < 0.05) and 52.4+/-2.6% (p < 0.01), respectively, compared to the corresponding untreated control (13.3+/-6.6%). Whereas verapamil and vitamin E were able to protect the heart when present alone, they offered no additive effect in the presence of PBN. Therefore, PBN can be used to estimate the radical scavenger properties of an agent in the heart. However, because of the protective properties of PBN itself, the results of simultaneous investigations of the effects of other compounds, such as Ca antagonists or lipophilic radical scavengers, on heart function may be limited.
Mol Cell Biochem 1998 Sep
PMID:PBN spin trapping of free radicals in the reperfusion-injured heart. Limitations for pharmacological investigations. 977 91

Generation of free radicals upon reperfusion has been cited as one of the major causes of ischaemia/reperfusion injury. The following series of experiments was designed to study the effect of manganese superoxide dismutase (MnSOD) overexpression in transgenic mice on ischemia/reperfusion injury. A species of 1.4 kb human MnSOD mRNA was expressed, and a 325% increase in MnSOD activity was detected in the hearts of transgenic mice with no changes in the other antioxidant enzymes or heat shock proteins. Immunocytochemical study indicated an increased labeling of MnSOD mainly in the heart mitochondria of the transgenic mice. When these hearts were perfused as Langendorff preparations for 45 min after 35 min of global ischemia, the functional recovery of the hearts, expressed as heart rate x left ventricular developed pressure, was 52 +/- 4% in the transgenic hearts as compared to 31 +/- 4% in the non-transgenic hearts. This protection was accompanied by a significant decrease in lactate dehydrogenase release from the transgenic hearts. Overexpression of MnSOD limited the infarct size in vivo in a left coronary artery ligation model. Our results demonstrate that overexpression of MnSOD renders the heart more resistant to ischemia/reperfusion injury.
J Mol Cell Cardiol 1998 Nov
PMID:Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. 992 65

Endothelin-1 (ET-1) is the most potent vasoconstrictor known to date, and it was proposed that this peptide plays a major role in myocardial ischemia/reperfusion injury. ET-1 could increase myocardial susceptibility to ischemia by two mechanisms: via coronary flow reduction and/or via direct, metabolic effects on the heart. In isolated, buffer-perfused rat hearts, function was measured with a left ventricular balloon, and energy metabolism (ATP, phosphocreatine, inorganic phosphate, intracellular pH) was estimated by 31NMR-spectroscopy. Under constant pressure perfusion, hearts were subjected to 15 min of control perfusion, 15 ("moderate injury") or 30 ("severe injury") min of global ischemia, followed by 30 min of reperfusion. Hearts were pre-treated with ET-1 (boluses of 0.04, 4, 40 of 400 pmol) 5 min prior to ischemia. In the control period, ET-1 reduced coronary flow, ventricular function, phosphocreatine and intracellular pH dose-dependently: during ischemia/reperfusion, coronary flow, functional recovery and high-energy phosphate metabolism were adversely affected by ET-1 in a dose-related manner. To study effects of ET-1 not related to coronary flow reduction, additional hearts were perfused under constant flow conditions (ET-1 0 or 400 pmol) during 15 min of control, 15 min of ischemia and 30 min of reperfusion. When coronary flow was held constant, functional and energetic parameters were similar for untreated and ET-1 treated hearts during the entire protocol, i.e. the adverse effects of ET-1 on function and energy metabolism during ischemia/reperfusion were completely abolished. In both constant pressure and constant flow protocols, 400 pmol ET-1 reduced the extent of ischemic intracellular acidosis. The authors conclude that ET-1 increases the susceptibility of isolated hearts to ischemia/reperfusion injury via reduction of coronary flow.
J Mol Cell Cardiol 1998 Dec
PMID:Endothelin-1 increases susceptibility of isolated rat hearts to ischemia/reperfusion injury by reducing coronary flow. 999 May 37

There is increasing evidence that reactive oxygen species (ROS) contribute to post-ischemic reperfusion injury, but determination of the specific ROS involved has proven elusive. In the present study electron paramagnetic resonance (EPR) spectroscopy was used in vitro to measure the relative quenching of singlet oxygen (1O2) by histidine and carnosine (beta-alanyl-L-histidine) utilizing the hindered secondary amine 2,2,6,6-tetramethyl-4-piperidone HCl (4-oxo-TEMP). The relative effect of histidine and carnosine on functional recovery of isolated perfused rat hearts was also studied. Functional recovery was measured by left ventricular developed pressure (LVDP), first derivative of left ventricular pressure (dP/dt), heart rate (HR) and coronary flow (CF). EPR measurements and Stern-Volmer plots showed that 400 microM carnosine quenched 1O2 twice as effectively as equimolar histidine in vitro. Moreover, 10 mM histidine improved functional recovery of isolated rat hearts significantly more than 1 mM histidine. Furthermore, 1 mM carnosine improved functional recovery significantly more than equimolar histidine and as effectively as 10 mM histidine. Experiments with 1 mM mannitol, a known hydroxyl radical scavenger, did not show an improvement in functional recovery relative to control hearts, thereby decreasing the likelihood that hydroxyl radicals are the major damaging species. On the other hand, the correlation between improved functional recovery of isolated rat hearts with histidine and carnosine and their relative 1O2 quenching effectiveness in vitro provides indirect evidence for 1O2 as ROS participating in reperfusion injury.
J Mol Cell Cardiol 1999 Jan
PMID:Improved functional recovery of ischemic rat hearts due to singlet oxygen scavengers histidine and carnosine. 1007 20

Isolated, perfused heart preparations suffer an inevitable peri-operative delay (POD) before retrograde perfusion restores coronary flow. By varying this ischaemic period we investigated the threshold of POD-induced inadvertent preconditioning (PC) in the rat heart. Hearts subjected to POD at 37 degrees C increasing from 1, 2, 3, 5, 10 up to 15 min prior to 20 min retrograde perfusion were further subjected to 30 min global, normothermic ischaemia and 30 min reperfusion (index I/R). The functional recovery was 32 +/- 4.1% in hearts subject to 1 min POD. After 3 min POD functional recovery started to improve and peaked at 10 min POD (78 +/- 7.1%, P < 0.001). At 4 degrees C functional recovery started to improve after 5 min POD and peaked at 10 min POD. To demonstrate that the POD-mediated protection was true PC, two conventional models of PC were established. In both models, hearts were retrogradely perfused within 1 min POD prior to a standard PC protocol (one episode of 10 min ischaemia, or four episodes of 5 min ischaemia). In the conventional PC models protection against the index I/R was abolished using 100 microM 5-hydroxydecanoate (5-HD), the mitrochondrial KATP channel inhibitor. Likewise, 10 min POD-mediated recovery at 37 degrees C (70 +/- 3.2%) was reversed by 100 microM 5-HD perfusion (36 +/- 5.9%; NS v.s. 2 min POD). We conclude: (1) the threshold for PC is greater than 3 min at 37 degrees C and greater than 5 min at 4 degrees C: (2) blockade of the mitochondrial KATP channel abolishes protection in three models of PC in the rat heart, including prolonged POD.
J Mol Cell Cardiol 1999 Mar
PMID:Normothermic transfer times up to 3 min will not precondition the isolated rat heart. 1019 82

Repetitive brief ischemic episodes (ischemic preconditioning, PC) result in transient intracellular acidosis and protect the heart from subsequent ischemic injury, potentially through a protein kinase C (PKC)-dependent mechanism. We hypothesized that repetitive brief acidification of the heart without concomitant ischemia would also protect the heart from ischemic injury via a PKC-dependent mechanism. Isolated rat hearts underwent 30 min of global ischemia following control perfusion (CTL), or after PC or repetitive acidosis (RA), in the presence of absence of chelerythrine, a specific PKC inhibitor. Intracellular pH, PCr and ATP were measured using 31P NMR spectroscopy, while intracellular sodium [Na]i was measured using 23Na spectroscopy. Na,K-ATPase activity was measured prior to ischemia and on reperfusion. Both PC and RA resulted in transient acidification prior to ischemia. Ischemic injury, as assessed by creatinine kinase (CK) release on reperfusion, was reduced in both the PC and RA hearts [63+/-14 and 16+/-4 IU/g dry weight (dw) respectively, v 705+/-72 IU/gdw for control P<0.001], and was associated with improved functional recovery on reperfusion. PC and RA each significantly reduced Na,K-ATPase activity prior to ischemia (8.18+/-0.47 and 7.76+/-0.54 micromol ADP/h/mg protein) when compared to control (11.05+/-0.54 micromol ADP/h/mg protein P<0.05), limited the rate of ATP depletion during ischemia, and resulted in more rapid normalization of [Na]i on reperfusion. Chelerythrine resulted in intermediate CK release in PC and RA hearts (443+/-48 and 375+/-72 IU/gdw, P<0.001 v PC, P<0.01 v control), but did not alter the rate of ATP depletion or [Na]i kinetics in either PC or RA hearts. PC and RA each protect the ischemic heart, having in common ATP preservation during ischemia and more rapid normalization of [Na]i on reperfusion. These effects, not modulated by protein kinase C, are consistent with the hypothesis that ATP preservation during ischemia provides enhanced substrate for sodium efflux via the Na,K-ATPase on reperfusion.
J Mol Cell Cardiol 1999 Apr
PMID:Repetitive acidosis protects the ischemic heart: implications for mechanisms in preconditioned hearts. 1032 17

Macromolecular synthesis inhibitors protect cells from apoptosis in many systems. To determine whether the protein synthesis inhibitor cycloheximide (CHX) might inhibit apoptosis and protect the myocardium during ischemia-reperfusion, we subjected isovolumic isolated perfused rat hearts to 25 min of normothermic global ischemia followed by reperfusion. We monitored coronary flow, end-diastolic pressure and rate-pressure product (RPP) throughout and assessed apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL). Regardless of the treatment regimen (only before ischemia; only during reperfusion; or both before ischemia and during reperfusion), CHX significantly improved functional recovery during reperfusion. These effects were most pronounced when CHX was present during reperfusion. When hearts were treated with CHX only during reperfusion the recovery of sinus rhythm was more frequent in the CHX-treated hearts than control hearts (80% v 53%) and earlier for CHX-treated than control hearts: 6.4 +/- 2 v 19.4 +/- 4.7 min of reperfusion. The maximal RPP recoveries for the CHX-treated hearts were 45 +/- 4.0% (P=0.005) of pre-ischemic values, compared to 26 +/- 3% for controls. In control hearts reperfused for 2 h, TUNEL identified 49.5 +/- 10 intact nuclei and 7.5 +/- 2 fragmented nuclei per 1000 nuclei counted. A significantly lower incidence of labeled nuclei with or without fragmentation was observed in CHX treated hearts: 7.6 +/- 3.4 (P=0.009) intact labeled nuclei and 1.8 +/- 0.7/10(3)fragmented labeled nuclei. Our results suggest that CHX-induced inhibition of apoptosis in reperfused myocardium is cardioprotective and promotes functional recovery in vitro.
J Mol Cell Cardiol 1999 May
PMID:Inhibition of apoptosis after ischemia-reperfusion in rat myocardium by cycloheximide. 1033 45

Heat stress (HS) and the subsequent expression of 72 kDa heat shock protein (HSP 72) has been shown to enhance post-ischemic functional recovery and reduce infarct size. Because the synthesis of heat shock proteins involves activation of heat shock transcription factors through phosphorylation, we hypothesized that inhibition of protein kinase C (PKC) would block HS mediated protection and expression of HSP 72 in the heart. Five groups of rats were studied (1) Sham anesthetized, (2) HS group--animals were heat shocked by raising the whole body core temperature to 42 degrees C for 15 min, (3) Vehicle group--HS rats treated with 50% DMSO in saline, (4) PKC inhibitor-treated group--specific PKC antagonist, chelerythrine chloride (5 mg/kg, i.p) given 30 min prior to HS and (5) Vehicle treated control--non-HS rats treated with vehicle prior to ischemia/reperfusion. Hearts were subjected to 30 min of regional ischemia and 90 min of reperfusion 24 h after HS. Risk area was delineated by injection of 10% Evan's blue and infarct size determined using computer morphometry of tetrazolium stained sections. Infarct size (% area at risk) reduced significantly from 49.4 +/- 2.3% (n = 7) in sham to 10.0 +/- 2.5% (p < 0.01) and 9.1 +/- 3.0% in HS and vehicle treated HS groups respectively (p < 0.05) Treatment with chelerythrine prior to HS increased infarct size to 49.4 +/- 2.3% (p < 0.05). Infarct size in chelerythrine-treated non-HS ischemic/reperfused heart was 40.7 +/- 5.4%, which did not differ significantly from vehicle-treated sham group. Western blot analysis demonstrated marked increase in HSP 72 in HS groups (with or without vehicle treatment) and pretreatment with chelerythrine chloride failed to inhibit the expression of HSP 72. The results suggest that HS-induced ischemic tolerance is mediated via PKC pathway and this protection does not appear to be directly related to the expression of HSP 72 in rat heart.
Mol Cell Biochem 1999 May
PMID:Role of protein kinase C and 72 kDa heat shock protein in ischemic tolerance following heat stress in the rat heart. 1039 76


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