UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of different periods of myocardial ischemia on sarcoplasmatic reticulum function were studied in porcine hearts in which successive occlusions of branches of the left anterior descending coronary artery yielded myocardium ischemic for 0.5, 1 or 2 h. Sarcoplasmatic reticulum vesicles were isolated from transmural biopsies of control and ischemic segments. Ca2+ pumping ATPase was already impaired after 0.5 h of ischemia (77 +/- 9% of control, n = 5) and had decreased to 44 +/- 9% of control (n = 4) after 1 h of ischemia. The functional damage caused by ischemia may be related to an altered second messenger control of the Ca2+ pump because the in vitro phosphorylation of phospholamban by catalytic subunit was also reduced.
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PMID:Sarcoplasmatic reticulum function in the ischemic myocardium. 244 93

Acute myocardial ischemia maintained for 30 and 60 min with subsequent reperfusion did not induced alterations in the cyclic AMP-mediated phosphorylation capacity of phospholamban and troponin I. Inotropic stimulation of the normal heart with 0.1/uM isoprenaline for 2 min resulted in a simultaneous P-incorporation into phospholamban and troponin I to 44.4 +/- 7.5 pmoles P/mg protein and 42.4 +/- 2.9 pmoles P/mg protein, respectively, assayed by a standardized back-phosphorylation procedure. The adrenergic responsiveness, however, was markedly reduced in the time course of ischemia. After an ischemic period of 60 min the adrenergic-stimulated phosphorylation of phospholamban was diminished to 41 per cent of the control value, whereas the increase of troponin I phosphorylation was completely lost. This differential effect can be discussed in terms of the existence of cytosolic compartments for cA, possessing different lability to ischemic injury of cardiac cells. After post-ischemic reperfusion the isoprenaline responsiveness of the phosphorylation of phospholamban and troponin I was found to be normal demonstrating a reversibility at the level of two important regulator proteins, if the transient ischemia do not exceed 60 min period.
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PMID:Phosphorylation of phospholamban and troponin I in the ischemic and reperfused heart: attenuation and restoration of isoprenaline responsiveness. 252 30

The present study was designed to examine the relation between the loss of Ca2+ uptake activity and the change of protein phosphorylation in sarcoplasmic reticulum from ischemic myocardium. Ischemic (0.5, 1 and 2 h duration) and non-ischemic tissue samples were taken from the coronary-ligated porcine left ventricle and sarcoplasmic reticulum fractions were isolated. The membranes were tested for Ca2+ uptake and ATPase activities and phosphorylation of phospholamban. The in vitro 32P incorporation into phospholamban in the presence of cAMP plus the catalytic subunit of cyclic AMP dependent protein kinase became markedly reduced depending on the duration of ischemia. The activities of the Ca2+ pump (Ca2+ uptake and ATPase) were also decreased. The 32P incorporation into the myofibrillar component troponin I, which is also a specific substrate for catalytic subunit, was not affected by ischemia. The reduction of the Ca2+ pump activity correlated with the reduction of 32P incorporation into phospholamban. It is postulated that the ischemia induced inactivation of the Ca2+ pump is not only a consequence of specific loss of enzyme activity, but it is also caused by altered characteristics of phospholamban.
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PMID:Calcium transport and phospholamban in sarcoplasmic reticulum of ischemic myocardium. 252 77

To investigate whether slow Ca2+ channel blockers protect against development of changes in properties of the sarcolemma and in the tissue ultrastructure during myocardial ischemia, nifedipine was administered prior to occlusion (up to 3 hours) of the left anterior descending coronary artery in anesthetized pigs. Intravenous doses which reduced arterial blood pressure by 20-25%, had no effect on the time-dependent reduction of Ca2+-calmodulin and cyclic AMP-dependent 32P incorporation into sarcolemmal phospholamban-like protein. Nifedipine blocked the reduction in the activity of sarcolemmal 5'-nucleotidase. Nifedipine had no significant effect on the long-chain fatty acylcarnitine accumulation in sarcolemma. A marked delay in the appearance of ultrastructural indicators of irreversible tissue injury in subepicardial myocardium was observed, when nifedipine was infused. Particularly the reduced appearance of electron-dense bodies in mitochondria suggested a reducing effect of nifedipine on cellular net gain of Ca2+. Apparently, ischemia-induced loss of the ability of the proteinkinases to incorporate phosphate into sarcolemmal phospholamban-like protein is not a process secondary to Ca2+ overload of the myocardium. The involvement of accumulation of long-chain fatty acylcarnitine within the sarcolemma may also be excluded. The membrane defect as indicated by a change in phosphorylation-mediated control of Ca2+ transport may itself be associated with the development of ischemia (-reperfusion)-induced Ca2+ overload.
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PMID:The effect of nifedipine on ischemia-induced changes in the biochemical properties of isolated sarcolemmal vesicles and the ultrastructure of myocardium. 303 May 20

Myocardial contractility depends on Ca2+ release from and uptake into the sarcoplasmic reticulum (SR). The Ca2+ gradient between the SR matrix and the cytosol (SR Ca2+ gradient) is maintained by the SR Ca2+-ATPase using the free energy available from hydrolysis of ATP. The activity of the SR Ca2+-ATPase is not only dependent on the energy state of the cell but is also kinetically regulated by SR proteins such as phospholamban. To evaluate the importance of thermodynamic and kinetic regulation of the SR Ca2+ gradient, we examined the relationship between the energy available from ATP hydrolysis (DeltaGATP) and the energy required for maintenance of the SR Ca2+ gradient (DeltaGCa2+SR) during physiological and pathological manipulations that alter DeltaGATP and the phosphorylation state of phospholamban. We used our previously developed 19F nuclear magnetic resonance method to measure the ionized [Ca2+] in the SR of Langendorff-perfused rabbit hearts. We found that addition of either pyruvate or isoproterenol resulted in an increase in left ventricular developed pressure and an increase in [Ca2+]SR. Pyruvate increased DeltaGATP, and the increase in the SR Ca2+ gradient was matched to the increase in DeltaGATP; DeltaGATP increased from 58.3+/-0.5 to 60.4+/-1.0 kJ/mol (P<0.05), and DeltaGCa2+SR increased from 47.1+/-0.3 to 48.5+/-0.1 kJ/mol (P<0.05). In contrast, the increase in the SR Ca2+ gradient in the presence of isoproterenol occurred despite a decline in DeltaGATP from 58. 3+/-0.5 to 55.8+/-0.6 kJ/mol. Thus, the data indicate that the SR Ca2+ gradient can be increased by an increase in DeltaGATP, and that the positive inotropic effect of pyruvate can be explained by improved energy-linked SR Ca2+ handling, whereas the results with isoproterenol are consistent with removal of the kinetic limitation of phospholamban on the activity of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, which allows the SR Ca2+ gradient to move closer to its thermodynamic limit. Ischemia decreases DeltaGATP, and this should also have an effect on SR Ca2+ handling. During 30 minutes of ischemia, DeltaGATP decreased by 12 kJ/mol, but the decrease in DeltaGCa2+SR was 16 kJ/mol, greater than would be predicted by the fall in DeltaGATP and consistent with increased SR Ca2+ release and increased SR Ca2+ cycling. Because ischemic preconditioning is reported to decrease SR Ca2+ cycling during a subsequent sustained period of ischemia, we examined whether ischemic preconditioning affects the relationship between the fall in DeltaGATP and the fall in DeltaGCa2+SR during ischemia. We found that preconditioning attenuated the fall in DeltaGCa2+SR during ischemia; the fall in DeltaGCa2+SR was of comparable magnitude to the fall in DeltaGATP, and this was associated with a significant improvement in functional recovery during reperfusion. The data suggest that there is both thermodynamic regulation of the SR Ca2+ gradient by DeltaGATP and kinetic regulation, which can alter the relationship between DeltaGATP and DeltaGCa2+SR.
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PMID:Regulation of the Ca2+ gradient across the sarcoplasmic reticulum in perfused rabbit heart. A 19F nuclear magnetic resonance study. 979 38

To examine the effects of ischemic preconditioning on ischemia-reperfusion-induced changes in the sarcoplasmic reticulum (SR) function, isolated rat hearts were either perfused with a control medium for 30 min or preconditioned with three episodes of 5-min ischemia and 5-min reperfusion before sustained ischemia for 30 min followed by reperfusion for 30 min was induced. Preconditioning itself depressed cardiac function (left ventricular developed pressure, peak rate of contraction, and peak rate of relaxation) and SR Ca2+-release and -uptake activities as well as protein content and Ca2+/calmodulin-dependent protein kinase (CaMK) phosphorylation of Ca2+-release channels by 25-60%. Global ischemia for 30 min produced marked depressions in SR Ca2+-release and -uptake activities as well as SR Ca2+-pump protein content in control hearts; these changes were significantly attenuated by preconditioning. Compared with the control preparations, preconditioning improved the recovery of cardiac function and SR Ca2+-release and -uptake activities as well as Ca2+-release channel and Ca2+-pump protein contents in the ischemic-reperfused hearts. Unlike the protein kinase A-mediated phosphorylation in SR membranes, the CaMK-mediated phosphorylations at Ca2+-release channels, Ca2+ pump, and phospholamban were depressed in the ischemic hearts; these changes were prevented by preconditioning. These results indicate that ischemic preconditioning may exert beneficial effects on ischemia-reperfusion-induced alterations in SR function by preventing changes in Ca2+-release channel and Ca2+-pump protein contents in the SR membrane.
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PMID:Modification of ischemia-reperfusion-induced changes in cardiac sarcoplasmic reticulum by preconditioning. 984 29

Although the sarcoplasmic reticulum (SR) is known to regulate the intracellular concentration of Ca2+ and the SR function has been shown to become abnormal during ischemia-reperfusion in the heart, the mechanisms for this defect are not fully understood. Because phosphorylation of SR proteins plays a crucial role in the regulation of SR function, we investigated the status of endogenous Ca2+/calmodulin-dependent protein kinase (CaMK) and exogenous cAMP-dependent protein kinase (PKA) phosphorylation of the SR proteins in control, ischemic (I), and ischemia-reperfused (I/R) hearts treated or not treated with superoxide dismutase (SOD) plus catalase (CAT). SR and cytosolic fractions were isolated from control, I, and I/R hearts treated or not treated with SOD plus CAT, and the SR protein phosphorylation by CaMK and PKA, the CaMK- and PKA-stimulated Ca2+ uptake, and the CaMK, PKA, and phosphatase activities were studied. The SR CaMK and CaMK-stimulated Ca2+ uptake activities, as well as CaMK phosphorylation of Ca2+ pump ATPase (SERCA2a) and phospholamban (PLB), were significantly decreased in both I and I/R hearts. The PKA phosphorylation of PLB and PKA-stimulated Ca2+ uptake were reduced significantly in the I/R hearts only. Cytosolic CaMK and PKA activities were unaltered, whereas SR phosphatase activity in the I and I/R hearts was depressed. SOD plus CAT treatment prevented the observed alterations in SR CaMK and phosphatase activities, CaMK and PKA phosphorylations, and CaMK- and PKA-stimulated Ca2+ uptake. These results indicate that depressed CaMK phosphorylation and CaMK-stimulated Ca2+ uptake in I/R hearts may be due to a depression in the SR CaMK activity. Furthermore, prevention of the I/R-induced alterations in SR protein phosphorylation by SOD plus CAT treatment is consistent with the role of oxidative stress during ischemia-reperfusion injury in the heart.
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PMID:Status of Ca2+/calmodulin protein kinase phosphorylation of cardiac SR proteins in ischemia-reperfusion. 1048 25

We sought to identify mechanisms for chronic dysfunction in hibernating myocardium. Pigs were instrumented with a left anterior descending artery stenosis for 3 mo. Angiography demonstrated high-grade stenoses and hibernating myocardium with 1) severe anterior hypokinesis (P < 0.001 vs. shams), 2) reduced subendocardial perfusion [0.73 +/- 0.05 (SE) vs. 1.01 +/- 0.06 ml. min(-1). g(-1) in normal, P < 0.001], and 3) critically reduced adenosine flow (1.0 +/- 0.17 vs. 3.84 +/- 0.26 ml. min(-1). g(-1) in normal, P < 0.001). Histology did not reveal necrosis. Northern blot analysis of hibernating myocardium demonstrated regional downregulation in mRNAs for sarcoplasmic reticulum (SR) proteins phospholamban (0.76 +/- 0.08 vs. 1.07 +/- 0.06, P < 0.02) and SR Ca(2+)-ATPase (0.83 +/- 0.06 vs. 1.02 +/- 0.06, P < 0.05) with no change in calsequestrin (1.08 +/- 0.06 vs. 0.96 +/- 0.05, P = not significant). Heat shock protein (HSP)-70 mRNA was regionally induced in hibernating myocardium (2.4 +/- 0.3 vs. 1.0 +/- 0.11, P < 0.01). Directionally similar changes were confirmed by Western blot analysis of respective proteins. Our results indicate that hibernating myocardium exhibits a molecular phenotype that on a regional basis is similar to end-stage ischemic cardiomyopathy. This supports the hypothesis that SR dysfunction from reversible ischemia may be an early defect in the progression of left ventricular dysfunction.
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PMID:Regional alterations in SR Ca(2+)-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium. 1051 77

Adenosine has several potentially cardioprotective effects including vasodilatation, reduction in heart rate and alterations in metabolism. Adenosine inhibits catecholamine-induced increase in contractile function mainly through inhibition of phosphorylation of phospholamban (PLB), the main regulatory protein of Ca(2+)-ATPase in sarcoplasmic reticulum (SR), and during ischemia it reduces calcium (Ca2+) overload. In this study we examined the effects of endogenous adenosine on contractile function and metabolism during low-flow ischemia (LFI) and investigated whether endogenous adenosine can alter expression of the Ca(2+)-ATPase/PLB-system and other Ca(2+)-regulatory proteins. Isolated blood-perfused piglet hearts underwent 120 min 10% flow. Hearts were treated with either saline, the adenosine receptor blocker (8)-sulfophenyl theophylline (8SPT, 300 micromol/l) or the nucleoside transport inhibitor draflazine (1 micromol/l). During LFI, 8SPT did not substantially influence metabolic or functional responses. However, draflazine enhanced the reduction in heart rate, contractile force and MVO(2), with less release of H+ and CO2. Before LFI there were no significant differences between groups for any of the proteins (Ca(2+)-ATPase, ryanodine-receptor, Na+/K(+)-ATPase) or mRNAs (Ca(2+)-ATPase, PLB, calsequestrin, Na+/Ca(2+)-exchanger) measured. At end of LFI mRNA-level of PLB was higher in draflazine-treated hearts compared to both other groups (P<0.01 vs both). Also, at end of LFI protein-level of Ca(2+)-ATPase was lower in draflazine-treated hearts (P<0.05 vs both), and a parallel trend towards a lower mRNA-level was seen (P=0.11 vs saline and P=0.43 vs 8SPT). During LFI tissue Ca2+ tended to rise in saline- and 8SPT-treated hearts but not in draflazine-treated hearts (at end of LFI, P=0.01 vs 8SPT). We conclude that the amount of adenosine normally produced during LFI does not substantially influence function and metabolism. However, increased endogenous levels by draflazine enhance downregulation of function and reduce signs of anaerobic metabolism. At end of LFI associated changes in expression of PLB and Ca(2+)-ATPase were seen. The functional significance was not determined in the present study. However, altered protein-levels might influence Ca(2+)-handling in sarcoplasmic reticulum and thus affect contractile force and tolerance to ischemia.
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PMID:Elevated levels of endogenous adenosine alter metabolism and enhance reduction in contractile function during low-flow ischemia: associated changes in expression of Ca(2+)-ATPase and phospholamban. 1052 27

Although beta-adrenoceptor (beta-AR) blockers are used for the treatment of ischemic heart disease, the mechanisms of their beneficial actions have not been fully elucidated. In view of the role of sarcoplasmic reticular (SR) abnormalities in cardiac dysfunction due to ischemia-reperfusion (I/R), we examined the effects of beta-AR blockers on the I/R-induced changes in SR Ca(2+) uptake and release, as well as the protein contents and gene expression of ryanodine receptor, SR Ca(2+)-pump, phospholamban, and calsequestrin. I/R in isolated rat hearts was induced by stopping the perfusion for 30 min and then reperfusing the ischemic hearts for 60 min. Hearts were treated with or without 10 microM atenolol, a beta(1)-specific blocker, or 10 microM propranolol, a nonspecific beta-blocker, 10 min before inducing ischemia as well as during the reperfusion period. I/R depressed cardiac performance, SR Ca(2+) uptake, and Ca(2+) release activities, protein contents, as well as Ca(2+)/calmodulin-dependent protein kinase and cAMP-dependent protein kinase-mediated phosphorylations, significantly. The mRNA levels for SR Ca(2+) pump, ryanodine receptors, phospholamban, and calsequestrin were also reduced by I/R. All these changes due to I/R were partially prevented by beta-AR blocker treatment. The results indicate that the beneficial effects of beta-AR blockers on cardiac performance in the I/R hearts may be related to the prevention of changes in SR Ca(2+) uptake and release activities, protein contents, as well as Ca(2+)/calmodulin-dependent protein kinase and cAMP-dependent protein kinase phosphorylations of SR proteins. On the other hand, the protection of I/R-induced alterations in mRNA levels for SR proteins by beta-AR blockers suggests cardiac SR gene expression as a molecular site of their cardioprotective action.
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PMID:Effect of beta-adrenoceptor blockers on sarcoplasmic reticular function and gene expression in the ischemic-reperfused heart. 1073 48

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