Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to explore the effect of ischemia on the Na(+)-K(+)-ATPase activity and ouabain receptor of the myocardial sarcolemma in hypercholesterolemic rabbits. Male New Zealand white rabbits were fed with either standard chow or standard chow supplemented with 0.5% (w/w) cholesterol and 10% (w/w) coconut oil. After an 8 week feeding period, the rabbits underwent a thoracotomy and myocardial ischemia was induced by occlusion of the coronary artery. Myocardial samples from the ischemic and non-ischemic regions of the left ventricle of control and cholesterol-fed rabbits were taken for study. The cholesterol-fed group showed a decrease in both Na(+)-K(+)-ATPase activity and [3H]ouabain binding sites as compared to the control group. Ischemia caused a reduction in both Na(+)-K(+)-ATPase activity [3H]ouabain bindings sites in both control and cholesterol-fed rabbits. The combination of ischemia and hypercholesterolemia produced an additive effect, with a further decrease in both Na(+)-K(+)-ATPase activity and [3H]ouabain binding sites. Neither the activity of Mg+(+)-ATPase nor the binding affinity for [3H]ouabain was affected by either hypercholesterolemia or ischemia. These findings indicate that hypercholesterolemia may exaggerate certain aspects of functional deterioration arising during myocardial ischemia.
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PMID:Ischemia-induced alteration of myocardial Na(+)-K(+)-ATPase activity and ouabain binding sites in hypercholesterolemic rabbits. 900 5

The effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate) on major ion transporters were studied in canine cardiac sarcolemmal and sarcoplasmic reticular vesicles. KB-R7943 inhibited the Na+/Ca2+ exchange more potently than the Na+/H+ exchange, the Na+/K(+)-ATPase and the Ca2(+)-ATPase. The effects of KB-R7943 on ischemia/reperfusion-induced injury were studied in isolated rat perfused hearts in comparison with those of diltiazem and lidocaine. In normal hearts, diltiazem (10 microM) and lidocaine (100 microM) markedly reduced contractile function, but KB-R7943 (1, 10 microM) had no such effect. In the hearts subjected to 25-min ischemia and 30-min reperfusion, KB-R7943 concentration-dependently and significantly improved post-ischemic recovery of left ventricular developed pressure, left ventricular dP/dtmax and left ventricular end-diastolic pressure by pre-ischemic treatment (5 min) or post-ischemic treatment (10 min). Diltiazem and lidocaine showed similar improvement of recovery by pre-ischemic treatment, but they had no effect by post-ischemic treatment. Furthermore, the effect of KB-R7943 on arrhythmia was studied in anesthetized rats subjected to 5-min cardiac ischmeia and 10-min reperfusion. KB-R7943 (1, 10 mg/kg, i.v.) dose-dependently reduced the incidence and the duration of ventricular fibrillation. These results indicate that KB-R7943, a selective Na+/Ca2+ exchange inhibitor, has beneficial effects against myocardial ischemia/reperfusion injury and suggest that activation of the Na+/Ca2+ exchange mainly occurs immediately after reperfusion in the pathophysiological process of myocardial ischemia/reperfusion injury.
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PMID:[Effects of KB-R7943, a novel Na+/Ca2+ exchange inhibitor, on myocardial ischemia/reperfusion injury]. 955 49

Recent evidence suggests the existence of several endogenous Na+,K+-ATPase inhibitors in mammals. Previously, we have shown that the amphibian Na+,K+-ATPase inhibitor marinobufagenin (3,5-dihydroxy-14,15-epoxy bufodienolide) acts as a vasoconstrictor in isolated rat and human arteries. Mammalian plasma was shown to contain marinobufagenin-like immunoreactive material, which is responsive to saline volume expansion. The present study describes purification of a bufodienolide, which is similar to marinobufagenin, from the urine of patients after acute myocardial infarction with the use of thin-layer chromatography and reverse-phase high-performance liquid chromatography (HPLC). The purified substance cross-reacted with marinobufagenin antibody, demonstrated maximal UV absorbance at 300 nm characteristic of bufodienolides, and eluted from HPLC columns with the same retention time as marinobufagenin. Mass spectrometry of purified material revealed the presence of a substance indistinguishable from amphibian marinobufagenin and having molecular mass of 400 D. The present studies show that one of the human digitalis-like factors may have a bufodienolide structure and is likely to represent marinobufagenin or its isomer, and they suggest a role for this substance in the pathogenesis of myocardial ischemia.
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PMID:Characterization of a urinary bufodienolide Na+,K+-ATPase inhibitor in patients after acute myocardial infarction. 957 20

Because the net Ca2+ uptake in the sarcoplasmic reticulum (SR) of cardiac muscle is a result of the activity of Ca(2+)-ATPase and of the SR Ca(2+)-release channel, an abnormal Ca2+ uptake may be the result of the dysfunction of either or both structures. The site or sites of action for oxygen-derived free radicals (OFR) damage are unknown, although previous studies on the SR have focused on damage to the Ca2+ pump. Direct effects of OFR on SR Ca(2+)-release channels may be important in understanding their potential contribution to myocardial ischemia/reperfusion injury. We confirmed that superoxide anion radical (O2.-) generated from hypoxanthine-xanthine oxidase reaction decreases calmodulin content and increases 45Ca2+ efflux from the heavy fraction of canine cardiac SR vesicles. Electron spin resonance study showed that hydroxyl radicals are generated in addition to O2.- from hypoxanthine-xanthine oxidase reaction, and data indicate that O2.- is responsible for the observed effect. Current fluctuations through single Ca(2+)-release channels have been also monitored after incorporation into planar phospholipid bilayers. We directly demonstrate that activation of the channel by O2.- stimulates Ca2+ release from heavy SR vesicles and suggest the importance of accessory proteins such as calmodulin in modulating the effect of O2.-.
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PMID:[Superoxide anion radical selectively increases Ca2+ release from cardiac sarcoplasmic reticulum through ryanodine receptor Ca2+ channel]. 1019 Jan 35

The goal of this study was to test the hypothesis that during myocardial ischemia, slowing of the Ca(2+) transient decline causes slowed relaxation. Our approach was to monitor pressure and Ca(2+) transients in isovolumic rat hearts during control and low flow ischemia conditions. In addition, we experimentally slowed the decline of the Ca(2+) transient using cyclopiazonic acid (CPA) to inhibit the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA, the most important pump for rapidly transporting Ca(2+) out of the cytosol). Using 9 microm CPA during normoxia, we were able to reproduce the slowed Ca(2+) transient decline and slowed relaxation found during low flow ischemia. The time constants of cytosolic [Ca(2+)] decline and pressure decline (tau(Ca) and tau(P) respectively) with CPA (78+/-5 ms and 64+/-3 ms) were similar to those found with ischemia (89+/-12 ms and 72+/-10 ms, mean+/-SEM, n=7) and were considerably greater than for controls (41+/-3 and 25+/-2 ms, mean+/-SEM, n=14, P<0.01). Furthermore, the relationship of tau(P) v tau(Ca) with CPA was similar to that found with ischemia. These findings are consistent with the hypothesis that the slowed Ca(2+) transient decline with both CPA and ischemia causes slowed relaxation. Consistent with this conclusion, a simple mathematical model to relate cytosolic [Ca(2+)] and pressure also suggests that slowed pressure relaxation can be explained by slowing of the Ca(2+) transient decline. This study suggests that impaired Ca(2+) uptake is a major injury causing slowed relaxation during ischemia.
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PMID:Role of slowed Ca(2+) transient decline in slowed relaxation during myocardial ischemia. 1047 57

Myocardial ischemia results in an increase in intracellular sodium concentration ([Na]i), which may lead to cellular injury via cellular swelling and calcium overload. Because protein kinase C (PKC) has been shown to reduce Na-K-ATPase activity, we postulated that pharmacological inhibition of PKC would directly increase Na-K-ATPase activity, reduce [Na]i during ischemia, and provide protection from ischemic injury. Isolated rat hearts were subjected to 30 min of global ischemia with and without the specific PKC inhibitor chelerythrine. Intracellular pH, ATP, and [Na]i were assessed using 31P and 23Na NMR spectroscopy, whereas Na-K-ATPase and PKC activity were determined using biochemical assays. Na/H exchanger activity was determined using the ammonium prepulse technique under nonischemic conditions. Chelerythrine increased Na-K-ATPase activity (13.76 +/- 0.89 vs. 10.89 +/- 0.80 mg ADP. h(-1). mg protein(-1); P = 0.01), reduced PKC activity in both the membrane and cytosolic fractions (39% and 28% of control, respectively), and reduced creatine kinase release on reperfusion (48 +/- 5 IU/g dry wt vs. 689 +/- 63 IU/g dry wt; P = 0.008). The rise in [Na](i) during ischemia was significantly reduced in hearts treated with chelerythrine (peak [Na](i) chelerythrine: 21.5 +/- 1.2 mM; control: 31.9 +/- 1.2 mM; P < 0.0001), without an effect on either acidosis (nadir pH 6.16 +/- 0.05 for chelerythrine vs. 6.08 +/- 0.04 for control), the rate of ATP depletion or Na/H exchanger activity. These data support the hypothesis that pharmacological inhibition of PKC before ischemia induces cardioprotection by reducing intracellular sodium overload via an increase in Na-K-ATPase activity.
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PMID:Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts. 1048 22

In myocardial ischemia, adrenergic terminals undergo ATP depletion, hypoxia, and intracellular pH reduction, causing the accumulation of axoplasmic norepinephrine (NE) and intracellular Na(+) [via the Na(+)-H(+) exchanger (NHE)]. This forces the reversal of the Na(+)- and Cl(-)-dependent NE transporter (NET), triggering massive carrier-mediated NE release and, thus, arrhythmias. We have now developed a cellular model of carrier-mediated NE release using an LLC-PK(1) cell line stably transfected with human NET cDNA (LLC-NET). LLC-NET cells transported [(3)H]NE and [(3)H]N-methyl-4-phenylpyridinium ([(3)H]MPP(+)) in an inward direction. This uptake was abolished by the NET inhibitors desipramine (100 nM) and mazindol (300 nM) and by extracellular Na(+) removal. Na(+)-gradient reversal induced an efflux of (3)H-substrate from preloaded LLC-NET cells. Desipramine and mazindol blocked this efflux. Because of its greater intracellular stability and higher sensitivity to Na(+)-gradient reversal, [(3)H]MPP(+) proved preferable to [(3)H]NE as an NET substrate; therefore, only [(3)H]MPP(+) was used for subsequent studies. The K(+)/H(+) ionophore nigericin (10 microM) evoked a large efflux of [(3)H]MPP(+). This efflux was potentiated by the Na(+),K(+)-ATPase inhibitor ouabain (100 microM), was sensitive to desipramine, and was blocked by the NHE inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA; 10 microM). In contrast, EIPA failed to inhibit the [(3)H]MPP(+) efflux elicited by the Na(+) ionophore gramicidin (10 microM). Furthermore, [(3)H]MPP(+) efflux induced by the NHE-stimulant proprionate (25 mM) was negatively modulated by imidazoline receptor activation. Our findings suggest that LLC-NET cells are a sensitive model for studying transductional processes of carrier-mediated NE release associated with myocardial ischemia.
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PMID:LLC-PK(1) cells stably expressing the human norepinephrine transporter: A functional model of carrier-mediated norepinephrine release in protracted myocardial ischemia. 1052 59

In myocardial ischemia, rapid inactivation of Na(+)-K(+)-ATPase and continuing influx of sodium induce Na(+)-overload which is the basis of Ca(2+)-overload and irreversible tissue injury following reperfusion. The Na(+)-H(+)-exchanger of subtype 1 (NHE-1) is assumed to play a major role in this process, but previously available inhibitors were non-specific and did not allow to verify this hypothesis. Cariporide (HOE 642) is a recently synthesized NHE-1 inhibitor. We have investigated its effects on Na+ homeostasis (23Na NMR spectroscopy), cardiac function and energy metabolism (31P NMR) in ischemia and reperfusion. In the well-oxygenated, isolated guinea-pig heart, cariporide (10 microM) had no effect on intracellular Na+, pH or cardiac function. NHE-1 inhibition by cariporide was demonstrated using the NH4Cl prepulse technique. When hearts were subjected to 15 min of ischemia, cariporide markedly inhibited intracellular Na(+)-accumulation (1.3 +/- 0.1 vs 2.1 +/- 0.1-fold rise) but had no effect on the decline in pH. In reperfusion, NHE-1-blockade significantly delayed pH recovery. With longer periods of ischemia (36 min), cariporide delayed the onset of contracture, reduced ATP depletion, Na(+)-overload and again had no effect on pH. In reperfusion, hearts treated with cariporide showed an improved recovery of left ventricular pressure (60 +/- 1 vs 16 +/- 8 mmHg): end-diastolic pressure was normalized and phosphocreatine fully recovered, while there was only a partial recovery in controls. The data demonstrate that Na(+)-H(+)-exchange is an important port of Na(+)-entry in ischemia and contributes to H(+)-extrusion in reperfusion. By reducing Na(+)-overload in ischemia and prolonging acidosis in reperfusion, NHE-blockade represents a promising cardioprotective principle.
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PMID:Blocking Na(+)-H+ exchange by cariporide reduces Na(+)-overload in ischemia and is cardioprotective. 1059 Oct 25

Skinned and hybrid myocardial fibers were studied by methods of tensometry, determination of the ATP hydrolysis intensity, and resonance fluorescent energy transfer between highly selective labels bound to various amino acid residues. It was established that development of the early stage of heart failure in the case of acute myocardial ischemia caused by 15-min coronary artery occlusion (CAO) is related to a reversible damage or adaptive (functional) depression of the contractile protein system. As a result, the system features isolated submolecular post-translational variation in the properties of major proteins in a thin actin filament (myosin is not significantly damaged). This leads to a decrease in the force developed by the hybrid fibers (reconstructed using ghost myocardial fibers taken from ischemic area and normal myosin) and in the ATPase activity of actomyosin (ATP hydrolysis intensity) without any significant change in the Ca-sensitivity, cooperativity of the Ca-response of the actomyosin ensemble, and efficiency of the contractile process. In actin of the ischemic area, CAO results in a serious damage of the Lys61 and Cys374 regions and in a less pronounced damage of the Tyr69 and Cys10 regions. These results suggest that the Lys61 and, probably, Cys374-Lys61 regions are included in the actin monomer as a protomer, without adequate prepolymerization structural-conformational changes necessary to provide for the normal functioning of the filament. In the CAO-induced early stage of heart failure, cardiac glycosides (beta-acetyldigoxin, beta-methyldigoxin, and strophanthin K) produce a direct effect upon the intramolecular structure of myocardial actin, restore the generated force level, and increase the intensity of ATP hydrolysis by actomyosin ensemble. This is achieved by improving or normalizing the structural-conformational state and conformational mobility of the Lys61 and Cys374 region of actin.
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PMID:[A disorder of myocardial contractile function in acute experimental coronary failure: the submolecular mechanisms and the action of cardiac glycosides]. 1083 90

Recent studies on the IF(1) inhibitor protein of the mitochondrial F(1)F(0)-ATPase from molecular biochemistry to possible pathophysiological roles are reviewed. The apparent mechanism of IF(1) inhibition of F(1)F(0)-ATPase activity and the biophysical conditions that influence IF(1) activity are summarized. The amino acid sequences of human, bovine, rat and murine IF(1) are compared and domains and residues implicated in IF(1) function examined. Defining the minimal inhibitory sequence of IF(1) and the role of conserved histidines and conformational changes using peptides or recombinant IF(1) is reviewed. Luft's disease, a mitochondrial myopathy where IF(1) is absent, is described with respect to IF(1) relevance to mitochondrial bioenergetics and clinical observations. The possible pathophysiological role of IF(1) in conserving ATP under conditions where cells experience oxygen deprivation (tumor growth, myocardial ischemia) is evaluated. Finally, studies attempting to correlate IF(1) activity to ATP conservation in myocardial ischemic preconditioning are compared.
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PMID:The IF(1) inhibitor protein of the mitochondrial F(1)F(0)-ATPase. 1083 49


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