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Query: UNIPROT:P06889 (Mol)
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The effects of chronic hypoxia on isolated neonatal rat cardiac myocytes were investigated in a model system of myocardial hypoxia. Spontaneously beating myocardiocytes were cultured for up to one week inside an environmental chamber at an oxygen tension of between 4 and 8 mmHg. In order to stimulate a chronic reduced flow condition fresh hypoxic culture medium was replenished frequently to eliminate or minimize contributions of extracellular metabolite build-up, pH changes, or energy depletion. Under these conditions contractions became progressively impaired and irregular compared with aerobic cultures and beating frequency decreased to about 50% of control over 3 days. Reduced contractility was paralleled by a progressive decrease in the basal intracellular level of cAMP. Both of these effects could be reversed by introducing isoproterenol. Visualization of calcium fluxes using the fluorescent calcium chelator Indo-1 demonstrated that the slower contractions were associated with a pronounced decrease in the rate of calcium efflux during muscle relaxation. Changes in the expression of cAMP dependent genes was apparent in the hypoxic cells and the chronic administration of cAMP elevating drugs was toxic specifically to cells under hypoxia. We propose that cAMP may regulate some short and long-term adaptations of cardiac myocytes to chronic hypoxia.
J Mol Cell Cardiol 1992 Jul
PMID:Molecular regulation of cardiac myocyte adaptations to chronic hypoxia. 132 57

The accumulation of calcium during myocardial hypoxia or ischaemia followed by reoxygenation or reperfusion is related to the development of cell necrosis and may be an important causal mechanism. Influx of calcium is a late event during hypoxia but occurs abruptly on reoxygenation or reperfusion. On reoxygenation calcium influx is not altered by nifedipine or quiescence but can be prevented by nickel (3 mM), cyanide (5 mM) or FCCP (10(-6) M). The extracellular marker 51Cr-EDTA does not enter the intracellular fluid on reoxygenation but can when the cell membrane is disrupted by a detergent, Brij'35, or the calcium paradox. The results suggest that the uptake of calcium on reoxygenation or reperfusion is related to the reintroduction of oxygen and caused by an increased calcium influx down the concentration gradient. The flux is not through the slow calcium channel and is not due to disruption of the membrane. The effects of CN- and FCCP and the unaltered calcium efflux suggest that the major part of the calcium uptake is stored in intracellular compartments and is not located in the intracellular fluid.
J Mol Cell Cardiol 1984 Feb
PMID:Calcium out of control. 637 Dec 54

Positive inotropic agents that increase the sensitivity of myofilaments to calcium have recently been described (Kitada et al., 1987; Cottney et al., 1990; Ferroni et al., 1991; Lee and Allen, 1991; Beier et al., 1992). These drugs appear to augment contractility independently of cAMP or calcium, and thus may have fewer of the adverse side effects seen with other currently available agents (Katz, 1986; Packer 1989). The clinical utility of "calcium-sensitizers" has been questioned on the theoretical grounds that such agents may interfere with relaxation and impair diastolic function (Hajjar and Gwathmey, 1991). Previous studies have shown a small but significant negative lusitropic effect of the calcium sensitizer EMD 53998 in ferret papillary muscle, although this effect was considered to be outweighed by powerful augmentation of contractility. Modelling studies have suggested that the impairment of relaxation by calcium-sensitizers may be even more severe when myocardial calcium is abnormally elevated, such as in hypoxia (Allen and Orchard, 1987; Lodge and Gelband, 1988) and end-stage heart failure (Hajjar and Gwathmey, 1991). We have examined the effects of EMD 53998 and milrinone on contractility and calcium flux in a cell culture model of myocardial hypoxia. The results indicate that increased calcium sensitivity results in marked impairment of relaxation under hypoxic conditions, possibly due to the impaired calcium sequestration and increased calcium availability exhibited by hypoxic myocytes. These studies show that the effects of calcium sensitizers can be strongly influenced by the prevailing status of intracellular calcium handling, and may be deleterious in the diseased or ischemic myocardium.
J Mol Cell Cardiol 1993 Jul
PMID:Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998. 823 Feb 39

Increased tolerance to ischemia exhibited in chronically hypoxia immature rabbit hearts is associated with increased activation of ATP-sensitive potassium (KATP) channels. We determined whether exposure to hypoxia from birth alters the electrophysiological characteristics of Purkinje fibers obtained from rabbits (n = 12/group) which were raised in a normoxic (F O2 = 0.21) or hypoxic (F1O2 = 0.12) environment from birth to 9 days of age and the involvement of the KATP channel. The endocardial surface was exposed and impaled with microelectrodes to record action potential characteristics from Purkinje fibers under control conditions and following exposure to glibenclamide (3 microM). Action potential durations (APD)90 in Purkinje fibers were significantly shorter in hypoxic hearts compared with normoxic controls (110 +/- 5 ms v 121 +/- 4 ms). Glibenclamide increased APD90 in hypoxic hearts (120 +/- 4 ms) to values similar to those observed in normoxic controls (121 +/- 4 ms). Glibenclamide had no effect on APD90 in normoxic hearts. Maximum diastolic potential was more negative in hypoxic hearts and this effect was attenuated by glibenclamide. We conclude that chronic myocardial hypoxia results in a shorter APD as compared with normoxic controls by enhanced activation of KATP channels.
J Mol Cell Cardiol 1997 Feb
PMID:KATP channel activation in a rabbit model of chronic myocardial hypoxia. 914 Aug 41

Brief myocardial hypoxia causes both systolic and diastolic dysfunction, the latter often persisting during re-oxygenation. The underlying mechanisms may involve cytosolic Ca2+ overload as well as altered myofilament properties. Recent studies show that nitric oxide enhances myocardial relaxation via a cGMP-induced reduction in myofilament response to Ca2+. We studied the effects of pretreatment with a nitric oxide donor, sodium nitroprusside (0.1-1 microM) on the response to 5 min hypoxia in isovolumic rat hearts perfused at constant coronary flow. Left ventricular relaxation was assessed by an exponential time constant of pressure fall. Sodium nitroprusside reduced the depression of peak left ventricular pressure and peak dP/dt during hypoxia, and improved left ventricular relaxation both during hypoxia and re-oxygenation. Similar results were observed with a Ca2+ antagonist, nicardipine (10 nM). However, adenosine (400 nM), which reduced coronary perfusion pressure to a similar extent as the other two drugs, failed to improve left ventricular function. Addition of sodium nitroprusside or nicardipine at re-oxygenation did not improve relaxation, but instead impaired recovery of peak left ventricular pressure. These results suggest that exogenous nitric oxide improves LV contractile function, in particular relaxation, during brief hypoxia-re-oxygenation independent of changes in coronary flow or coronary perfusion pressure. Its failure to be protective if administered only during re-oxygenation suggests that its action does not involve an anti-oxidant effect.
J Mol Cell Cardiol 1997 Apr
PMID:Beneficial effects of a nitric oxide donor on recovery of contractile function following brief hypoxia in isolated rat heart. 916 Aug 71

Myocardial adenosine formation varies with myocardial oxygen consumption (MVO(2)), but whether concurrent hypoxia is required for adenosine formation is uncertain. Changes in right coronary (RC) perfusion pressure (RCP) produce directionally similar alterations in right ventricular (RV) MVO(2)and in RC venous P O(2)(P(v)O(2)), an index of myocardial P O(2). RCP was varied in 10 anesthetized, open chest dogs to determine if, under these conditions, RV formation of adenosine would increase with MVO(2)in absence of myocardial hypoxia. Dialysis probes were implanted in the mid myocardium of RV free wall for collecting dialysate samples for HPLC analyses to estimate interstitial adenosine and other purines. Coronary venous blood was sampled from a superficial vein draining the RC artery (RCA) perfusion territory. At 115+/-3 mmHg baseline RCP, RC blood flow (RCBF)=0.51+/-0.04 ml/min/g, MVO(2)=4.6+/-0.5 ml/min/100 g, P(v)O(2)=34+/-1.5 mmHg, and dialysate adenosine=0. 27+/-0.03microM. When RCP was lowered to 61+/-1 mmHg by adjusting an occluder on the proximal RCA, RCBF decreased to 0.36+/-0.03 ml/min/g, MVO(2)fell to 3.7+/-0.4 ml/min/100 g, lactate uptake remained positive, P(v)O(2)fell to 30+/-1.7 mmHg, and dialysate adenosine decreased to 0.20+/-0.03microM. Reactive hyperemia of 1.25+/-0.13 ml/min/g was observed when the RCA constriction was released, although dialysate adenosine had fallen. When RCP was elevated to 164+/-2 mmHg by inflating a balloon catheter in the descending aorta, RCBF increased to 0.70+/-0.06 ml/min/g, MVO(2)increased to 5.8+/-1. 0 ml/min/100 g, P(v)O(2)rose to 39+/-2.3 mmHg, and dialysate adenosine increased to 0.33+/-0.04microM. These data indicate that (1) RV oxygen demand varies with RCP; (2) if RV ischemia is absent, myocardial adenosine formation is modulated by MVO(2), with no requirement for hypoxia; (3) pressure-flow autoregulation is relatively ineffective in the RC circulation, where adenosine does not mediate and may even blunt autoregulation.
J Mol Cell Cardiol 2000 Mar
PMID:Myocardial oxygen consumption modulates adenosine formation by canine right ventricle in absence of hypoxia. 1073 34

Chronic myocardial hypoxia results in elevated nitric oxide (NO) production and increased current through the sarcolemmal K(ATP) channel. We hypothesized these two processes are related and determined whether NO alters the electrophysiology of Purkinje fibers obtained from rabbits (n=12/group) raised in a normoxic (F(I)O2=0.21) or hypoxic (F(I)O2=0.12) environment from birth to 9 days of age. Action potential duration (APD)(90) was shorter (112+/-3 ms v 126+/-3 ms) and maximum diastolic potential (MDP) was more negative (-84+/-2 mV v-80+/-1 mV) in hypoxic hearts compared with normoxic controls. In normoxic hearts the NO donors, S-nitrosoglutathione (GSNO) 50 microM and spermine NONOate (50 microM) shortened APD(90) and increased MDP to levels present in chronically hypoxic hearts. This effect was completely abolished by the K(ATP) channel blocker glibenclamide (3 microM) and by a nitric oxide trap, Carboxy-PTIO (100 microM). The NO carrier glutathione (50 microM) and decomposed spermine NONOate had no effect on APD(90) or MDP. GSNO had no effect in hypoxic hearts; however, when GSNO was combined with glibenclamide APD(90) increased, and MDP decreased to normoxic values. 8-Bromo cGMP (100 microM) shortened APD(90) and increased MDP to levels present in chronically hypoxic hearts. This effect was abolished by glibenclamide. A soluble guanylyl cyclase inhibitor, ODQ (10 microM), had no effect on action potentials in normoxic hearts but in hypoxic hearts resulted in an increase in APD(90) to levels present in normoxic hearts and a decrease in MDP. The effect of ODQ could not be reversed by GSNO. We conclude that NO activates the sarcolemmal K(ATP) channel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism.
J Mol Cell Cardiol 2001 Feb
PMID:Nitric oxide activates the sarcolemmal K(ATP) channel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism. 1116 37

Myocardial ischemia and heart failure are accompanied by well characterized changes in myocardial substrate metabolism. While the normal heart in the fasting state mostly relies on oxidation of fatty acids for energy production, acute myocardial ischaemia is accompanied by increased exogenous myocardial glucose uptake and suppressed utilization of fatty acids. This metabolic shift can be detected using metabolic imaging using labeled glucose and fatty acid analogs. Recently, also specific tracers for the detection of myocardial hypoxia have been tested. In the assessment of myocardial viability metabolic imaging has an established role. Metabolic imaging has also greatly improved our understanding about metabolic derangements in the failing heart and currently metabolic modulation as a therapy of heart failure is studied. While experimental and clinical results are promising, larger clinical trials are warranted to better understand the value of metabolic imaging in the detection and prognosis of ischemic heart disease.
Q J Nucl Med Mol Imaging 2010 Apr
PMID:Metabolic imaging in myocardial ischemia and heart failure. 2058 13

Atrial tachyarrhythmias, the most common type of cardiac arrhythmias, are associated with greater stroke risk. Muscarinic cholinergic agonists have been shown to facilitate atrial tachyarrhythmia maintenance in the absence of cardiac disease. This has been attributed to action potential shortening, which enhances myocardial electrical anisotropy, and thus creates a substrate for reentrant excitation. In this study, we describe a similar effect of the ATP-sensitive K(+) channel (KATP) opener pinacidil on tachyarrhythmia induction in isolated rat atria. Pinacidil, which activates a weakly inwardly-rectifying current in isolated atrial myocytes, enhanced arrhythmia induction in the right and left atria. This effect was abolished by the KATP blocker glibenclamide, but not by atropine, which rules out a possible indirect effect due to stimulation of acetylcholine release. However, pinacidil attenuated carbachol-induced tachyarrhythmia facilitation, which may indicate that the action of these agonists converges to a common cellular mechanism. Both agonists caused marked action potential shortening in isolated atrial myocytes. Moreover, during arrhythmia in the presence of pinacidil and carbachol, the atrial vectorelectrographic patterns were similar and consistent with reentrant propagation of the electrical activity. From these results, we conclude that the KATP channel opening is pro-arrhythmic in atrial tissue, which may pose as an additional risk in the scenario of myocardial hypoxia. Moreover, the similarity of the electrophysiological effects of pinacidil and carbachol is suggestive that the sole increase in background K(+) conductance is sufficient for atrial tachyarrhythmia facilitation.
J Mol Cell Cardiol 2013 Dec
PMID:Muscarinic stimulation and pinacidil produce similar facilitation of tachyarrhythmia induction in rat isolated atria. 2414 Aug

Myocardial hypoxia is a major cause of cardiac dysfunction due to its triggering cell injury and apoptosis. Deregulated microRNAs and their roles in cardiomyocyte apoptosis have attracted much attention. miR-133a is among the most abundant of the miRNAs present in the normal heart, and significant changes in expression of miR-133a were observed in response to anoxia stress. However, the role of this microRNA in myocardial hypoxia-induced apoptosis is presently unclear. In this study, we identified that miR-133a expression was down-regulated in hypoxic H9c2 cells, and its expression gradually decreased with hypoxia time. Functional analysis revealed that miR-133a attenuated hypoxia-induced apoptosis. We further detected expression of apoptosis-related proteins. The results showed that miR-133a suppressed the expression of apoptotic proteins caspase-8, caspase-9, and caspase-3 significantly, while improved the expression of Bcl-2. Bioinformatics analysis, combined with dual-luciferase reporter analysis, was applied to determine that miR-133a directly was binded to the 3'-untranslated region (3'-UTR) of TAGLN2 mRNA and suppressed expression at both transcriptional and translational levels. Next, TAGLN2 knockout was used to reveal that TAGLN2 modulated hypoxia-induced apoptosis via caspase-8 apoptotic pathway. Taken together, our data demonstrated the roles of miR-133a in hypoxia-induced apoptotic and implicate its potential in cardiac dysfunctions therapy.
Mol Cell Biochem 2015 Feb
PMID:miR-133a mediates the hypoxia-induced apoptosis by inhibiting TAGLN2 expression in cardiac myocytes. 2542 10


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