Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac sarcoplasmic reticulum (SR) Ca(2+)-loading ability was assessed in a coronary artery ligation model of heart failure. Heart failure was produced in New Zealand White rabbits by ligation of the left marginal coronary artery. Sham-operated animals were used as controls. After hemodynamic and echocardiographic assessment 8 wk after coronary ligation, a free-running trabecula was isolated from the left or right ventricle, mounted for isometric tension measurement, and permeabilized with the chemical skinning agent saponin, leaving the SR functionally intact. The SR was Ca2+ loaded by exposure of the preparation to a mock intracellular solution with a Ca2+ concentration ([Ca2+]) of 150-300 nM. The amplitude of the caffeine-induced contracture was used as a measure of Ca2+ loaded by the SR. The same preparation was then treated with Triton X-100 to disrupt all cell membranes, and Ca2+ sensitivity {expressed as [Ca2+] required to produce 50% of maximal activation (pCa50)} of isometric tension production and maximum Ca2+ activated force (Cmax) were measured. Ligated animals demonstrated enhanced SR Ca(2+)-loading ability that correlated with the degree of left ventricular dysfunction. Enhanced SR Ca2+ loading was associated with evidence of SR Ca2+ overload revealed as spontaneous tension oscillations. Cmax and pCa50 were not significantly different from controls. Increased SR Ca(2+)-loading ability may predispose the SR to Ca2+ overload and could contribute to both contractile dysfunction and arrhythmogenesis in heart failure.
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PMID:Enhanced SR function in saponin-treated ventricular trabeculae from rabbits with heart failure. 885 17

Epidemiologic studies suggest that daily ingestion of small amounts of alcohol may protect the heart, whereas higher intake may be detrimental. We studied: 1) cardiac performance, bioenergetics, and [Mg2+]i of isolated working rat hearts during perfusion with Krebs-Henseleit medium containing different concentrations of ethanol (EtOH), 2) mechanical responses. Ca2+ metabolism and Mg content of isolated coronary arteries obtained from dogs, sheep, and piglets subjected to varying concentrations of EtOH and [Mg2+]o and 3) intracellular free Ca2+ of isolated rat cardiac myocytes. In intact hearts, EtOH produced a biphasic hemodynamic change, depending upon concentration; 15 mM EtOH (0.07 g/dl) and 45 mM EtOH (0.21 g/dl) were stimulatory: 90 (0.42 g/dl), 135 (0.63 g/dl), and 170 mM (0.79 g/dl) EtOH were depressive. EtOH 15 and 45 mM increased coronary flow up to 150%, cardiac output up to 130%, stroke volume up to 135%, and oxygen consumption (VO2) up to 130%. However, 90 mM and higher EtOH depressed most hemodynamic parameters (except for heart rate) dose dependently. Lactic acid, lactic acid dehydrogenase, and creatine phosphokinase levels in the perfusate tended to be elevated progressively with increasing duration of EtOH perfusion and pH tended to be reduced (p < 0.05). [31P]NMR spectroscopy on hearts revealed that EtOH > or = 90 mM resulted in rises in Pi/ATP concentration ratio with no significant change in PCr/ATP ratio; [Mg2+]i levels fell and cytosolic pH tended to become slightly acidotic [19F]NMR spectroscopy of isolated myocytes revealed that [Ca2+]i rises at high concentrations of EtOH. With respect to coronary vascular muscle (CVM), low concentrations of EtOH resulted in a concentration-dependent reduction in contractions induced by K+, angiotensin II, and 5-HT; concentration-effect curves were shifted rightward to higher concentrations. Low [Mg2+]o potentiated contractions of CVM induced by EtOH. Low EtOH also resulted in reductions in exchangeable and membrane-bound 45Ca in CVM; medium to high concentrations of EtOH reduced Mg content in CVM and increased 45Ca. In the absence of [Ca2+]o, caffeine and EtOH induced similar, transient contractions followed by relaxation in K(+)-depolarized coronary arterial tissues. EtOH-induced contractions were completely abolished by pretreatment of tissues with caffeine. These results on isolated coronary vessels suggest that in addition to a need for [Ca2+]o, an intracellular release of Ca2+ is needed for EtOH to induce contractions. Overall, the data indicate that low concentrations of EtOH (15, 45 mM) are beneficial on cardiac performance, at least in the intact rat heart and coronary arteries: higher concentrations of EtOH (90, 135 mM) are detrimental. High concentrations of EtOH decrease coronary flow, lead to loss of cellular Mg2+, hypoxia, metabolic acidosis of the myocardium, cell membrane damage, and Ca2+ overload, which could result in cardiac failure. Cellular loss of Mg2+ appears to be causative in the detrimental actions of EtOH on the heart.
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PMID:Beneficial vs. detrimental actions of ethanol on heart and coronary vascular muscle: roles of Mg2+ and Ca2+. 888 48

Intracellular Ca2+-release channels on the sarcoplasmic reticulum of striated muscle [ryanodine receptors (RyRs)] and on the endoplasmic reticulum of almost all types of cells [inositol 1,4,5-trisphosphate receptors (IP3Rs)] comprise a unique family of molecules that are structurally and functionally distinct from all other known ion channels. These channels play crucial roles in Ca2+-mediated signaling that triggers excitation-contraction coupling, T-lymphocyte activation, fertilization, and many other cellular functions. Three forms of RyR have been identified: RyR1, expressed predominantly in skeletal muscle; RyR2, expressed predominantly in cardiac muscle; and RyR3, expressed in specialized muscles and nonmuscle tissues including the brain. RyR channels are tetramers composed of four subunits each with a molecular mass of approximately 560,000 Da. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein known as the FK506 binding protein (FKBP). FKBP is the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin that inhibit the prolyl isomerase activity of FKBP and can dissociate FKBP from RyRs. Rapamycin and FK506 increase the sensitivity of RyRs to agonists such as caffeine and could be a cause of cardiac dysfunction associated with high-dose immunosuppressant therapy by promoting leakage of Ca2+ from the sarcoplasmic reticulum. The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP. Three forms of IP3Rs (types 1, 2 and 3) have been characterized by cDNA cloning. Most cells have at least one form of IP3R, and many express all three types. Like RyRs, the IP3R channels are tetramers composed of four subunits (approximately 300,000 Da each). IP3R1 function is regulated by at least two major cellular signaling pathways: the second messenger IP3 activates the channel, and phosphorylation by nonreceptor protein tyrosine kinases (e.g., Fyn) increase its open probability. During end-stage human heart failure, RyR2 mRNA and protein are downregulated, whereas IP3R1 is upregulated, suggesting that altered Ca2+-release channel levels may contribute to defects in Ca2+ homeostasis. Cells that are deficient in IP3R1 exhibit defective T cell-receptor signaling and thus cannot be activated by T cell-receptor stimulation. IP3R1-deficient cells are also resistant to induced apoptosis. Thus RyRs and IP3Rs play critical roles in fundamental and diverse signaling phenomena that include excitation-contraction coupling, T-cell activation, and programmed cell death.
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PMID:Intracellular calcium-release channels: regulators of cell life and death. 912 14

During heart failure, force production by the heart decreases. This may be overcome by Ca2+-sensitizing drugs, which increase myofibril Ca2+ sensitivity without necessarily altering intracellular Ca2+ concentration. However, Ca2+ sensitizers slow the relaxation of intact cardiac muscle. We used diazo-2, a caged chelator of Ca2+, to study the effects of the Ca2+ sensitizers caffeine and CGP 48506 on the intrinsic relaxation rate of cardiac myofibrils. Trabeculae from rat right ventricles were skinned by 1% Triton X-100 and were activated in a 10-microL bath. In steady state experiments, CGP 48506 (10 micromol/L) shifted the force-pCa curve leftward by 0.41+/-0.03 pCa units (mean+/-SEM, n=6). An identical shift was induced by caffeine (20 mmol/L). Photolysis of diazo-2 by a flash of light (160 mJ, 310 to 400 nm) caused an immediate decrease in Ca2+-activated force produced by the trabeculae. Relaxation was fitted by a double-exponential decay, and the rate constants were found to be independent of force and preflash Ca2+ concentration. The initial fast rate, corresponding to myofibrillar relaxation, was increased from 17.3+/-2.0 to 30.9+/-3.7 s(-1) (n=4) by caffeine but was unaffected by CGP 48506 (16.6+/-1.7 and 14.4+/-2.3 s(-1) in the absence and presence of drug, respectively; n=5). Thus, myofibril relaxation need not be slowed by Ca2+-sensitizing agents but can even be accelerated. Despite similarities in their effects on myofibril Ca2+ sensitivity, caffeine and CGP 48506 affect the myofibrils at least partly via different mechanisms.
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PMID:Differential effects of the Ca2+ sensitizers caffeine and CGP 48506 on the relaxation rate of rat skinned cardiac trabeculae. 913 Apr 49

Sarcoplasmic reticular function of rats with chronic heart failure (CHF) following coronary artery ligation was examined. The coronary artery ligation produced 43% infarction of the left ventricle and increased left ventricular end-diastolic pressure 8 weeks after the operation, suggesting the development of CHF by this period. The developed force transients of the skinned fiber of coronary artery-ligated rats were decreased when the skinned fiber was preloaded for 0.25-0.5 min with 10(-5)M Ca2+ (53-70%) and when preloaded with 10(-6)M Ca2+ and then exposed to 0.1-1 mM caffeine (39-87%). The results suggest that the rate of Ca2+ uptake by the sarcoplasmic reticulum (SR) and its ability to release Ca2+ were reduced in the failing heart. [3H]Ryanodine binding activities in homogenates and SR-enriched fractions were significantly reduced in the coronary artery-ligated group (32% and 21%, respectively). The results suggest that the amount of Ca2+ released from SR decreased due to decreased Ca2+ uptake rate of SR and down-regulation of the SR Ca(2+)-release channel, which contributes to cardiac dysfunction in failing hearts following acute myocardial infarction.
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PMID:Cardiac sarcoplasmic reticular function in rats with chronic heart failure following myocardial infarction. 914 Aug 32

Cellular Ca2+ regulation is abnormal in diseased hearts. We designed this study to assess the role of the Na(+)-Ca2+ exchanger in excitation-contraction coupling in surviving myocardium of the infarcted heart. We measured cellular contractions and whole-cell currents in single left ventricular myocytes isolated from the hearts of rabbits with healed myocardial infarction (MI). Eight weeks after MI, rabbits had left ventricular dysfunction without overt heart failure. Myocytes isolated from regions adjacent to the infarcted zone were significantly longer than cells from control hearts. At low stimulation rates (0.5 Hz), the amplitude of field-stimulated contractions was increased (11.6 +/- 0.5% versus 10.2 +/- 0.6% resting cell length), whereas the time to peak shortening and action potential duration were prolonged in the MI cells. When stimulation frequency was increased to 2.0 Hz, cellular shortening did not change or decreased in myocytes from infarcted hearts, whereas control cells had a positive shortening-interval relationship. Cells from infarcted hearts had a significantly decreased (31%) L-type Ca2+ current (ICa) density but no change in the current-voltage relationship or the kinetics of ICa inactivation. Maximal Na(+)-Ca2+ exchange current density was significantly increased (32%) in the cells from infarcted hearts. Sarcoplasmic reticulum (SR) Ca2+ content during a stable train of contractions, as estimated from caffeine-induced inward currents, was slightly increased (P = NS) in the MI myocytes. To determine whether Na(+)-Ca2+ exchange influenced SR Ca2+ content, cells were clamped at potentials between -70 and +90 mV for 400 ms. The amplitude of the contraction during a subsequent clamp step to +10 mV was then measured as an index of SR loading that occurred during the preceding clamp step. Steps to positive potentials produced greater augmentation of the subsequent contraction in MI than in control myocytes. In myocytes from the infarcted heart, increased activity of the Na(+)-Ca2+ exchanger may promote Ca2+ entry or decrease Ca2+ extrusion. This relative augmentation of inward Ca2+ flux by the exchanger may enhance SR Ca2+ loading and thus support contractility that would otherwise be impaired as a result of decreased Ca2+ current. However, Ca2+ influx by the exchanger may contribute to the prolongation of contractions in myocytes from infarcted hearts.
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PMID:Enhanced Na(+)-Ca2+ exchange in the infarcted heart. Implications for excitation-contraction coupling. 940 Mar 90

1 Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction. 2 CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF. 3 The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned fibre was preloaded for 0.25-1 min with 10(-5) M Ca2+ (48-88%) and when preloaded with 10(-6) M Ca2+ and then exposed to 0.1-1 mM caffeine (45-93%). 4 The [3H]-ryanodine-binding activity in SR-enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca2+ released from SR is decreased due to a reduced rate of SR Ca2+ uptake and a downregulation of the SR Ca2+-release channel. 5 Rats were treated orally with 3 mg kg(-1) day(-1) trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end-diastolic pressure, and improved the developed force transients of the skinned fibre of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF. 6 It is concluded that long-term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca2+ release channel.
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PMID:Effects of long-term treatment with trandolapril on sarcoplasmic reticulum function of cardiac muscle in rats with chronic heart failure following myocardial infarction. 948 22

To probe the physiological role of calsequestrin in excitation-contraction coupling, transgenic mice overexpressing cardiac calsequestrin were developed. Transgenic mice exhibited 10-fold higher levels of calsequestrin in myocardium and survived into adulthood, but had severe cardiac hypertrophy, with a twofold increase in heart mass and cell size. In whole cell-clamped transgenic myocytes, Ca2+ channel- gated Ca2+ release from the sarcoplasmic reticulum was strongly suppressed, the frequency of occurrence of spontaneous or Ca2+ current-triggered "Ca2+ sparks" was reduced, and the spark perimeter was less defined. In sharp contrast, caffeine-induced Ca2+ transients and the resultant Na+-Ca2+ exchanger currents were increased 10-fold in transgenic myocytes, directly implicating calsequestrin as the source of the contractile-dependent pool of Ca2+. Interestingly, the proteins involved in the Ca2+-release cascade (ryanodine receptor, junctin, and triadin) were downregulated, whereas Ca2+-uptake proteins (Ca2+-ATPase and phospholamban) were unchanged or slightly increased. The parallel increase in the pool of releasable Ca2+ with overexpression of calsequestrin and subsequent impairment of physiological Ca2+ release mechanism show for the first time that calsequestrin is both a storage and a regulatory protein in the cardiac muscle Ca2+-signaling cascade. Cardiac hypertrophy in these mice may provide a novel model to investigate the molecular determinants of heart failure.
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PMID:Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin. 952 81

Systolic [Ca2+]i-transients have been shown to be depressed in isolated ventricular myocytes from patients with terminal heart failure compared to controls. Experiments were performed in human ventricular cells to investigate whether this reduced systolic [Ca2+]i-transient may be due to a decreased Ca(2+)-content of the sarcoplasmic reticulum (SR). Single myocytes were isolated from left ventricular myocardium of patients with terminal heart failure undergoing cardiac transplantation. These results were compared to those obtained from cells of healthy donor hearts that were not suitable for transplantation for technical reasons. [Ca2+]i-transients were recorded from isolated cells under voltage clamp perfused internally with the Ca(2+)-indicator fura-2. The Ca(2+)-content of the SR was estimated by rapid extracellular application of caffeine (10 mM) to open the Ca(2+)-release channel of the SR and comparison of the caffeine-induced [Ca2+]i-transients in cells from patients with heart failure and from controls without heart failure. Upon steady-state depolarizations to +10 mV (maximum of the Ca(2+)-current), [Ca2+]i-transients in cells from patients with heart failure were significantly smaller than in myocytes from undiseased hearts (333 +/- 26 v 596 +/- 80 nM, P < 0.05). Application of caffeine caused a [Ca2+]i-transient that was always larger than during depolarization. Caffeine-induced [Ca2+]i-transients were significantly smaller in cells from diseased hearts compared with controls (970 +/- 129 v 2586 +/- 288 nM, P < 0.01). A positive correlation was found between left ventricular ejection fraction and caffeine-induced [Ca2+]i-transients in these cells. It is concluded, that depressed [Ca2+]i-transients in myocytes from patients with heart failure may be caused by a decreased Ca(2+)-content of the SR possibly due to an altered Ca(2+)-ATPase activity in these hearts. It is not necessary to postulate an additional defect of the Ca(2+)-release function of the SR to account for the alterations of intracellular (Ca2+]i-handling.
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PMID:Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure. 960 23

Calcium uptake by cardiac sarcoplasmic reticulum (SR) is reported to be reduced in heart failure in the human and in a number of animal models. However, the majority of studies have examined end-stage heart failure in the human and few animal studies have taken account of the duration and severity of left ventricular dysfunction. In this study we have compared SR Ca2+ loading in a haemodynamically assessed, coronary artery ligation model of heart failure at 8 and 15 weeks after ligation. Trabeculae were isolated from the right ventricle and mounted for isometric tension measurement. They were treated with saponin to permeabilize the sarcolemma but retain SR function and bathed in a mock intracellular solution including adenosine triphosphate (ATP) and buffered Ca2+. Caffeine was used to release Ca2+ from the SR. The amplitude of the caffeine-induced contracture was used as a quantitative gauge of the Ca2+ content of the SR. Eight weeks after ligation, trabeculae demonstrated enhanced SR Ca2+ uptake as manifest by larger caffeine-induced contractures (e.g. 200 nM [Ca2+], 120 s loading - 38.2+/-9.2 versus 67.3+/-10.1% of maximum Ca2+-activated force, FCa, max, P=0.03). At 15 weeks, trabeculae from ligated hearts were not significantly different from controls with SR Ca2+ loading returning to control levels (e.g. 200 nM [Ca2+], 120 s loading - 47.3+/-9.6 versus 30.2+/-12.8% FCa, max, P=0.12). These data suggest that SR Ca2+ loading may increase in the early stages of heart failure and fall back to normal with an increasing duration of left ventricular dysfunction. Increased incidence of spontaneous Ca2+ release observed from the SR at 8 weeks and not at 15 weeks may represent an arrhythmogenic mechanism specific to the early phase of heart failure.
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PMID:Sarcoplasmic reticulum Ca2+ loading in rabbits 8 and 15 weeks after coronary artery ligation. 964 27


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