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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the human heart the beta-adrenergic receptor-G-protein-adenylyl cyclase system is the most powerful physiologic mechanism to acutely increase contractility and/or heart rate. In the failing human myocardium beta 1-adrenergic receptor number is decreased, and this is accompanied by a reduced beta 1-adrenergic receptor mediated positive inotropic effect. Cardiac beta 2-adrenergic receptor number may or may not decrease; however, beta 2- adrenergic receptor mediated positive inotropic effects are also reduced, possibly because the functional activity of myocardial Gi is increased, thereby inhibiting cyclic AMP formation. The aging human heart shows some similarities with the failing human heart: in both settings, of chronic heart failure and age, beta-adrenergic receptor mediated effects and all other cyclic AMP dependent effects are depressed and Gi-protein is increased.
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PMID:Beta-adrenergic receptors in failing human myocardium. 895 42

Depression of myocardial contractility plays an important role in the development of heart failure; therefore, intensive interest and passion have been generated to develop cardiotonic agents to improve the contractile function of the failing heart. Inotropic agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exert dramatic short-term hemodynamic benefits, but these acute effects cannot be extrapolated into long-term improvement of the clinical outcome in patients with advanced heart failure. Administration of these agents to an energy-starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, but ironically the drug has now been proved to favorably affect the neurohormonal disorders and its reevaluation is now being intensively investigated. More recently, attention has been focused on other inotropic agents that have a complex and diversified mechanism. Recent clinical studies have demonstrated that they are potentially useful in the long-term treatment of heart failure patients. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including acting as cytokine inhibitors, immunomodulators, or calcium sensitizers. However, their therapeutic ratio is narrow and further studies are warranted to establish their optimal doses and their eventual status in the treatment of heart failure.
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PMID:Inotropic agents in the treatment of heart failure: despair or hope? 911 Jan 13

Early heart failure is characterized by elevated plasma atrial natriuretic peptide (ANP) levels, but little is known about the direct effects of ANP on cardiac myocytes. In neonatal rat cardiac myocytes, ANP induced apoptosis in a dose-dependent and cell type-specific manner. Maximum effects occurred at 1 microM ANP, with a 4-5-fold increase in apoptotic cells, reaching a maximum apoptotic index of 19%. In contrast, the maximum apoptotic index of ANP-treated non-myocytes was 1.1 +/- 0.2%, equivalent to control cultures. ANP treatment also sharply reduced levels of Mcl-1 mRNA, a Bcl-2 homologue, coincident with the increase in the incidence of apoptosis. ANP induction of apoptosis was receptor-dependent and mediated by cyclic GMP: the effect was mimicked by 8-bromo-cGMP, a membrane-permeable analog, and by sodium nitroprusside, an activator of soluble guanylyl cyclase, and was potentiated by a cGMP-specific phosphodiesterase inhibitor, zaprinast. Interestingly, norepinephrine, a myocyte growth factor, inhibited ANP-induced apoptosis via activation of the beta-adrenergic receptor and elevation of cyclic AMP. These results show that ANP is a specific effector of cardiac myocyte apoptosis in culture via receptor-mediated elevation of cGMP. Furthermore, at least in this model, ANP and norepinephrine may have opposing roles in the modulation of cardiac myocyte growth and survival.
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PMID:Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. 916 55

Coronary artery disease and ischemic myocardial damage form the most common cause of failure of the heart to pump enough blood for oxygenation of the body at a healthy blood pressure and at a low pressure in the veins. This paper gives an overview of the mechanisms involved in excitation-contraction coupling which are important to control of the force of the heartbeat. The inability of the heart in failure to eject a sufficient amount of blood in order to meet the needs of the body is thought to result from molecular changes in cardiac cells causing decreased active (systolic) force and impaired (diastolic) relaxation together with a greater stiffness of the remodelled ventricular wall. The failure to generate a forceful contraction is in part a consequence of derailment of the processes in the failing cardiac cells to manipulate calcium ions, despite the increased stimulus from nervous and hormone systems to enhance cardiac performance. By lack of adequate release and uptake of calcium ions, the amount of mechanical work that can be put out by the heart muscle is diminished and the heart may fail. Uptake of calcium ions by the intracellular store-the sarcoplasmic reticulum-is impaired in congestive heart failure probably as result of inadequate gene expression. In consequence, the amount of calcium that is released during each heartbeat is less than normal, thus force is reduced; in addition, the positive response of force to increased heart rate is lost. In normal heart muscle, the response of the contractile filaments to calcium ions depends strongly on sarcomere length thus explaining Starling's Law of the heart. Recent evidence suggests that this sensitivity is largely lost in congestive heart failure thereby reducing the effectiveness of stretch of cardiac cells on the mechanical output. The reduction of the maximal velocity of shortening of the cardiac sarcomere in heart failure is not well understood, but may in part be related to changes in the internal load as a result of changes in visco-elastic components of the myocardium Lastly, the effect of longstanding sympathetic drive to the heart during the development of heart failure induces a loss of sensitivity of the myocardium to catecholamines by loss of beta 1 receptors and partial uncoupling of the beta receptors from production of cyclic AMP; hence the effect of sympathetic activation is diminished and the heart has to rely more on Starling's Law. Increase of the filling pressure of the left ventricle may in part accommodate the ongoing demands of the body. However, in the case of a stenosed coronary arterial system, the increased end-diastolic pressure carries the substantial risk of aggravating pre-existent myocardial ischemia.
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PMID:Heart failure and Starling's Law of the heart. 919 98

The phosphodiesterase type III inhibitors piroximone (PIR) and enoximone (ENO) exert positive inotropic and vasodilating effects in patients with severe heart failure. PIR and ENO raise cyclic AMP levels in cardiac and vascular smooth muscle cells. Platelet activity is also regulated by intracellular levels of cyclic AMP. In this study we have investigated the effects of PIR and ENO on platelet activity in vivo and in vitro. PIR and ENO inhibited ADP induced platelet aggregation in a time- and concentration-dependent manner with IC50-values of 67 +/- 14 mumol/l and 129 +/- 6 mumol/l, respectively. Coincubation of PIR with the adenylate cyclase activator iloprost resulted in a synergistic potentiation of the platelet inhibitory effect. In anesthetized rats PIR and ENO (2 mg/kg bw) exerted an effective inhibition of collagen induced reduction in peripheral platelet count (vehicle 49 +/- 7%, PIR 22 +/- 8%, ENO 30 +/- 6%; P < 0.01). In washed human platelets incubation with PIR and ENO resulted in a time- and concentration-dependent increase of the intracellular second messenger cyclic AMP. In Fura-2 AM loaded platelets PIR and ENO diminished PAF induced Ca2+ mobilization concentration dependently. Thus, the observed antiplatelet effects following PIR and ENO might exert beneficial effects in patients with cardiovascular disease.
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PMID:Phosphodiesterase inhibitors piroximone and enoximone inhibit platelet aggregation in vivo and in vitro. 936 63

1 Characteristics of cyclic GMP- and cyclic AMP-mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation. 2 Cardiac output indices of coronary artery-ligated and sham-operated rats were 125+/-8 and 189+/-10 ml min(-1) kg(-1), respectively (P<0.05), indicating the development of CHF at this period. 3 The maximal relaxant response of aortic segments to 10 microM acetylcholine in rats with CHF and sham-operated rats was 64.0+/-5.7 and 86.9+/-1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham-operated rats. 4 In endothelium-intact segments of rats with CHF, the maximal relaxant response to 10 microM isoprenaline (44.5+/-6.7%) was lower that sham-operated rats (81.3+/-2.5%, P<0.05) and the concentration-response curve for NKH477, a water-soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline-induced relaxation of aortic segments was attenuated by NG-nitro-L-arginine methyl ester (L-NAME) in sham-operated rats, but not in rats with CHF. Relaxation to 30 microM dibutyryl cyclic AMP in rats with CHF (26.8+/-2.7%) was lower than that in sham-operated rats (63.4+/-11.8%, P<0.05). 5 Trandolapril (3 mg kg(-1) day(-1)) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5+/-3.6 ml min(-1)) was lower than that of sham-operated rats (55.0+/-3.0 ml min(-1)), and this reduction was reversed (54.1+/-3.4 ml min(-1)) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril-treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7+/-1.0%; that to isoprenaline, 80.5+/-2.8%; that to dibutyryl cyclic AMP, 54.7+/-6.2%). However, aortic segments of trandolapril-treated rats with CHF, L-NAME did not attenuate isoprenaline-induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged. 6 The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP-mediated signal transduction, was partially restored by long-term treatment with trandolapril. The mechanism underlying the restoration may be attributed in part to prevention of CHF-induced endothelial dysfunction.
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PMID:The effect of chronic treatment with trandolapril on cyclic AMP-and cyclic GMP-dependent relaxations in aortic segments of rats with chronic heart failure. 948 24

Binding of [3H]inositol 1,4,5-trisphosphate ([3H]IP3) to guinea pig heart has been characterised, localised and the effect of the in vivo desensitisation of cardiac beta-adrenoceptorcyclic AMP signalling examined. Quantitative autoradiography showed highest levels of [3H]IP3 binding associated with coronary blood vessels and with the endothelial cells of the aorta and the mitral and tricuspid valves. Moderate levels of [3H]IP3 bound to the atrioventricular conducting system, cardiac valves and aortic smooth muscle. Lower levels of [3H]IP3 binding were detected in atrial and ventricular myocardium. Although the phosphoinositide signalling pathway does not contribute greatly to normal cardiac function, there is evidence of an increased importance in situations of compromised excitation-contraction such as occurs in cardiac failure or with, beta-adrenoceptor desensitisation. We examined whether chronic in vivo stimulation of beta-adrenoceptor-adenylate cyclase signalling affected cardiac binding of [3H]IP3. Infusion of guinea pigs with isoprenaline (400 micrograms kg-1 h-1, 7 days) tended to reduce [3H]IP3 binding in myocardium although not significantly (P > 0.05, n = 4). These data indicate that [3H]IP3 binding has a heterogeneous distribution in guinea pig heart with highest levels of binding discretely localised to endothelial cells. Desensitisation of beta-adrenoceptor-cyclic AMP signalling in heart did not lead to upregulation of [3H]IP3 binding.
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PMID:Cardiac binding of [3H]inositol 1,4,5-trisphosphate following chronic stimulation of cyclic AMP signalling in guinea pigs. 957 64

Early studies in enzymatically isolated animal cardiomyocytes indicated that voltage-gated "L-type" Ca2+ currents (ICaL) can be upregulated following an increase of the frequency of activation. Recently, we evidenced a similar regulation of ICaL in human cardiomyocytes from both left and right ventricles and atria over a physiopathological range of stimulations (between 0.5 and 5 Hz). This regulation, enhanced by the beta-adrenergic stimulation, may be involved in the frequency-dependent potentiation of cardiac contractile force in the human healthy myocardium. We show here that the frequency-dependent regulation of ICaL is controlled by the level of phosphorylation, as well as dephosphorylation, of the Ca2+ channels. It was enhanced following activation of the protein kinase A activated by intracellular cyclic AMP (cAMP). Therefore, we anticipate that all agents stimulating cAMP production will favor this process, which was demonstrated here by activating 5HT-4 receptors using serotonin. Alternatively, it was also enhanced by the phosphatase inhibitor okadaic acid which prevents Ca2+ channels dephosphorylation. Alteration or abnormal modulation by beta-adrenergic receptor stimulation of the frequency-dependent facilitation of ICaL may partly explain the altered force-frequency relation described in heart failure.
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PMID:Heart rate as a determinant of L-type Ca2+ channel activity: mechanisms and implication in force-frequency relation. 983 31

We have tested the hypothesis that decreased functioning of creatine kinase (CK) at sites of energy production and utilization may contribute to alterations in energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart failure was induced by aortic banding in 3-week-old rats. Myofilaments, sarcoplasmic reticulum (SR), mitochondrial functions, and CK compartmentation were studied in situ using selective membrane permeabilization of left ventricular fibers with detergents (saponin for mitochondria and SR and Triton X-100 for myofibrils). Seven months after surgery, animals were in CHF. A decrease in total CK activity could be accounted for by a 4-fold decrease in activity and content (Western blots) of mitochondrial CK and a 30% decrease in M isoform of CK (MM-CK) activity. In myofibrils, maximal force, crossbridge kinetics, and alpha-myosin heavy-chain expression decreased, whereas calcium sensitivity of tension development remained unaltered. Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR were estimated from the surface of caffeine-induced tension transient (SCa) after loading with different substrates. In CHF, SCa decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing calcium uptake. Oxidative capacities of the failing myocardium measured as oxygen consumption per gram of fiber dry weight decreased by 28%. Moreover, the control of respiration by creatine, ADP, and AMP was severely impaired. Our observations provide evidence that alterations in CK compartmentation may contribute to alterations of energy fluxes and calcium homeostasis in CHF.
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PMID:Subcellular creatine kinase alterations. Implications in heart failure. 1040 Sep 12

In the human heart, as in the heart of several other species, muscarinic receptors are predominantly of the M2-subtype that couple via a pertussis toxin-sensitive Gi-protein to inhibit adenylyl cyclase. However, it is not clear whether an additional muscarinic receptor subtype exists in the human heart. In human right atrium, stimulation of muscarinic M2 receptors causes direct negative inotropic and chronotropic effects; in human ventricular myocardium, however, the negative inotropic effect can be only achieved when basal force of contraction has been pre-stimulated by cyclic AMP-elevating agents such as beta-adrenoceptor agonists, forskolin or phosphodiesterase inhibitors (indirect effect); this has been shown in various in vitro and in vivo studies. Evidence has accumulated that in chronic heart failure vagal activity is decreased. Cardiac muscarinic M2 receptor density and functional responsiveness (inhibition of adenylyl cyclase activity and negative inotropic effects), however, are not considerably changed when compared with non-failing hearts although cardiac Gi-activity is increased.
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PMID:Muscarinic receptors in the failing human heart. 1044 75


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