UMLS:C0018801 - FACTA Search

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

Acute myocardial ischemia and subsequent reperfusion result in biochemical and ionic changes in cardiac myocytes which cause contracture of the muscle and a reduced contractile force. Whether changes observed in single myocytes isolated from ischaemic ventricles are a direct consequence of the acute insult, or develop more slowly due to subsequent alterations in load and neurohumoural environment, is controversial. Myocytes from ischemic hearts have a similar contraction amplitude to those from non-failing hearts at physiological or maximally activating levels of ca2+. This could be partly due to the method of cell selection, or could represent the detection of a population of myocytes that have recovered from the original insult. However, there are significant decreases in the velocities of contraction and, particularly, relaxation in myocytes from the ischaemic heart. These resemble alterations caused by anoxia/reperfusion, but similar changes have also been observed in non-ischaemic causes of heart failure. Responses of beta-adrenoceptor stimulation are reduced in single cells from the failing heart, and a post-receptor defect has also been detected. Treatment with pertussis toxin, which reduces the activity of the inhibitory guanine-nucleotide binding protein (Gi) was able to restore beta-adrenoceptor responses to normal. The hypothesis that alterations in the beta-adrenoceptor/Gi/cAMP pathway represent the response of the myocyte to continued exposure to noradrenaline, because of the high sympathetic drive in these patients, is supported by the strong parallels observed with catecholamine-treated animals, and by the fact that non-ischemic aetiologies exhibit similar desensitization. It is concluded that the surviving myocytes in an ischaemic heart are damaged by the neurohumoral alterations that represent the body's attempt to restore cardiac output.
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PMID:Abnormalities of the myocytes in ischaemic cardiomyopathy. 882 61

Transduction of the beta-adrenergic signal plays an important role in the regulation of cardiac contractility. It is mediated by three sarcolemmal proteins: the beta-adrenergic receptor, G proteins and adenylyl cyclase which is the catalytic unit of the system which generates cAMP, the second messenger of the system. Each protein comprises a number of isoforms which yields a wide range of potential regulations, many of which are not yet elucidated. Among the three proteins, the adenylyl cyclase is the one which has been less studied. However, the recent cloning of many of its isoforms allows now investigations of their expression in many tissues and cell types. We have shown in rats that among the five isoforms detected in the myocardium, type V and VI adenylyl cyclase mRNAs are the most abundant ones. Type V and VI adenylyl cyclase mRNA abundance is similar in late fetal hearts. Type V mRNA accumulates in the heart during postnatal development whereas type VI mRNA concentration remains unchanged. Consequently, type V mRNA becomes highly predominant compared to type VI mRNA in the adult rat ventricle (type V/type VI adenylyl cyclase mRNAs approximately 10). Whatever the developmental stage, cardiac adenylyl cyclase activity is inhibited by submicromolar calcium concentrations. In adult ventricles, adenylyl cyclase activity in the presence of 1 mM ATP is at least three times higher than that observed in fetal and new born rat hearts. Since this increase parallels the accumulation of type V adenylyl cyclase mRNA, one can hypothesize that the former is due to the latter. In contrast, our preliminary results seem to indicate that during heart failure in rats, decreased adenylyl cyclase activity is not associated with decreased cardiac concentrations of type V and VI adenylyl cyclase mRNAs. Isoform specific antibodies are now required to understand the reasons for such discrepancy.
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PMID:[Beta adrenergic signal transduction and heart adenyl cyclase]. 886 32

1. The goal of this review is to emphasize four major points regarding the development of catecholamine desensitization in heart failure (HF). 2. Catecholamine desensitization occurs prior to the development of HF (i.e. after 1 day of rapid pacing, physiological responses to beta-adrenoceptor stimulation are depressed by over 50%, yet no evidence of HF is observed for 3-4 weeks of rapid pacing). 3. Multiple mechanisms in the beta-adrenoceptor cascade are involved. In HF there are decreases in beta 1-adrenoceptors, high affinity beta-adrenoceptors, adenylyl cyclase activity and messenger RNA and increases in Gi. 4. Not all mechanisms appear simultaneously (i.e. early decreases occur in high affinity beta-adrenoceptors and adenylyl cyclase; late increases in Gi and decreases in beta-adrenoceptor density evolves). 5. Mechanisms distal to cAMP generation also play a role (i.e. alterations in ryanodine receptor binding and excitation-contraction coupling also occur).
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PMID:Beta-adrenoceptor desensitization during the development of canine pacing-induced heart failure. 888 92

Heart failure is a problem of increasing importance in cardiovascular medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor downregulation) and impaired receptor function (receptor uncoupling). These changes in the section-adrenergic receptor (section-AR) system may in part account for some of the abnormalities of contractile function in this disease. Myocardial contraction is closely regulated by G protein coupled beta-adrenergic receptors through the action of the second messenger cAMP. The beta-adrenergic receptors themselves are regulated by a set of specific kinases, termed the G-protein-coupled receptor kinases. The study of this complex system in vivo has recently been advanced by the development of transgenic and gene targeted ("knockout") mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful strategy to study the regulation of myocardial contractility in the normal and failing heart.
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PMID:Myocardial beta-adrenergic receptor signaling in vivo: insights from transgenic mice. 889 53

Beta-adrenoreceptor-cAMP-dependent inotropic interventions lose their effectiveness depending on the degree of myocardial failure. This blunted effect of beta-adrenoreceptor-dependent stimulation might be due to a downregulation of beta-adrenoreceptors and an increase of inhibitory G-proteins leading to decreased intracellular cAMP-concentrations. However, the maximal positive inotropic effect elicited by elevation of the extracellular [Ca2+] does not differ between failing and nonfailing human myocardium, indicating that terminally failing human myocardium is effective to increase force of contraction to the same degree as nonfailing tissue. Agents which increase force of contraction primarily via increasing the intracellular [Na+], e.g., cardiac glycosides and the Na(+)-channel activator BDF 9148, exert a higher potency in failing myocardium than in nonfailing tissue to increase force of contraction. This could result from an enhanced protein expression of the Na+/Ca(2+)-exchanger observed in diseased human hearts. Alterations in the intracellular Ca(2+)-homeostasis reported in failing myocardium lead to a negative force-frequency-relationship and a prolonged relaxation. As the protein expression of SERCA IIa and phospholamban seems to be similar in NYHAIV and nonfailing tissue, the reduced Ca(2+)- uptake may result from an altered regulation of these proteins, e.g., reduced phosphorylation of phospholamban or the SERCA IIa. After inhibition of the Ca(2+)-ATPase of the sarcoplasmic reticulum with the high specific inhibitor cyclopiazonic acid the former positive force-frequency-relationship became significantly less positive even in the nonfailing tissue and twitch course became similar to diseased hearts. These findings may be indicative for the importance of the Ca(2+)-reuptake mechanism into the sarcoplasmic reticulum in addition to the regulatory control at the site of the contractile apparatus for the regulation of contraction and relaxation in human myocardium.
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PMID:Altered inotropism in the failing human myocardium. 895 38

Increased expression of the inhibitory G protein Gi alpha-2 is assumed to contribute to desensitization of adenylyl cyclase in human heart failure. The mechanisms of upregulation involve increases in myocardial Gi alpha-2 protein, mRNA and gene transcriptional activity. To elucidate these mechanisms in more detail, the 5' flanking region of the human Gi alpha-2 gene (-1214/+115 bp) was cloned upstream of the bacterial chloramphenicol acetyltransferase (CAT) gene and transfected in embryonic chick cardiomyocytes. CAT activity was measured 48 h after transfection. Unstimulated activity of the -1214/+115 bp construct was about 10-fold higher than activity of the basal CAT-construct (pGEMCAT). 5' deletion from -1214/+115 to -85/+115 bp upstream of the transcriptional start site increased, further stepwise deletions to 46/+115 gradually decreased promotor activity. Deletion from -46/+115 to -33/+115 bp completely abolished promotor activity. Stimulation of cardiomyocytes that had been transfected with the -1214/+115 CAT-construct with isoprenaline (10 microM), forskolin (10 microM), forskolin (10 microM) plus IBMX (10 microM) or dibutyryl-cAMP (1 mM) for 24 h induced an increase in CAT activity to 139 +/- 12% (n = 9), 211 +/- 18% (n = 12), 256 +/- 20% (n = 5) and 198 +/- 28% (n = 7) of unstimulated values, respectively. We conclude: 1) In chicken cardiomyocytes a sequence element of 52 bp between -85 and -33 bp is necessary to provide basal Gi alpha-2 promotor activity. 2) Elevation of cAMP has a stimulatory effect on the human Gi alpha-2 promotor, thereby offering a mechanism for beta-adrenoceptor-mediated increases in Gi alpha-2 in the heart.
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PMID:Regulation of the human Gi alpha-2 gene promotor activity in embryonic chicken cardiomyocytes. 895 43

Evidence from ventricular preparations of cat, sheep, rat and dog suggests that both beta 1-adrenoceptors (beta 1AR) and beta 2-adrenoceptors (beta 2AR) mediate positive inotropic effects but that only beta 1AR do it through activation of a cAMP pathway. On the other hand, our evidence has shown that both beta 1AR and beta 2AR hasten relaxation of isolated human myocardium consistent with a common cAMP pathway. We have now investigated in the isolated human right atrial appendage, a tissue whose beta-AR comprise around 2/3 of beta 1AR and 1/3 of beta 2AR, whether or not beta 2AR-mediated effects occur via activation of a cAMP pathway. We carried out experiments on atria obtained from patients without advanced heart failure undergoing open heart surgery. To activate beta 2AR, we used the beta 2AR-selective ligand zinterol. Experiments were carried out on paced atrial strips (1 Hz) and tissue homogenates and membrane particles. Zinterol caused positive inotropic and lusitropic (i.e. reduction of t1/2 of relaxation) effects with EC50 values of 3 and 2 nM, respectively. The zinterol-evoked effects were unaffected by the beta 1AR-selective antagonist CGP 20712A (300 nM) but blocked surmountably by the beta 2AR-selective antagonist ICI 118551 (50 nM) which reduced both EC50 values to 1 microM. Zinterol stimulated adenylyl cyclase activity with an EC50 of 30 nM and intrinsic activity of 0.75 with respect to (-)-isoprenaline (600 microM); the effects were resistant to blockade by CGP 20712A (300 nM) but antagonised surmountably by ICI 118551 (50 nM). Zinterol bound to membrane beta AR labelled with (-)-[125I] cyanopindolol with higher affinity for beta 2AR than for beta 1AR; the binding to beta 2AR but not to beta 1AR was reduced by GTP gamma S (10 microM). In the presence of CGP 20712A (300 nM) (-)-isoprenaline (400 microM) (to activate both beta 1AR and beta 2AR maximally) and zinterol (10 microM) increased contractile force 3.4-fold and 2.5-fold respectively and reduced relaxation t1/2 by 32% and 18% respectively. These effects of (-)-isoprenaline and zinterol were associated (5 min incubation) with phosphorylation (pmol P/mg supernatant protein) of troponin I and C-protein to values of 8.4 +/- 2.0 vs 12.4 +/- 2.3 and 10.1 +/- 2.5 vs 8.6 +/- 1.6 respectively. (-)-Isoprenaline and zinterol also caused phosphorylation of phospholamban (1.8 +/- 0.3 vs 0.4 +/- 0.1 pmol P/mg respectively) specifically at serine residues. We conclude that in human atrial myocardium activation of both beta 1AR and beta 2AR leads to cAMP-dependent phosphorylation of proteins involved in augmenting both contractility and relaxation.
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PMID:Beta 2-adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium. 897 46

To elucidate pathophysiological alterations in vascular relaxation in rats with chronic heart failure (CHF), guanosine 3',5'-cyclic monophosphate (cGMP)- and adenosine 3',5'-cyclic monophosphate (cAMP)-mediated vasorelaxations in pulmonary artery (PA) and thoracic aorta (TA) of rats were examined 12 wk after coronary artery ligation. Acetylcholine (ACh)-induced relaxation was attenuated in endothelium-intact segments of both arteries, whereas sodium nitroprusside-induced relaxation was attenuated only in endothelium-intact TA segments of rats with CHF. Vasorelaxations elicited by isoproterenol and NKH-477, a water-soluble forskolin analogue, were diminished mainly in PA segments of the CHF rat. NG-nitro-L-arginine methyl ester (L-NAME)-induced decrease in cGMP level was less in endothelium-intact TA segments of the rat with CHF (0.20 +/- 0.06 vs. 0.99 +/- 0.26 pmol/mg protein in control), suggesting that basal nitric oxide (NO) production is reduced in CHF. Treatment with L-NAME attenuated the isoproterenol-induced relaxation only in endothelium-intact TA segments in control rats but not in CHF rats. The results suggest that both cGMP- and cAMP-mediated relaxations are impaired in CHF, and a reduction of NO synthesis, presumably in endothelial cells, plays a significant role in pathophysiological alterations in vessels of rats with CHF.
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PMID:Impairment of cGMP- and cAMP-mediated vasorelaxations in rats with chronic heart failure. 899 78

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.
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PMID:Differential modulation of cytokine production by drugs: implications for therapy in heart failure. 900 65

The aim of this study was to determine whether a defect at the post-receptor level of adenylyl cyclase may also contribute to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease. The severity of congestive heart failure in 31 patients with congenital heart disease was graded by a scoring system which included a description of historical and clinical variables. Patients were divided into a group with no or mild heart failure (score < or = 6) and a group with severe heart failure (score > 6). beta-Adrenoceptor-stimulated adenylyl cyclase activity was significantly decreased by 65% in patients with severe heart failure in comparison to the group of patients with no or mild heart failure. In addition, receptor-independent adenylyl cyclase stimulation by forskolin was reduced by 52% in patients with score > 6 compared to patients with score < or = 6. This post-receptor defect of adenylyl cyclase was apparently due to a decrease in the activity of catalytic subunit of adenylyl cyclase as adenylyl cyclase stimulation by forskolin in the presence of Mn2+ which uncouples catalytic subunit from the G proteins, G(s) and G(i), was also significantly diminished in the patients with severe heart failure. In contrast, the level of inhibitory G protein alpha-subunits was apparently not different in the two groups. In summary, the data indicate that a defect at the catalytic subunit of adenylyl cyclase apparently contributes to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease.
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PMID:A post-receptor defect of adenylyl cyclase in severely failing myocardium from children with congenital heart disease. 922 16

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