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

The aim of our study was to compare the effects on contractile function and action potential duration of the new Na+ channel modulator BDF 9148 with the parent compound DPI 201-106 in human ventricular myocardium. Right ventricular papillary muscles were obtained from explanted hearts of heart transplant recipients or from non-failing hearts not suitable for transplantation. BDF 9148 induced an increase in force of contraction that was accompanied by prolongation of action potential duration. The action potential duration prolonging effect of BDF 9148 was not significantly different to that of DPI 201-106. The effects of BDF 9148 were similar in muscles obtained from non-failing and failing hearts. Using Na(+)-sensitive electrodes, we have demonstrated that the positive inotropic effect of BDF 9148 is accompanied by an increase in intracellular Na+ activity. Our results indicate: (i) that BDF 9148 is as effective as DPI 201-106 in increasing force of contraction and prolonging action potential duration in human ventricular myocardium: (ii) that BDF 9148 is effective in enhancing force of contraction, in spite of heart failure; (iii) that the positive inotropic effect is related to an increased Na+ load; and (iv) due to action potential duration prolongation, changes in Q-T interval of the electrocardiogram could be possible during in vivo use of BDF 9148.
J Mol Cell Cardiol 1994 Aug
PMID:Comparison of the action potential prolonging and positive inotropic activity of DPI 201-106 and BDF 9148 in human ventricular myocardium. 779 53

The present study explored the possibility that an alteration in the transmembrane calcium current (ICa), through its ability to modulate Ca2+ release from the sarcoplasmic reticulum, could contribute to the depressed peak [Ca2+]i we previously observed in hypertrophied failing myocardium. Whole-cell patch clamp was used to measure ICa in single guinea pig ventricular myocytes isolated from hearts of normal guinea pigs and from guinea pig hearts in which hypertrophy and failure were induced by gradually developing left ventricular pressure overload subsequent to ascending aortic banding of young animals. Membrane capacitance (Cm) was significantly greater. and ICa, normalized for Cm, was significantly lower in myocytes from hypertrophied failing hearts. Myocytes from hypertrophied failing hearts did not differ significantly from normal myocytes in terms of the voltage-dependence of the activation variable (d) of ICa (except at -30 mV), the time course of removal of inactivation of ICa, and the time constant of decay of ICa. Measurement of the voltage dependence of the inactivation variable (f) of ICa showed that significantly more steady-state inactivation was present at 0, -10, and -20 mV in myocytes from hypertrophied failing hearts. Multiple regression analysis of all data indicated that ICa density decreased with increasing myocyte membrane area (as reflected by Cm) irrespective of any specific effects of hypertrophy and heart failure. We conclude that ICa, normalized for Cm, is significantly reduced in myocytes isolated from hypertrophied failing hearts, probably by a process associated with increased cell size, per se.
J Mol Cell Cardiol 1994 Sep
PMID:Reduced calcium current density in single myocytes isolated from hypertrophied failing guinea pig hearts. 781 57

Our own previous ultrastructural studies in human hearts with dilated cardiomyopathy and heart failure showed sarcomeric and cytoskeletal disarrangement. On the basis of these findings we tested the hypothesis that in cardiomyopathic failing hearts not only the sarcomere structure but also the organization and the amount of numerous contractile proteins are disturbed. Titin was included in this study because it is the elastic "third" filament of the sarcomere and also plays an important role as template for myosin and actin filaments in sarcomerogenesis. Human cardiac tissue obtained at the time of transplantation surgery was investigated using immunohistochemistry with monoclonal antibodies against titin, myosin, actin, tropomyosin, and troponin T. Additionally, isolated myocytes from rat or pig heart were used for the standardization of the localization pattern. In normal tissue, myosin and the thin filament complex showed a regular cross striation that was wider in myosin staining than for actin, troponin T, and tropomyosin corresponding with the different width of the A and I bands in the sarcomere. Titin localization in normal human and animal myocardium showed a regular cross striation pattern. In diseased cardiac tissue titin fluorescence intensity was reduced and frequently disorganization or almost complete loss of titin from many myocytes were present. Severe abnormalities of contractile proteins consisting of disarrangement or lack of filaments were also observed. Double staining procedures showed that in the same myocyte defects of the contractile apparatus were accompanied by a simultaneous reduction of titin indicating that the "third" sarcomeric filament system is involved in heart failure. Abnormalities of titin expression may be especially important because titin significantly influences sarcomeric elastic behaviour and is necessary as template for the organization of newly synthesized myosin and actin filaments. The loss of titin may contribute to the altered compliance in failing hearts. It is concluded that disorganization and loss of titin, myosin, and the thin filament complex are severe in the failing human heart because of dilated cardiomyopathy and that these changes may represent several of the most important components of the structural correlate of reduced cardiac function.
J Mol Cell Cardiol 1994 Oct
PMID:Altered expression of titin and contractile proteins in failing human myocardium. 786 90

L-type calcium currents were studied in ventricular myocytes isolated from non-failing hearts, i.e. donor hearts not suitable for transplantation, and from severely failing hearts, i.e. explanted hearts of organ recipients, in order to identify possible alterations of the currents in cardiomyopathy. Human atrial myocytes were investigated for comparative purposes. As deficient production of cyclic AMP might contribute to the development of cardiac failure, the responses to forskolin, a direct stimulator of adenylyl cyclase, were also studied. The patch-clamp technique was applied in the single electrode whole-cell mode. Calcium currents were similar in myocytes from non-failing and failing hearts: Maximum current-densities were 3.8 v 3.1 pA/pF, and 2.2 pA/pF in atrial cells. In human ventricular cells, threshold was at -33 mV, maximum at +6 mV and reversal potential at about +50 mV, potentials of half-maximum steady-state inactivation -24 mV and -18 mV. The slopes of steady-state inactivation curves were +4.1 mV in myopathic and +5.5 mV in non-failing cells. In all myocytes the current inactivated with two time constants, a fast one with weak and a slow one with pronounced potential dependency. Ventricular or atrial myocytes from patients pretreated with calcium antagonists and untreated did not differ in current density or steady-state inactivation. Forskolin (0.5 microM) increased calcium currents in myocytes from non-failing and failing hearts to the same extent (by 143 and 150%). While beta-adrenoceptor numbers are reported to decline in severely failing myocardium, our data do not suggest that alterations of the properties of calcium currents contribute to the pathophysiology of heart failure, though the number of investigated hearts is limited due to restricted access to non-failing cardiac tissue. No evidence for impairment of the signal transduction cascade beyond the level of GTP binding proteins was found.
J Mol Cell Cardiol 1994 Oct
PMID:L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. 786 91

In order to explain the attenuated sympathetic support during the development of heart failure, the status of beta-adrenergic mechanisms in the failing myocardium was assessed by employing cardiomyopathic hamsters (155-170 days old) at moderate degree of congestive heart failure. The norepinephrine turnover rate was increased but the norepinephrine content was decreased in cardiomyopathic hearts. The number and the affinity of beta receptors in the sarcolemmal preparations were not changed in these hearts at moderate stage of congestive heart failure. While the basal adenylyl cyclase activity was not altered in sarcolemma, the stimulation of enzyme activity by NaF, forskolin, Gpp(NH)p or epinephrine was depressed in hearts from these cardiomyopathic hamsters. Since G-proteins are involved in modifying the adenylyl cyclase activity, the functional and bioactivities as well as contents of both Gs and Gi proteins were determined in the cardiomyopathic heart sarcolemma. The functional stimulation of adenylyl cyclase by cholera toxin, which activates Gs proteins, was markedly depressed whereas that by Pertussis toxin, which inhibits Gi proteins, was markedly augmented in cardiomyopathic hearts. The cholera toxin and pertussis toxin catalyzed ADP-ribosylation was increased by 37 and 126%, respectively; this indicated increased bioactivities of both Gs and Gi proteins in experimental preparations. The immunoblot analysis suggested 74 and 124% increase in Gs and Gi contents in failing hearts, respectively. These results suggest that depressed adenylyl cyclase activation in cardiomyopathic hamsters may not only be due to increased content and bioactivity of Gi proteins but the functional uncoupling of Gs proteins from the adenylyl cyclase enzyme may also be involved at this stage of heart failure.
Mol Cell Biochem 1994 Nov 23
PMID:Alterations in G-proteins in congestive heart failure in cardiomyopathic (UM-X7.1) hamsters. 789 87

An increase of Gi alpha-related pertussis toxin substrates has been observed in the failing myocardium. In order to quantify the protein expression of Gi alpha directly, we developed a fast radioimmunoassay using the iodinated synthetic peptide 125I-KENLKDCGLF. beta-adrenoceptors were studied with 125I-cyanopindolol binding for comparison. Immunoblot experiments using recombinant G-protein alpha-subunits showed that DS4 immunostained the G-protein alpha-subunits with a rank order of potency rGi alpha 1 = rGi alpha 2 > rGo alpha >> rGi alpha 3. The G-protein alpha-subunits recognized by DS4 in human ventricular membranes comigrated with rGi alpha 1 and rGi alpha 2. The radioimmunoassay had a sensitivity of 2.5 micrograms/ml transducin alpha with an interassay variation of less than 10%. The non-labelled peptide selectively competed with the myocardial 40 kDa membrane protein for binding to the antiserum DS4. Radioimmunochemical quantification of Gi alpha from cardiac membranes showed that in left ventricular membranes (LV) from dilated cardiomyopathy (DCM), there was an increase of Gi alpha by 138.5% when related to mg protein and 135% when related to 3H-ouabain binding sites as membrane marker. In LV from ischaemic cardiomyopathy (ICM), the increase was smaller (58.4%) when related to mg protein compared to the increase of Gi alpha when related to 3H-ouabain binding sites as membrane marker (155% v NF). In contrast, in the right ventricles (RV) there was no increase of Gi alpha in ICM or DCM. The numbers of beta-adrenoceptors were reduced in RV and LV of both, ICM and DCM. It is concluded that the radioimmunoassay may become an important tool for studying the expression of Gi alpha-protein levels and changes thereof in pathological conditions. The amount of immunodetectable Gi alpha-proteins is increased in failing LV due to DCM and ICM but not in RV, while beta-adrenoceptor down-regulation occurred in RV and LV in both conditions. These findings might indicate that the liability of the LV but not of RV to express Gi alpha-proteins may be increased in predominant LV heart failure. Alternatively, the underlying mechanism, e.g. sympathetic activation, may be regulated locally in the failing heart producing different changes in adjacent chambers.
J Mol Cell Cardiol 1994 Feb
PMID:Radioimmunochemical quantification of Gi alpha in right and left ventricles from patients with ischaemic and dilated cardiomyopathy and predominant left ventricular failure. 800 75

The pivotal role that G proteins play in transmembrane signal transduction is highlighted by the rapidly expanding list of receptors and effector molecules that are coupled through G proteins. G proteins are poised to allow discrimination and diversification of cellular signals into the cytosolic milieu. The utilization of an evolutionarily conserved "GTPase clock" by G proteins, offers insight into the fundamental role these proteins play in biology. Knowledge of the implication of altered expression or function of G proteins in human disease is now emerging. It is not surprising that deficiency or expression of altered forms of these important proteins can lead to global or restricted metabolic disturbances, depending upon the distribution and role of the G protein. Human disorders, including heart failure, alcoholism, endocrine abnormalities, and neoplasia, are now recognized as due in part to altered expression or function of G proteins.
Prog Nucleic Acid Res Mol Biol 1994
PMID:Signal-transducing G proteins: basic and clinical implications. 801 26

We examined the role of the myocardial beta-adrenoceptor-G protein-adenylate cyclase complex in 10-week-old Wistar rats with ischemic heart failure produced by ligating the left coronary artery (l) and in sham-operated control rats (C). We determined the number of beta-adrenoceptors (Bmax), the dissociation constant (Kd) using a binding assay and adenylate cyclase activity. Levels of mRNA encoding for the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gs alpha) and the alpha subunit of the inhibitory guanine nucleotide-binding protein (Gi alpha) were measured by Northern blot analysis. The amounts of Gs alpha and Gi alpha were measured by Western blot analysis. Bmax and Kd did not differ significantly between the two groups: Bmax: l, 14.7 +/- 1.3 v C, 13.4 +/- 0.9 f mol/mg protein; Kd: l, 345 +/- 31 v C, 340 +/- 28 pM (mean +/- standard error, S.E.). There were no significant differences in Gs alpha and Gi alpha concentrations between the two groups as measured by Northern blot analysis (Gs alpha: l, 91.6 +/- 4.5 v C, 96.5 +/- 2.3%; Gia; l, 95.4 +/- 3.6 v C, 90.0 +/- 3.0%) or by Western blot analysis (Gs alpha: l, 95.2 +/- 2.0 v C, 94.5 +/- 2.6%; Gi alpha: l, 91.5 +/- 3.0 v C, 95.1 +/- 2.9%). Activity of basal and MnCl2-stimulated adenylate cyclase did not differ significantly in the two groups: basal: l, 7.5 +/- 0.7 v C, 8.1 +/- 0.5 pmol cAMP/mg protein/min; MnCl2 l, 80.8 +/- 5.8 v C, 86.4 +/- 6.7 pmol cAMP/mg protein/min. Sodium fluoride and forskolin-stimulated adenylate cyclase activity were significantly lower in the hearts with ischemic failure compared with controls (sodium fluoride: l, 68.5 +/- 5.6 v C, 103 +/- 4.8 pmol cAMP/mg protein/min; forskolin: l, 84.6 +/- 6.5 v C, 117.1 +/- 5.6 pmol cAMP/mg protein/min). These data suggest the presence of myocardial Gs alpha dysfunction in ischemic heart failure. We conclude that such a dysfunction in Gs alpha may contribute to the contractile abnormalities in ischemic heart failure.
J Mol Cell Cardiol 1994 May
PMID:Beta-adrenoceptor-G protein-adenylate cyclase complex in rat hearts with ischemic heart failure produced by coronary artery ligation. 807 16

The rat model of myocardial infarction is characterized by progressive cardiac hypertrophy and failure. Rats with infarcts greater than 30% of the left ventricle exhibited early and moderate stages of heart failure 4 and 8 weeks after the occlusion of the left coronary artery, respectively. As heart failure is usually associated with remodeling of the extracellular matrix, a histological and biochemical study of cardiac collagenous proteins was carried out using failing hearts. Total collagen content in the right ventricle increased at 2, 4, and 8 weeks following occlusion of the left coronary artery whereas such a change in viable left ventricle was seen after 4 and 8 weeks. Total cardiac hydroxyproline concentration was increased in both right and left ventricular samples from the infarcted animals when compared to those of control; this increase was due to elevation of pepsin-insoluble collagen fraction. The myocardial noncollagenous/collagenous protein ratio was decreased in experimental right and left ventricular samples when compared to control samples. These findings suggest that an increase in cross-linking of cardiac collagen as well as disparate synthesis of collagenous and noncollagenous proteins occurs in this model of congestive heart failure.
Mol Cell Biochem 1993 Dec 22
PMID:Alteration of collagenous protein profile in congestive heart failure secondary to myocardial infarction. 817 34

Calmodulin (CaM) is the primary Ca2+ regulatory protein in cardiac cells, thus alterations in calmodulin would greatly influence the contractile response and may play a role in the abnormal calcium handling observed in human heart failure. We used Northern blot analysis to determine changes in calmodulin mRNA expression in left ventricular tissues isolated from 20 failing and four control human hearts. Only hearts with failure due to idiopathic dilated cardiomyopathy (DCM) or ischaemic heart disease (IHD) were studied. A human calmodulin cDNA probe 95% homologous to Type 3 CaM was used, which hybridized to a single 2.3 kb mRNA. CaM mRNA levels were expressed as a function of total RNA, as determined by hybridization to an 18S cDNA probe, and as a function of myocyte specific mRNA, as determined by hybridization to a myosin heavy chain (MHC) cDNA probe. In both DCM and IHD, CaM mRNA expression relative to total RNA (CaM/18S), was significantly decreased (45% and 61%, respectively) compared to control hearts. CaM mRNA expression in DCM tissues was also significantly decreased (45%) relative to myocyte specific mRNA (CaM/MHC), when compared to control hearts. In IHD, CaM mRNA was not significantly decreased in relation to myocyte specific mRNA, which suggests a greater loss of myocytes or contractile proteins in IHD as compared with DCM. The decreased expressed of CaM mRNA observed in failing hearts could affect many Ca(2+)-dependent processes, and contribute to the inability of these hearts to handle Ca2+ in a viable manner.
J Mol Cell Cardiol 1994 Jan
PMID:Decreased expression of calmodulin mRNA in human end-stage heart failure. 819 73


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