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)

Since the use of cardiac glycosides for heart failure therapy is limited by their narrow margin of safety, numerous efforts have been made to find and develop novel cardiotonic agents that are superior to the cardiotonic glycosides. Positive inotropic drugs acting on beta-adrenoceptors and inhibitors of cAMP phosphodiesterase have been extensively studied for the treatment of patients with heart failure. The main mechanism of these agents is elevation of cAMP tissue levels. Furthermore, Ca sensitizers such as sulmazol, pimobendan, MCI-154, END 53998 and DPI 201-106 are of interest, since such a mechanism of action may be beneficial for the failing heart. Recently, cardiotonic substances with a novel mechanism of action such as gingerol and xestoquinone have been isolated from natural sources. Natural products, purealin, goniodomin and okadaic acid, have proven to be valuable pharmacological tools for studies on cardiac muscle contraction.
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PMID:[Novel types of cardiotonic drugs]. 139 36

Myofilament calcium sensitivity and maximal calcium-activated force are fundamental properties of the contractile proteins in the heart. We examined these properties in normal human right-ventricular trabeculae carneae obtained from hearts of brain-dead patients with no known cardiac disease, and from patients with end-stage heart failure undergoing cardiac transplantation. There were no differences in calcium-activation of the control and myopathic muscles from chemically-skinned trabeculae or from intact tetanized preparations. We then tested the effect of DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole - carbonitrile), a new inotropic agent, in both preparations. In myopathic muscles, 1 microM DPI sensitized the myofilaments to Ca2+, as evidenced by a significant shift of the [Ca2+]-force relationship towards lower [Ca2+], in both skinned and intact preparations. On the other hand, the same concentration of DPI did not affect the calcium-activation in control muscles in both preparations. We also found that the twitch [Ca2+]-force relationship, which has been used as an indication of myofilament sensitivity, was dissociated from the steady-state [Ca2+]-force relationship, and was shifted along the [Ca2+] axis by modulation in the time-course of the twitch and [Ca2+]i, and not by the sensitivity of the myofilaments to Ca2+. Protein kinase C stimulation differentially altered the responsiveness of the myofilaments to Ca2+ in normal and myopathic muscle fibers. We propose that even though calcium activation and maximal calcium-activated force are unaltered in myopathic hearts there are changes in thin filament regulation in myopathic hearts that result in altered responses to agents that directly act on the thin filaments, and that the potential for force development is similar in normal and myopathic human hearts.
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PMID:Responsiveness of the myofilaments to Ca2+ in human heart failure: implications for Ca2+ and force regulation. 149 67

Elevation of cytosolic sodium is thought to be correlated with an increase in force of contraction due to an activation of sodium-calcium exchange. We investigated the inotropic response mediated by the new sodium-channel activator BDF 9148 (0.01-100 mumol/l) on failing human myocardium. Force of contraction was studied using electrically driven human papillary muscle strips from moderately (NYHA II-III, mitral valve replacement) and terminally (NYHA IV, heart transplantation) failing hearts. We also investigated the effects in auricular trabeculae from non-failing hearts (aortocoronary bypass operation). Results were compared with inotropic responses to DPI 201-106 (DPI, 0.1-3 mumol/l), Ca2+ (1.8-15 mmol/l) and isoprenaline (0.001-1 mumol/l). Carbachol (100 mumol/l) and adenosine (1000 mumol/l) were examined in the presence of BDF 9148 and isoprenaline. Both sodium-channel activators, BDF 9148 and DPI 201-106, increased force of contraction in a dose-dependent manner in papillary muscle strips as well as in auricular trabeculae. BDF 9148 and DPI 201-106 were more effective (max. PIE NYHA II-III 1.6 +/- 0.2 mN, NYHA IV 5.9 +/- 0.7 mN, P less than 0.05) and more potent (EC50 (in mumol/l): NYHA IV 0.35, 0.19-0.66; NYHA II-III 1.85, 1.37-2.41) in terminally failing as compared to moderately failing left ventricular myocardium. Moreover, the positive inotropic effects of BDF 9148 were greater than those of DPI 201-106 in NYHA IV (max. PIE 2.7 +/- 0.3 mN, P less than 0.05). In NYHA IV, BDF 9148 was as effective as CA2+ (max. PIE 5.1 +/- 0.4 mN). In the same hearts, the positive inotropic effects of isoprenaline were reduced in NYHA IV (max. PIE 2.1 +/- 0.3 mN) compared to NYHA II-III (max. PIE 3.4 +/- 0.4 mN, P less than 0.05). Adenosine as well as carbachol did not affect the positive inotropic response of BDF 9148 or DPI 201-106 but reduced the effectiveness of isoprenaline (P less than 0.05). In myocardial membranes, BDF 9148 was 1000-fold less effective in competition experiments with 3H-ouabain than ouabain. We conclude that (1) sodium-channel activators may produce a significant cAMP-independent positive inotropic effect in left ventricular myocardium from failing human hearts; (2) the inotropic effect of sodium-channel activators were more potent and more effective in NYHA IV as compared to NYHA II-III. The degree of myocardial failure does not reduce the effectiveness of the sodium-channel activator BDF 9148.
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PMID:Evidence for a sustained effectiveness of sodium-channel activators in failing human myocardium. 165 40

In heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiac beta-adrenoceptors. Since noradrenaline acts primarily on the cardiac beta 1-adrenoceptor subtype, beta 1-adrenoceptors decrease in number, whereas the beta 2-adrenoceptor subpopulation remains unchanged in most instances. Consequently, the positive inotropic response to beta-adrenoceptor agonists is diminished. However, there is also a decrease in the positive inotropic effect of beta 2-adrenoceptor agonists, histamine and cAMP-phosphodiesterase inhibitors such as milrinone, whereas the positive inotropic effect of cAMP-independent Na(+)-channel activators such as DPI 206-106 and the effects of cardiac glycosides are not diminished. These observations suggest a more generalised alteration of the cAMP-adenylate cyclase system in the failing heart. Stimulatory guanine nucleotide-binding protein (Gs) couples receptors to adenylate cyclase that stimulate cAMP formation, such as beta-adrenoceptors, histamine receptors and glucagon receptors. In the failing human heart, Gs content has been reported to remain unchanged as compared with that in non-failing myocardium. However, there is a 35%-40% increase in inhibitory guanine nucleotide-binding proteins (Gi), which are involved in the receptor-mediated inhibition of adenylate cyclase. Taken together, two defects of the cAMP-adenylate cyclase system have been identified: an increase in Gi content and a decrease in the number of beta-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Alterations of the cAMP-adenylate cyclase system in the failing human heart. Consequences for the therapy with inotropic drugs]. 197 43

Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.
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PMID:Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure. 215 79

1. The present study was designed to characterize the positive inotropic response to DPI 201-106 in isolated papillary muscle strips obtained from heart failure patients undergoing surgery. 2. The positive inotropic responses to isoprenaline and milrinone and cardiac beta-adrenoceptor density were also determined. 3. DPI 201-106 increased the force of contraction in papillary muscle strips from patients with moderate (NYHA II-III) and severe (NYHA IV) heart failure, in a concentration-dependent manner. This positive inotropic effect was more pronounced in tissues from NYHA IV patients. Furthermore, these responses were greater than those produced by milrinone or isoprenaline. The positive inotropic effects of isoprenaline and milrinone were reduced in NYHA IV compared to NYHA II-III. Consistently, there was also a smaller density of beta-adrenoceptors in myocardium from NYHA IV than in NYHA II-III. The positive inotropic effect of Ca2+ was similar in tissues from both groups of patients. 4. The positive inotropic effect of DPI 201-106 was not antagonized by adenosine or carbachol, whereas both compounds reduced the positive inotropic effect of isoprenaline. 5. DPI 201-106 did not increase the Ca2+ -sensitivity of chemically skinned ventricular fibres, whereas a significant increase of the Ca2+ -sensitivity was obtained with trifluoperazine. 6. It is concluded that DPI 201-106 produces significant positive inotropic effects in tissue excised from the failing human heart. The lack of inhibition by adenosine and carbachol might contribute to its greater effectiveness in NYHA IV than NYHA II-III and indicates that its mechanism of action is cyclic AMP-independent. A sensitization of the contractile proteins to Ca2+ does not appear to be important for the positive inotropic action of DPI 201-106 in the failing human heart.
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PMID:Inotropic response to DPI 201-106 in the failing human heart. 255 90

The present study was designed to elucidate whether or not the positive inotropic effects of isoprenaline, milrinone, and DPI 201-106 in myocardial tissue from various sources reveal reliable results for the failing human heart. Therefore, in vitro positive inotropic responses were studied in human papillary muscle strips from patients with moderate heart failure (NNYHA II-III), human atrial trabeculae (HAT), isolated papillary muscles from Wistar-Kyoto rats (WK), and from spontaneously hypertensive rats (SHR). Results were compared with the effects of the compounds in papillary muscle strips from patients with severe heart failure (NYHA IV). In NYHA IV, positive inotropic responses were smaller for isoprenaline and milrinone than in NYHA II-III. The response to DPI 201-106 was more pronounced. In HAT, the effects of isoprenaline and milrinone were greater than in NYHA IV. The positive inotropic effect of DPI 201-106 was similar. In SHR, only the positive inotropic effect of isoprenaline was smaller than in WK. The effects of DPI 201-106 and milrinone did not differ. These data show that inotropic responses in NYHA II-III, HAT, WK, and SHR differ from the severely failing myocardium. It is concluded that new positive inotropic agents should be screened in human myocardial tissue from patients with heart failure, as experimental results from other sources may be irrelevant in this respect.
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PMID:Screening of positive inotropic agents in isolated cardiac preparations from different sources. 270 46

In a normal man sitting upright, pulmonary perfusion is several times greater in the lower lung zone than in the upper zone. This pattern may sometimes be reversed in patients with cardiac disease. Tc99m-macro-aggregated albumin pulmonary perfusion images were computerized to isocounts area images (digital perfusion images; DPI). DPI were applied to various types of cardiac disease and patterns of DPI were divided into 4 classes according to amount of nonperfused pulmonary vascular bed. C-0; normal perfusion. C-1; decrease of nonperfused pulmonary vascular bed. C-2; disappearance of nonperfused pulmonary vascular bed. C-3; decrease of pulmonary vascular bed. In 71 patients with mitral stenosis relationships between pulmonary hemodynamics during exercise and distribution of pulmonary perfusion were studied, i.e. at rest (n = 71, mean pulmonary arterial pressure; 23 mmHg-cardiac index; 2.4 L/m) and during exercise C-0 (n = 13, 41 mmHg-5.4 L/m), C-1 (n = 17, 52 mmHg-5.2 L/m), C-2 (n = 27, 52 mmHg-4.5 L/m) and C-3 (n = 14, 65 mmHg-3.6 L/m) respectively. In patients with congestive heart failure cardiac status was classified to 4 classes according to ejection fraction and DPI. Patients with EF less than 30% and DPI more than C-2 showed high morbidity and mortality (two years mortality 47%; 27/40). Pulmonary venous pressure increases to maintain the cardiac index (Starling's law) in cases of decline in cardiac function or mitral stenosis. It was shown that increases in pulmonary venous pressure cause changes in distribution of pulmonary perfusion, which in turn works to depress the cardiac index. A decline in cardiac function and changes in the distribution of pulmonary perfusion coexist, mediated by pulmonary venous pressure and cardiac index. The distribution of pulmonary perfusion reflects the severity of cardiac failure itself, so by using DPI the severity of cardiac failure can be easily evaluated.
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PMID:Severity of cardiac failure from the standpoint of pulmonary circulation: studies centered on distribution of pulmonary perfusion. 271 77

DPI 201-106 is a novel compound unrelated to other cardioactive agents and has been shown to have an inotropic effect in animal preparations. The drug was given by intravenous infusion (20 mg over 10 min) to 10 patients with moderate cardiac failure and the haemodynamic effects measured at intervals up to 1 h following infusion. Maximal effects were seen immediately following the infusion of DPI 201-106. Cardiac index showed an increase from baseline 2.72 (0.16) 1 min-1 m-2 to 3.18 (0.21) 1 min-1 m-2 at the end of infusion (P less than 0.001). Subsequent values were not significantly raised. Pulmonary capillary wedge pressure and pulmonary artery pressure fell from 27.6 (3.2) and 36.9 (4.4) to 15.3 (3.6) and 24.2 (4.9) mmHg, respectively (P less than 0.001 in both cases). A statistically significant effect on cardiac index was not seen at 1 h. However, pulmonary pressures remained reduced at this point. Radionuclide ejection fraction showed a significant increase from 15.4 (1.5) to 21.9 (2.2)% (P less than 0.005) at the end of infusion, and maintained a significant increase at 1 h. Having demonstrated beneficial, acute haemodynamic effects in this study, further work should be undertaken with DPI 201-106 to investigate the effect of chronic treatment in patients with cardiac failure.
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PMID:Haemodynamic effects of DPI 201-106, following single intravenous dose administration to patients with moderate cardiac failure. 340 65

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.
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PMID:Comparison of the action potential prolonging and positive inotropic activity of DPI 201-106 and BDF 9148 in human ventricular myocardium. 779 53

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