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

Tests conducted with adult (8--10 months) and old (26--28 months) rats brought evidence that in ageing the cardiac ejection, dp/dt max, contractility index, the ATP concentration, that of creatinophosphate, glycogen, pyruvate decline, the phosphorylation coefficient, the lactate content increase, while the level of water-soluble proteins and collagen diminishes and that of water-insoluble ones decreases. In adult rats hemodynamics and myocardial contractility change but unsignificantly on the 4--6th day after coarctation of the aorta, whereas in the old ones there occur functional and metabolic alterations in the heart that are indicative of a developing cardiac insufficiency. The age-specific differences persist also on the 14--16th day following coarctation of the aorta. During these periods the weight of the heart, the content of the myofribrillary proteins and collagen are on the rise, whereas in the old ones the weight of the heart remains unchanged and the level of water-soluble protein drops. Changes in the properties of the actomyosin complex, disruption of the calcium pump, shifts in the system of the energy generation, limitation of potential possibilities incident to the systems of protein biosynthesis in the myocardial cell, all this leads to the development of cardiac incompetence following loading in old age.
 ...
PMID:[Mechanisms of development of cardiac insufficiency in old age]. 102 32

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity.
 ...
PMID:Pharmacology of bipyridine phosphodiesterase III inhibitors. 160 Sep 69

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute or decompensated heart failure. These agents inhibit the intracellular hydrolysis of cyclic adenosine monophosphate, thereby promoting cyclic adenosine monophosphate--catalyzed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They have a wider therapeutic index than do the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoreceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent on some degree of basal adenylate cyclase activity.
 ...
PMID:Pharmacology of bipyridine phosphodiesterase III inhibitors. 185 89

Myocardial relaxation is an energy-dependent process. Indeed, adenosine triphosphate (ATP) is required to pump free myoplasmic calcium back into the sarcoplasmic reticulum. It is also necessary to extrude the calcium ions which enter the cell during the plateau phase of the action potential. The calcium-sodium exchange mechanism does not seem to require energy in itself, but sodium exchanged for calcium eventually needs to be extruded via sodium/potassium ATPase and there is also an ATP-dependent calcium pump. Thus, when ATP production is limited, calcium may remain fixed to troponin for part or for the whole of diastole, resulting in a slower rate of isovolumic relaxation and reduced distensibility of the myocardium. Alterations in diastolic function caused by inadequate energy production occur in the high-demand type of myocardial ischaemia. There is also growing evidence that most forms of heart failure are accompanied by a state of energy depletion. Alterations in mitochondrial density and enzymatic activity are common in the failing myocardium and may partially explain the reduction in ATP production. Inadequate growth of the capillary network in hypertrophied myocardium, impaired subendocardial perfusion due to increased diastolic wall stress and/or coronary artery disease, probably also contribute to an imbalance between energy production and utilization. As relaxation is intrinsically a much slower process than activation and since changes in ATP concentration may also affect calcium efflux by allosteric effects, impaired relaxation and reduced diastolic distensibility are almost universal in chronic congestive heart failure. Optimal therapy of heart failure should, therefore, also aim at improving this phase of the cardiac cycle.
 ...
PMID:Diastolic dysfunction and myocardial energetics. 218 40

Cardiac phosphodiesterase III (PDE) inhibitors derived from pyridinone, imidazolone, pyridazinone and related structures form a new class of positive inotropic vasodilator agents (e.g. milrinone) that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. Drugs such as milrinone have a wider therapeutic index than the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of PDE inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity. Individual PDE inhibitors differ in terms of both chronotropic and extracardiac properties. The reasons for this are not yet fully understood.
 ...
PMID:Pharmacology of positive inotropic phosphodiesterase III inhibitors. 255 11

It has been clearly established that ischemic heart disease, hypertension and ageing affect diastolic function before any change is observed in contractile function. Though an increasingly recognised clinical entity, cardiac failure with normal systolic function still does not have any specific treatment. Phosphodiesterase inhibitors which increase AMPc, in addition to their inotropic and vasodilator effects, accelerate relaxation. Major and isolated abnormalities of relaxation have been demonstrated in vitro in non necrosed tissues of both the dilated and hypertrophic forms of advanced cardiomyopathy. The myocardium seems unable to restore rapidly the low cytosolic calcium concentrations required for the deactivation of the contractile proteins. The underlying mechanisms are probably very complex but a deficit in AMPc production has been demonstrated in very advanced stages of cardiomyopathy. In ischemia, however, the abnormalities of relaxation seem to be directly related to a defect in free energy production inhibiting the sarcoplasmic reticulum calcium pump. If abnormalities of relaxation due to ischemia and those due essentially to a passive mechanism are excluded, phosphodiesterase inhibitors would seem to have pharmacological effects likely to improve diastolic function. Clinical studies confirm the beneficial effects of Milrinone and Enoximone on relaxation and the rapid phase of diastolic filling, both in acute and chronic studies. However, it has not yet been clearly established whether improved diastolic function is due to a direct action on the myocardium or an indirect action due to improved conditions of load. In order to determine the specific effects of phosphodiesterase inhibitors on diastolic function, further research is required.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Effects of phosphodiesterase inhibitors on diastolic function]. 821 93

To determine the biochemical and related functional effects of the thyroid analog diiodothyroproprionic acid (DITPA) on primate myocardium, we examined, both before and after 23 days of DITPA (3.75 mg/kg): myosin heavy-chain (MHC) isoforms and sarcoplasmic reticulum (SR) calcium cycling proteins; left ventricular (LV) function; and the LV force-frequency relation in four baboons chronically instrumented with sonomicrometers and micromanometers. The force-frequency relation was measured as the response of isovolumic contraction (dP/dtmax) to incremental pacing and the critical heart rate (HRcrit) as the rate at which dP/dtmax reached its maximum. DITPA increased basal LV dPt/dtmax (3,300 +/- 378 versus 2,943 +/- 413 mm Hg/sec; p = .09), and velocity of circumferential shortening (1.13 +/- 0.30 versus 0.76 +/- 0.30 circ/sec; p < .01), decreased the basal time constant of isovolumic relaxation (24.2 +/- 1.6 versus 29.9 +/- 2.5 msec; p < .05), and increased the HRcrit (203 +/- 19 versus 168 +/- 20 bpm; p < .05), without effecting significant changes in either basal heart rate (119 +/- 14 versus 111 +/- 17 bpm) or systolic blood pressure (137 +/- 14 versus 126 +/- 8 mm Hg). Quantitative immunoblotting revealed significant decreases in both phospholamban and the ratio of phospholamban to SR Ca2+ adenosine triphosphatase in DITPA-treated animals when compared to four untreated controls. By contrast, alpha-MHC isoform was undetectable in both DITPA treated and control baboons. Thus, DITPA favorably alters the stoichiometry between the SR calcium pump and its inhibitor, phospholamban, and has positive inotropic and lusitropic effects in the normal primate left ventricle, which may be useful in the treatment of heart failure. Unlike thyroid hormone, these changes occur in the absence of detectable alpha-MHC isoform protein expression and without an increase in heart rate.
 ...
PMID:The effects of a thyroid hormone analog on left ventricular performance and contractile and calcium cycling proteins in the baboon. 906 82

Cardiac hypertrophy and heart failure are known to be associated with a reduction in Ca2+-ATPase pump levels of the sarcoplasmic reticulum (SR). To determine whether, and to what extent, alterations in Ca2+ pump numbers can affect contraction and relaxation parameters of the heart, we have overexpressed the cardiac SR Ca2+-ATPase specifically in the mouse heart using the alpha-myosin heavy chain promoter. Analysis of 2 independent transgenic lines demonstrated that sarco(endo)plasmic reticulum Ca2+-ATPase isoform (SERCA2a) mRNA levels were increased 3.88+/-0. 4-fold and 7.90+/-0.2-fold over those of the control mice. SERCA2a protein levels were increased by 1.31+/-0.05-fold and 1.54+/-0. 05-fold in these lines despite high levels of mRNA, suggesting that complex regulatory mechanisms may determine the SERCA2a pump levels. The maximum velocity of Ca2+ uptake (Vmax) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca2+ uptake function. However, the apparent affinity of the SR Ca2+-ATPase for Ca2+ remains unchanged in transgenic hearts. To evaluate the effects of overexpression of the SR Ca2+ pump on cardiac contractility, we used the isolated perfused work-performing heart model. The transgenic hearts showed significantly higher myocardial contractile function, as indicated by increased maximal rates of pressure development for contraction (+dP/dt) and relaxation (-dP/dt), together with shortening of the normalized time to peak pressure and time to half relaxation. Measurements of intracellular free calcium concentration and contractile force in trabeculae revealed a doubling of Ca2+ transient amplitude, with a concomitant boost in contractility. The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport.
 ...
PMID:Targeted overexpression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts. 985 37

During administration of the anthracycline antitumour agents, their cardiotoxicity can progress from cardiac dysfunction to heart failure. Cardiomyopathy can also develop years after receiving anthracyclines. To determine if persistent and/or progressive anthracycline effect(s) are referable to anthracycline effects on cardiac gene expression, steady-state mRNA levels were determined 4 days (n=8), 4 weeks (n=7) and 10 weeks (n=7) after doxorubicin (DOX; 2 mg/kg IV) in a well-characterized rabbit model. Levels of mRNA for alpha -actin, beta -myosin heavy chain and the calcium pump of the sarcoplasmic reticulum (SERCA2a) in the left ventricle (LV) were determined by Northern blot hybridization and expressed relative to an 18S constitutive marker. The mRNA levels for the high molecular weight subunit (cardiac isoform) of the ryanodine receptor (RyR2), sarcolemmal calcium channel (dihydropyridine receptor; DHPR), angiotensin-converting enzyme (ACE), angiotensin II receptor (ATR) and atrial naturetic peptide prohormone (ANP) were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis, and expressed relative to GAPDH, a constitutive marker. Histopathologic evidence for anthracycline-induced myocardial cell injury was absent (score <1) in all hearts examined except one (score=1.1; 4 weeks post-DOX), which was considered separately. Relative mRNA levels for beta -myosin heavy chain 4 days after DOX increased 1.9-fold compared to the vehicle-treated group, but by 4 weeks levels had returned to baseline. Relative mRNA levels for DHPR were increased 1.2-fold 4 days after DOX and were persistently increased 1.9- and 2.2-fold 4 and 10 weeks after DOX, respectively. The mRNA levels for ANP were first decreased (4.5-fold) 4 days after DOX. Four weeks after DOX, ANP message levels approached Control in seven out of eight rabbits. The one rabbit with early LV histopathology 4 weeks post-DOX had increased mRNA for DHPR (2.7-fold) and ANP (80-fold). Between 4 and 10 weeks after DOX, mRNA levels for ANP increased C 16-fold: evidence for late progression. In situ hybridization with specific riboprobes localized the persistent increase in DHPR and the progressive increase in ANP to myocytes. Thus, DOX alters steady-state mRNA levels in LV that are referable to both persistent and progressive anthracycline effects on myocellular gene expression.
 ...
PMID:Persistent effects of doxorubicin on cardiac gene expression. 1042 42

Accumulating evidence points to the critical role of phospholamban (PLB) regulation of the cardiac sarcoplasmic reticulum (SR) calcium ATPase in influencing the kinetics of calcium handling within the cardiac myocyte under normal and pathological conditions. Based on the data, it has been hypothesized that PLB inhibitors (e.g., calcium ATPase stimulators) would be of potential importance as positive lusitropes and inotropes in the treatment of heart failure. Experiments measuring tension transients in saponin-permeabilized cardiac muscles from genetically engineered mice under a variety of SR calcium loading conditions provide evidence of the functional alterations that can be achieved by manipulation of the degree of PLB inhibition of the calcium pump. Testing of the above hypothesis will ultimately require a selective, high-affinity, membrane-permeable small molecule stimulator of the cardiac calcium pump. Screening for cardiac calcium pump activators has produced a series of agents exerting apparently different mechanisms of action; some may be tools to help to elucidate the nature of the PLB-calcium ATPase interaction(s). The rationale for PLB as a drug target, the optimal profile of a PLB inhibitor, and the properties of several low-molecular-weight compounds will be explored.
 ...
PMID:Pharmacology of the cardiac sarcoplasmic reticulum calcium ATPase-phospholamban interaction. 1060 85


1 2 3 4 Next >>