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

The following studies were carried out to examine energy metabolites and cardiac performance of the failing heart (hereditary cardiomyopathy) of the Syrian hamster (strain UM-X7.1) perfused either by normal or stress conditions, and to determine whether cyclical changes in energy-related metabolites occurred in the glucose-perfused hearts of both normal and heart failure animals. Hamster hearts from 250-day-old animals with moderate heart failure were removed and perfused either as nonworking hearts (Langendorff method, an afterload pressure of 90 mm Hg and 2.5 mM calcium in the perfusate) or as working hearts with stress conditions [an afterload of 110 mm Hg, high calcium concentrations in the perfusate (3.5 mM), and 10(-8) M isoproterenol]. Mechanical parameters (developed pressure and max dP/dt) and measurements of oxygen consumption indicated that both contractility and oxygen consumption had fallen 50% in myopathic hearts, compared with those of normal hamsters perfused with either of the two conditions. By means of a specially designed stimulator-triggered freeze clamp, hearts were terminated at systole and diastole, and tissue content of ATP, ADP, AMP, adenosine, phosphocreatine, creatine, pyruvate, lactate, and inorganic phosphate were analyzed. A 50% reduction in cardiac performance of the cardiomyopathic hamster hearts was associated with a corresponding reduction in systolic ATP, adenosine, and phosphocreatine values, while inorganic phosphate and lactate increased. With glucose as the sole substrate, the high energy phosphates, ATP and phosphocreatine, reached maximum values during diastole and minimum values during systole.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Energy levels at systole vs. diastole in normal hamster hearts vs. myopathic hamster hearts. 664 Aug 62

In contrast to cyclic AMP-dependent positive inotropes, the calcium-sensitizer and partial phosphodiesterase (PDE) inhibitor pimobendan may induce beneficial effects in heart failure. However, its effect on relaxation, myocardial energetics and neurohormones are unknown. Twelve patients with heart failure, New York Heart Association (NYHA) classification II-III, due to ischemic cardiomyopathy, were studied for 1 h after they received 5 mg pimobendan intravenously (i.v.). Pimobendan progressively reduced systemic resistance and left ventricular end-diastolic pressure (LVEDP) (22 and 50%, respectively) and improved isovolumetric contractility and relaxation parameters by 30% (all p < 0.05 vs. control). LV end-diastolic and end-systolic volumes (LVEDV, LVESV) decreased significantly by 20 and 19%, respectively. Cardiac output (CO) increased by 17% due to a simultaneous increase in heart rate (HR) from 75 +/- 3 to 86 +/- 5 beats/min (mean +/- SEM, p < 0.05). Pimobendan did not change coronary hemodynamics, but myocardial O2 extraction and consumption were decreased significantly by 18 and 20%, respectively. Catecholamines, angiotensin II (AII), and aldosterone levels did not change significantly. In contrast, arterial and coronary venous renin increased significantly from 57 +/- 17 and 53 +/- 14.7 microM/h at control to 69 +/- 20 and 69 +/- 20 microM/h, respectively, 60 min after pimobendan administration. Simultaneously, cardiac renin uptake at baseline (0.449 +/- 0.185 mumol/min) changed to release (-0.071 +/- 0.145 mumol/min, p < 0.05). Serious side effects did not occur. Thus, pimobendan had progressive positive inotropic and lusitropic effects, diminished preload and afterload despite modest stimulation of plasma renin activity (PRA), and reduced systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic, neurohumoral, and myocardial energetic effects of pimobendan, a novel calcium-sensitizing compound, in patients with mild to moderate heart failure. 753 50

Although the interrelationship between the two messengers Ca2+ and cyclic AMP in platelet function is well documented, its mechanism of action still remains to be established. We investigated here the question of the regulation of platelet Ca(2+)-ATPases by cyclic AMP through the phosphorylation of the Rap1 protein using a pathological model. We first found experimental conditions where Ca(2+)-transport by platelet membrane vesicles appeared to be dependent on the phosphorylation of the Rap1 protein. Then, we studied platelets of patients with congestive heart failure for their expression of the potential 97 kDa Ca(2+)-ATPase target of regulation through the Rap1 protein as well as the phosphorylation of the Rap1 protein using the catalytic subunit of the cyclic AMP-dependent protein kinase (C. Sub.). In the first patients studied, we found no significant modification in the expression of the 97 kDa Ca(2+)-ATPase by Western blotting using the PL/IM 430 monoclonal antibody which specifically recognized this isoform. In contrast, the Rap1 protein was differentially phosphorylated when using 15 micrograms/ml of the C. Sub. These results allowed us to use these pathological platelets to study the relationship between the expression of Rap1 protein and the regulation of Ca2+ transport by selecting a patient with severe heart failure. We could show a decrease in the expression as well as in the phosphorylation of Rap1 protein and demonstrate a lower effect of C. Sub. on Ca2+ transport. Finally, by studying a further series of patients, we could confirm that the decrease in Rap1 protein expression in heart failure, whatever its extent, was variable, and could strictly correlate the expression of Rap1 protein with the stimulatory effect of C. Sub. on Ca2+ transport. Besides the evidence for regulation of the expression of the Rap1 protein in platelets from patients with heart failure, these findings constitute a new approach in favour of the regulation of platelet Ca2+ transport through the phosphorylation of the Rap1 protein.
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PMID:Relationship between Rap1 protein phosphorylation and regulation of Ca2+ transport in platelets: a new approach. 765 84

The cardiovascular properties of NSP-804 (4,5-dihydro-6-[4-[(2-methyl-3-oxo-1-cyclopentenyl)-amino] phenyl]-3(2H)-pyridazinone) and NSP-805 (4,5-dihydro-5-methyl-6-[4-[(2-methyl-3-oxo-1-cyclopentenyl) amino]phenyl]-3(2H)-pyridazinone), novel cardiotonic agents, were investigated in vitro and in vivo in comparison with those of other cardiotonic agents. In isolated guinea pig left atria, the positive inotropic EC50 values (microM) in order of potency were about 0.18 (NSP-805), 0.39 (indolidan), 1.1 (MCI-154), 1.7 (NSP-804, milrinone), 2.0 (denopamine), 4.0 (papaverine), 4.4 3-isobutyl-1-methylxanthine, IBMX, 6.5 (imazodan), and 27 (amrinone). In anesthetized dogs, intravenous (i.v.) injection of NSP-804 and NSP-805 produced dose-dependent increases in left ventricular VVdp/dtmax and decreases in aortic blood pressure (ABP) with relatively small increases in heart rate (HR). The ED50 values (micrograms/kg) for LVdP/dtmax of NSP-804, NSP-805, denopamine, milrinone, MCI-154, and indolidan were 15, 12, 22, 23, 15, and 7.3, respectively. When the drugs were administered intraduodenally to anesthetized dogs, the ED50 values (micrograms/kg) for LVdP/dtmax of NSP-804, NSP-805, milrinone and indolidan were approximately 30, 10, 200, and 25 respectively. In the propranolol-induced heart failure model, NSP-804 and NSP-805 completely improved the hemodynamic state of heart failure to normal levels. The in vitro positive inotropic effects of NSP-804 and NSP-805 were accompanied by increases in tissue cyclic AMP and abolished by carbachol. NSP-805 was the most potent and selective inhibitor of guinea pig cardiac phosphodiesterase (PDE) III among the agents examined, and NSP-804 was a potent and selective inhibitor of PDE III similar to indolidan. The cardiovascular properties determined in this study suggest that both NSP-804 and NSP-805 may have beneficial effects for treatment of congestive heart failure (CHF).
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PMID:Cardiovascular effects of NSP-804 and NSP-805, novel cardiotonic agents with vasodilator properties. 768 27

1. The decreased response to beta-adrenoceptor stimulation seen in heart failure may be related to a defect in cyclic AMP production. The inotropic effects of the selective phosphodiesterase (PDE) III inhibitors, SK&F 94120 and SK&F94836, and the non-selective PDE inhibitor, 3-isobutyl-l-methylxanthine (IBMX), alone and when combined synergistically with isoprenaline, were studied in control and beta-adrenoceptor-desensitized ventricular myocytes. 2. Myocytes isolated from noradrenaline-treated guinea-pigs had a reduced maximum response to isoprenaline compared with control animals (60.0 +/- 2.5%, n = 42 vs 79.5 +/- 1.7% maximum calcium: n = 46, P < 0.001). Together with an approximately 20 fold increase in the isoprenaline EC50, this is indicative of beta-adrenoceptor desensitization as a result with chronic infusion with noradrenaline. 3. The maximum inotropic response of IBMX was depressed following noradrenaline treatment, from 74.9 +/- 4.6% (n = 7) in control, to 61.7 +/- 2.70% (n = 6), as a percentage of maximum calcium in noradrenaline-treated guinea-pig ventricular myocytes (P < 0.02). The pD2 value for IBMX was also reduced (P < 0.02). No significant differences in the inotropic effects of SK&F94120 and SK&F94836 were seen between control and beta-adrenoceptor desensitized myocytes. 4. Threshold inotropic concentrations of SK&F94120 and SK&F94836 caused a five fold decrease in the EC50 of control myocytes for isoprenaline, and an 11 fold decrease in the noradrenaline-treated guinea-pig ventricular myocytes. 5. The maximum response to isoprenaline in myocytes isolated from normal guinea-pigs was unaffected by PDE inhibition; either at threshold or maximum inotropic concentrations, or by CPT cyclic AMP, an analogue of cyclic AMP.6. A significant potentiation of the maximum isoprenaline response by threshold inotropic concentrations was observed with SK&F 94120 (P<0.05), but not with IBMX or SK&F 94836, in myocytes isolated from noradrenaline-treated guinea-pig hearts. This potentiation, however, did not completely restore the response to levels seen in control myocytes.7. The extent of potentiation of the maximum isoprenaline response by maximum inotropic concentrations of either IBMX or CPT cyclic AMP, was no greater than that by threshold concentrations of IBMX, in myocytes isolated from noradrenaline-treated guinea-pig hearts.8. In cardiac myocytes isolated from the explanted hearts of 16 patients with heart failure, threshold concentrations of IBMX and SK&F 94120 decreased the isoprenaline EC50 by a factor of four and six,respectively, but potentiation of the maximum isoprenaline response occurred only with SK&F 94120.The attenuated isoprenaline response was increased from 60.3 +/- 4.5% to 74.3 +/- 4.2% as a % maximum calcium (P<0.05, n = 6), but remained substantially lower than the 116 +/- 7% (P<0.001, n = 6) seen in myocytes isolated from non-failing hearts.9. We conclude that the reduced maximum contraction amplitude with isoprenaline in cardiac myocytes from either patients in end-stage failure, or noradrenaline-treated guinea-pigs, is partly but not solely due to insufficient cyclic AMP levels, since inhibition of cyclic AMP degradation does not result incomplete reversal of the beta-adrenoceptor desensitization.
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PMID:Incomplete reversal of beta-adrenoceptor desensitization in human and guinea-pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors. 769 63

1. The signal transduction process mediated by cyclic AMP that leads to the characteristic positive inotropic effect (PIE) in association with a positive lusitropic effect (acceleration of rate of twitch relaxation) has been well established. Relationships between accumulation of cyclic AMP, changes in intracellular Ca2+ transients and the PIE differ, however, depending on the mechanism of particular drugs that affect different steps in the metabolism of cyclic AMP. Selective partial agonists of beta 1-adrenoceptors and inhibitors of phosphodiesterase (PDE) III cause the accumulation of less cyclic AMP for a given PIE than does isoproterenol. In addition, in aequorin-microinjected canine ventricular muscle, selective inhibitors of PDE III, OPC 18790 and Org 9731, produced smaller decreases in the responsiveness of myofilaments to Ca2+ ions than isoproterenol, while a partial agonist of beta 1-adrenoceptors, denopamine, elicits a decrease in Ca2+ responsiveness of the same extent as does isoproterenol. 2. Activation of myocardial alpha 1-adrenoceptors, as well as stimulation of receptors for endothelin and angiotensin II, which accelerates hydrolysis of phosphoinositide (PI) to result in production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) are associated with very similar inotropic regulation: (1) the dependence on the species of animals of induction of the PIE; (2) an excellent correlation between the extent of acceleration of hydrolysis of PI and the PIE; (3) isometric contraction curves associated with a negative lusitropic effect; (4) the PIE associated with increases in myofibrillar responsiveness to Ca2+ ions; and (5) the selective inhibition of the PIE by an activator of protein kinase C (PKC), phorbol 12,13-dibutyrate (PDBu), with little effect on the PIE of isoproterenol and Bay k 8644. 3. A novel class of cardiotonic agents, namely, Ca2+ sensitizers such as EMD 53998 and Org 30029, act on the Ca(2+)-binding site of troponin C, increasing the affinity of these sites for Ca2+ ions, or at the actin-myosin interface to facilitate the cycling of cross-bridges. These agents produce a PIE with little change or decrease in Ca2+ transients and may bring about a significant breakthrough in the development of drugs for reversal of myocardial failure in the treatment of congestive heart failure.
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PMID:The effects of various drugs on the myocardial inotropic response. 771 48

In this work we analyze the renal and systemic factors involved in the sodium retention in two conditions: in extracellular volume depletion and in edema forming states, particularly liver cirrhosis with ascitis. In this paper we accept that the volume loss of body fluids stimulates the "effective arterial blood volume" (VAE). This term results from a decrease in the arterial blood volume secondary to a fall in cardiac output or a peripheral arterial vasodilatation. The reduction in the VAE stimulates: the high pressure baroreceptors (carotid sinus and aortic arch); the intrarrenal mechanisms, such as the yuxtaglomerular apparatus and the renin angiotensin aldosterone system; the sympathetic adrenergic system; the non osmotic release of antidiuretic hormone; prostaglandins (PGE1, Tromboxane) and endothelin; and inhibits the atrial natriuretic peptide. We also describe the sodium transport mechanisms along the nephron during physiological conditions and after volume depletion, and in edema formation states, specially hepatic cirrhosis with ascitis. We speculate that the intrarenal mechanisms are more important and persistent than the systemic mechanisms. It is possible that the sodium retention of these states might be the result of direct stimuli of the tubular sodium transport mechanisms in the different segments of the nephron, mediated by the co and counter transports, ATPase activity or by the second messengers cyclic AMP and cyclic GMP. The clonation and structural characterization of the different sodium transports may help us to establish, more precisely, the intracellular tubular mechanisms responsible for the tendency of the body to retain sodium. The amount of information generated in the future may help us to demonstrate, with more precision, the mechanisms responsible for the sodium retention and excretion in normal and pathological conditions, particularly the edema forming states such as cardiac failure, nephrotic syndrome and hepatic cirrhosis with ascitis.
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PMID:[Renal and extra-renal mechanisms of sodium and water retention in cirrhosis with ascites]. 777 18

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.
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PMID:L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. 786 91

Glucagon has been reported to be one of the most effective treatments for severe beta-blocker poisoning. Recently, amrinone was suggested as an alternative therapeutic choice for beta-blocker poisoning. Milrinone, a derivative of amrinone, acts independently of beta-adrenoceptors and increases cyclic AMP. Therefore milrinone may also be effective in the treatment of beta-blocker poisoning. In the present study, we compared the effect of glucagon and milrinone in treating severe beta-blocker poisoning. Following the administration of 10 mg/kg propranolol i.v. over 10 min, heart rate, cardiac output, mean arterial pressure, stroke volume, and end tidal CO2 were depressed, while central venous pressure, and pulmonary capillary wedge pressure increased significantly (p < 0.05). Following the administration of saline (Group S, N = 3), glucagon 20 micrograms/kg (Group G, N = 5), and milrinone 300 micrograms/kg (Group M, N = 5), hemodynamic parameters were observed for 30 min. In group M, mean arterial pressure, cardiac output and stroke volume recovered to their baseline values, while central venous pressure and pulmonary capillary wedge pressure decreased. Although there were no significant differences between groups G and M, the heart rate, central venous pressure and pulmonary capillary wedge pressure, mean arterial pressure and stroke volume did not return to baseline values in group G. Milrinone administration produced a significant hemodynamic improvement without increasing the heart rate in the canine model of severe heart failure caused by propranolol. In the glucagon treatment group, central venous pressure and pulmonary capillary wedge pressure improved less than the milrinone group. Although more data are needed before a clinical recommendation, milrinone might be an effective drug to treat beta-blocker poisoning.
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PMID:Milrinone versus glucagon: comparative hemodynamic effects in canine propranolol poisoning. 800 35

Inodilation, i.e., the combination of positive inotropic and vasodilating therapy, conceptually should be an ideal form of heart failure treatment. However, available orally active inodilator drugs, such as beta-agonists, dopaminergic compounds, and agents with phosphodiesterase (PDE)-inhibiting properties, have not been generally accepted for the treatment of heart failure. In contrast, there is serious concern that agents that act predominantly through PDE inhibition and thereby increase cellular cyclic AMP (cAMP) content, e.g., amrinone, milrinone, and enoximone, not only are ineffective in heart failure but also may lead to serious adverse events, i.e., arrhythmogenicity, and may increase mortality rate in advanced heart failure. Similarly, combined beta 1- and beta 2-agonists do not afford long-term clinical efficacy and also may lead to serious ventricular arrhythmias. Moreover, dopaminergic compounds that, besides dopamine-1 and dopamine-2 activation, act through beta-receptor stimulation do not consistently improve the patient's clinical condition. Thus, inodilation by way of increasing cAMP may not be the right approach, at least not in advanced heart failure, in which cAMP-dependent inotropic activity is significantly diminished. In contrast, clinical efficacy may be present when partial PDE inhibitors that also act through calcium sensitization, such as pimobendan, are administered to patients with mild to moderate or moderately severe heart failure. Moreover, adverse events may be less at the lower dose level at which, consequently, the degree of PDE inhibition is reduced. Calcium-sensitizing properties may afford an alternative, more economical way to improve contractile force in failing hearts. Hence, agents that combine calcium sensitization with a relatively low degree of PDE inhibition may well be the inodilators of choice, in particular in mild to moderate failure. Whether they improve the condition of such patients without affecting relaxation and whether they do not lead to adverse events and an increase in mortality rate have as yet to be evaluated. Furthermore, the potential beneficial effect of additional neurohumoral modulation by dopaminergic inodilator compounds and of heart rate-reducing properties of inodilators, such as OPC-8212 and DPI 201-106, needs to be clarified to assess the place, if any, of inodilator therapy in heart failure.
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PMID:Inodilator therapy for heart failure. Early, late, or not at all? 809 71


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