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)

It has been suggested that amrinone and AR-L57 enhance cardiac contractility either by inhibiting phosphodiesterase activity or altering Ca++ homeostasis. Because these novel agents are potentially useful in the management of heart failure, it was of interest to more clearly define their mechanism(s) of action. Amrinone and AR-L57 caused concentration-dependent increases in the contractile states of either perfused guinea-pig hearts or cultured rat cardiomyocytes. To determine whether these actions might result from an increase in sarcolemmal Ca++ movement, the effects of these agents on Ca++ accumulation were studied in a simple system, dog erythrocytes. Both agents promoted erythrocyte Ca++ accumulation in time and concentration-dependent manners, effects that resulted primarily from increased Ca++ entry. However, because these effects were not measurable at inotropic drug concentrations and were apparent only after a 30-min incubation, they did not provide an explanation for the inotropic effects of these agents. Amrinone and AR-L57 inhibited dog heart phosphodiesterase activity (isozyme III) with EC50 values of 23 and 420 microM, respectively; however, only the inotropic responses to amrinone were attenuated by the muscarinic agonist, carbachol, thereby implying a cAMP (cyclic AMP)-dependent mechanism. In cultured ventricular cells, concentrations of amrinone (2 X 10(-4) M) and AR-L57 (3 X 10(-5) M) that caused maximal inotropic responses were associated with the activation of glycogen phosphorylase, but neither drug significantly increased the activation state of cAMP-dependent protein kinase. To further probe the effects of these drugs on intracellular cAMP and Ca++ metabolism, their effects on protein phosphorylation were studied.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular basis for the cardiovascular activities of amrinone and AR-L57. 608 73

There is an increasing use and variety of beta-adrenoceptor blocking agents (beta-blockers) available for the treatment of hyperthyroidism. Recent comparative studies suggest that atenolol (200mg daily), metoprolol (200mg daily); acebutolol (400mg daily), oxprenolol ( 160mg daily), nadolol ( 80mg daily) and timolol (20mg daily) produce a beneficial clinical response equal to that seen with propranolol ( 160mg daily). Most beta-blockers reduce resting heart rate by approximately 25 to 30 beats/min, although a lesser reduction is seen with those possessing intrinsic sympathomimetic activity such as oxprenolol and pindolol. While earlier studies employing large doses of intravenous propranolol concluded that beta-blockade reduced myocardial contractility, more recent non-invasive studies suggest that the predominant cardiac effect is on heart rate. In patients with cardiac failure, beta-blockers may, however, produce a profound fall in cardiac output. Nevertheless, in combination with digoxin they may be useful in controlling the atrial fibrillation of thyrocardiac disease. beta-Blockers improve nervousness and tremor (although to a lesser extent with cardioselective agents) and severe myopathy, and they also reduce the frequency of paralysis in patients with thyrotoxic periodic paralysis. There is often subjective improvement in sweating but usually no major effect on eye signs. Recent studies show a 10% reduction in oxygen consumption/basal metabolic rate with long term oral use of selective or nonselective beta-blockers. In addition, many agents (propranolol, metoprolol, nadolol and sotalol but not acebutolol, atenolol or oxprenolol) reduce circulating tri-iodothyronine (T3) concentration by between 10 and 40%, although the clinical significance of this effect (if any) is not established. beta-Blockers may also have endocrinological effects on gastrin, cyclic AMP, catecholamines and other hormone levels. Given in adequate dosage, propranolol has been shown to control thyrotoxic hypercalcaemia. Minor side effects (nausea, headaches, tiredness, etc.) are quite common but overall beta-blockers are well tolerated by the thyrotoxic patient. The major use of these drugs is in symptomatic control while awaiting definitive diagnosis or treatment. As an adjunct to antithyroid drugs or radioactive iodine, beta-blockers will produce a satisfactory clinical response in the weeks to months before these forms of therapy produce a euthyroid state. beta-Blockers are more convenient than antithyroid drugs in the control of patients receiving therapeutic radioiodine, in that continuous therapy and assessment of biochemical response is possible.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Use of beta-adrenoceptor blocking drugs in hyperthyroidism. 614 1

This study was designed to investigate the changes in the beta adrenergic system during the induction of cobalt cardiomyopathy in dogs. Cobalt sulphate, at a dose of 5 mg X kg-1 X day-1 was administered intravenously with a low protein, low thiamine diet to 13 dogs. The percentage change of the left ventricular minor axis with systole by echocardiogram (% delta D) and dP/dtmax were used to monitor left ventricular function. Noradrenaline (NA) was measured in 24 h urine samples. Left ventricular (LV) free wall biopsies were assayed for noradrenaline (LV-NA), cyclic AMP, cyclic GMP and dopamine beta hydroxylase (LV-DBH). Lymphocytes were assayed for beta-receptor density. All dogs were studied at baseline and seven were studied after a midpoint cumulative dose of 60 to 90 mg X kg-1 of cobalt; the remaining six dogs were studied when they were in heart failure and had received more than 110 mg X kg-1. During the induction of heart failure the heart rate rose from 112 +/- 6 (means +/- SE) at baseline to 154 +/- 9 at the midpoint and 153 +/- 9 (both P less than 0.05) at the final measurement while the % delta D fell from 35 +/- 2% to 31 +/- 3% and 23 +/- 2% (P less than 0.05) and dP/dt fell from 333 +/- 40 kPa X s-1 at baseline to 254 +/- 46 kPa X s-1 (P less than 0.05) and 207 +/- 33 kPa X s-1 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The evolution of beta-adrenergic dysfunction during the induction of canine cobalt cardiomyopathy. 631 98

The potential of forskolin as a research tool is just beginning to be realized. Its use has revealed further subtleties to the control of cyclic AMP generation by adenylate cyclase in both solubilized and membrane preparations and in intact cells. It appears that an effect of forskolin will become one of the criteria for implicating adenylate cyclase in any physiological or biochemical response or, conversely, in ruling out an involvement of cyclic AMP. Clinical applications of forskolin as a hypotensive, spasmolytic, lipolytic, or antithrombotic agents or for the treatment of glaucoma or cardiac insufficiency remain other challenges for the future.
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PMID:Forskolin, adenylate cyclase, and cell physiology: an overview. 632 47

The development of myocardial infarction was shown to be accompanied by a rise in blood cAMP, cGMP and AMP levels, cyclic nucleotides peaking within the first hours of the disease. The increase in plasma cAMP, associated with developing heart failure, was more persistent. The administration of GIP mixture during the acute phase of myocardial infarction was conducive to lowering the levels of cyclic nucleotides and AMP, and raising blood ATP and ADP values. Clinically, the effect of GIP was manifested in reduced ventricular arrhythmias and diminished signs of heart failure.
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PMID:[Effect of a glucose-insulin-potassium mixture on the cyclic and adenine nucleotide levels in the acute period of myocardial infarct]. 633 82

In acutely uremic animals, the contractile force of the heart is consistently increased; such an increase can be dissociated from changes of afterload or catecholaminergic drive. It is associated with diminished sarcolemmal Na,K-ATPase activity in the heart which, in turn, may be related to increased levels of endogenous digitalis-like substances (endigens) that have been postulated to represent a natriuretic factor. In patients with chronic uremia, myocardial contractility is usually normal, but occasionally there may be heart failure unrelated to pre-existing hypertension, coronary heart disease, anemia, fluid overload, or other recognizable factors. So far, the experimental basis for this clinical observation is uncertain. Possible causes for the clinical syndrome include an excess of parathyroid hormone or cardiodepressor substances. There is experimental evidence of impaired cardiac response to beta adrenergic agonists, e.g., decreased isoproterenol-dependent calcium uptake, diminished inotropic and chronotropic responses. In acutely uremic rats, cardiac cyclic AMP levels are high but can be reversed by beta blockers. Heart calcium content is variable and heart weight is constantly increased in acutely uremic rats, despite decreased skeletal muscle mass. The change in heart weight is not related to anemia, to an excess of parathyroid hormone, or to sympathetic activity; its cause remains unknown. Experimental studies to date have shown a variety of abnormalities, but do not provide a uniform concept of the mechanisms or an explanation for the cardiac dysfunction so often observed in patients with uremia.
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PMID:Cardiac function in experimental uremia. 636 51

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

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