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 positive inotropic effect of milrinone was investigated in isolated, electrically driven (1 Hz) human papillary muscle strips from nonfailing myocardium (control) and from patients with moderate (NYHA II-III) and severe (NYHA IV) heart failure. In the control hearts, milrinone increased force of contraction to about the same degree as Ca2+ at 15 mmol/l. In NYHA II-III, the positive inotropic effect was significantly reduced compared with the control hearts. In NYHA IV, the effectiveness (maximal increase in force of contraction) and potency (as judged from the EC50 values) were significantly less than in NYHA II-III and controls. Preexposure of the preparations to isoprenaline in NYHA II-III and NYHA IV shifted the concentration-response curve for milrinone to the left and, moreover, restored the effectiveness of the compound (i.e., similar positive inotropic effect as Ca2+). No difference in the cAMP-phosphodiesterase inhibition by milrinone could be detected between controls, NYHA II-III, and NYHA IV. It is concluded that diminished basal cAMP production is responsible for reducing the effectiveness of milrinone in the failing human heart. A diminished inhibition of cAMP-phosphodiesterase does not play a role. The fact that stimulation of cardiac beta-adrenoceptors increased the effectiveness of milrinone provides evidence that combined application of catecholamines and phosphodiesterase inhibitors may be useful in the treatment of patients with terminal heart failure.
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PMID:Enhancement of the effectiveness of milrinone to increase force of contraction by stimulation of cardiac beta-adrenoceptors in the failing human heart. 284 49

The contractile response and myocardial content of Gi-proteins were examined in cardiac preparations from explanted hearts of four different patients with end-stage heart failure. Three patients had idiopathic dilated cardiomyopathy and one patient had inflammatory heart disease. Preparations from patients with idiopathic dilated cardiomyopathy showed reduced contractile response to the cAMP-increasing agent isoprenaline and an increase in myocardial Gi-proteins, compared with preparations from non-failing hearts. Therefore it is conceivable that an increase in myocardial Gi-proteins is causally related to heart failure due to idiopathic dilated cardiomyopathy. In the preparation from the patient with inflammatory heart disease the contractile response to isoprenaline was not reduced and likewise content of Gi-proteins was not changed.
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PMID:Increase in myocardial Gi-proteins in heart failure. 290 84

Twenty-five years after the discoveries of the existence of atrial granules and of volume receptors in the heart atria the search for natriuretic hormones has led to the isolation and identification of the atrial natriuretic factors (ANF) now considered as a hormonal system. These peptides are probably synthesized and stored in the Golgi apparatus of cardiac myocytes and are released in response to atrial wall stretch following acute plasma volume expansion and increased central blood volume, e.g., during head-out water immersion, in arterial hypertension, or increased left and/or right atrial pressure in cardiac failure, but also possibly in response to increased frequency of myocardial contractions, e.g. in paroxysmal tachycardia. The mechanisms of the renal action of these potent natriuretic hormones are not yet precisely known. Increased GFR may contribute to the initial rise in urinary sodium excretion and increased renal medullary blood flow to the later phase of natriuresis. The proximal tubule, the thin descending and the ascending limb of Henle's loop and especially the medullary collecting tubule were so far incriminated as tubular sites of action of ANF. Finally, recycling of sodium in medullary tissue and secretion of sodium via back-flux from the interstitium into the medullary collecting tubule are postulated to result in the hypernatric urine observed after ANF administration. Direct suppression of the secretion of renin, aldosterone, vasopressin, and vasopressin-stimulated cAMP synthesis may also contribute to its diuretic, natriuretic, and antihypertensive effects. The renal hemodynamic and tubular as well as the adrenal and systemic vascular effects are related to enhanced cGMP synthesis in medium-sized arterial vessels, in glomeruli and specific tubular segments, and in adrenal tissue, and may be calcium dependent. Specific ANF-binding sites were detected in these target organs. Although increased ANF release was observed in response to atrial distension in various disease states, which may contribute to renal sodium elimination in human hypertension and congestive heart failure, further studies are needed to identify its precise physiological and pathophysiological significance.
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PMID:Atrial natriuretic hormones--thirty years after the discovery of atrial volume receptors. 294 41

Analysis of current data indicates that one of the important and unsolved problems in the concept of sudden cardiac death is the question on the trigger mechanisms of the ventricular fibrillation which is the most frequent cause of heart failure in the sudden death of patients with coronary heart disease. It can be assumed that the spread, with the circulating blood, in the myocardial tissue of the arythmogenic substances formed in the hypoxic areas of the ischemized heart muscle or as an effect of catecholamines favour the fibrillation. Penetration of the arythmogenic substances into the circulation is due to the blood circulation remaining in the ischemic zone or the reperfusion of the ischemic tissue. Amphiphilic lysophosphoglycerides, cAMP, free fatty acids, lipid peroxidation products, some forms of prostaglandins may play a role of arythmogenic substances.
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PMID:[Structural and functional bases of the mechanisms of myocardial fibrillation in sudden cardiac death]. 298 46

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

Plasma concentrations of cyclic nucleotides (adenosine monophosphate (AMP) and guanosine monophosphate (GMP) were measured by an ultrasensitive radioimmunoassay in 138 patients with heart failure due to various causes. Measurements were related to the New York Heart Association classification of symptoms, plasma noradrenaline concentrations, and mean pulmonary artery pressures. Serial concentrations of cyclic AMP and GMP were also measured daily in four patients treated for acute left ventricular failure. Plasma concentrations of cycle AMP were related to the severity of the heart failure, plasma noradrenaline concentrations, and pulmonary artery pressures. Cyclic AMP concentrations fell rapidly after treatment of acute left ventricular failure. Plasma concentrations of cyclic GMP also depended on the severity of heart failure and the pulmonary artery pressure, and decreased sharply with treatment although remaining at a high value. The cyclic GMP concentrations were significantly higher in patients with mitral stenosis than in those with other types of heart failure.
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PMID:Increased plasma cyclic nucleotide concentrations in congestive heart failure. 609 37

Developing myocardial infarction is shown to be accompanied by raised plasma cAMP and cGMP levels which peak within the first few hours of the disease. Two patterns of changes were noted in the content of cyclic nucleotides: cAMP increase prevailing (a more typical pattern) and cGMP increase prevailing. Primary ventricular fibrillation was recorded in some patients belonging to the latter group. The development of cardiac failure is accompanied by a more stable rise of plasma cAMP.
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PMID:[Dynamics of the cyclic nucleotide content in the acute period of myocardial infarct]. 629 97

The myocardial beta-receptor adenylate cyclase system was investigated in short-term streptozotocin-diabetic rats. Earlier reports of a decreased sensitivity of the myocardium to isoproterenol (ISO) in these animals were elucidated by measuring the in vivo production of cAMP after ISO. A substantial decrease was seen in diabetic animals compared with controls and starved animals, and thyroxine treatment, known to sensitize the myocardium to catecholamines, did not normalize the response. The desensitization was retained in a membrane fraction in such a way that ISO was unable to increase the cAMP production while stimulation via the nucleotide-binding protein (with NaF or GTP) leads to a normal cAMP response. As the beta-adrenergic receptor number and affinity turned out to be identical in control and diabetic animals, a functional uncoupling of the myocardial beta-receptor from productive adenylate cyclase activation seems thus to exist in experimental diabetes. It is unlikely that it has anything to do with the thyroid status of the animals, but the possibility of a catecholamine-induced densensitization cannot be excluded. The phenomenon is not universal as the beta-receptor-adenylate cyclase system is normal in isolated spleen lymphocytes. Whether the described phenomenon obtained in an animal study has any relevance for the increased incidence of heart failure in human diabetes mellitus is not known at present.
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PMID:The adrenergic beta-receptor adenylate cyclase system in heart and lymphocytes from streptozotocin-diabetic rats. In vivo and in vitro evidence for a desensitized myocardial beta-receptor. 631 97

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

The expression of different myocardial regulatory proteins is altered in human heart failure, e.g., beta 1-adrenoceptors, G-proteins and others. Similar changes in rats after 4 days treatment with isoproterenol led to the hypothesis of the cAMP pathway involved in these changes. In different cell types cAMP-dependent transcriptional activation is mediated by the cAMP-response element binding protein (CREB) which was recently shown to be expressed and phosphorylated in the human heart. Here, by the reverse transcriptase-polymerase chain reaction two alternatively spliced isoforms of CREB mRNA were found to be expressed in rat ventricles. Both isoforms were down-regulated in the ventricles of rats treated in vivo with isoproterenol (2.4 mg/kg per day) for 4 days proposing a possible mechanism involved in expressional changes mentioned above.
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PMID:In vivo isoproterenol treatment leads to downregulation of the mRNA encoding the cAMP response element binding protein in the rat heart. 748 29


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