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)

Cyclic nucleotide phosphodiesterase (PDE) isozymes isolated by DEAE-Sephacel or Mono-Q High Performance Liquid Chromatography from cardiac left ventricular tissue of normal subjects and patients with end-stage heart failure have been compared. With both separation techniques, four major peaks of PDE activity were evident in the soluble fractions; only one peak of activity was present in particulate fractions. The specific activity of the particulate PDE from myopathics was approximately 30-50% of that of normals while the specific activity of a soluble form of this PDE (peak IIIa) was reduced by 30% in myopathics. No differences in comparison of the other peaks of PDE activity were evident. The particulate PDE isozyme has a low Km for cAMP (0.27-0.29 microM), is inhibited by cGMP (60-80% at 1 microM), is sensitive to inhibition by submicromolar concentrations of CI-930 but not rolipram, and is competitively inhibited by milrinone (Kj = 0.3 microM). The first soluble peak of PDE activity hydrolyzes both cAMP and cGMP and is stimulated by calmodulin while cyclic AMP hydrolysis by peak II PDE is stimulated by cGMP. The other soluble peak III fractions (IIIa and IIIb) hydrolyze cAMP; peak IIIa is inhibited by cGMP or by CI-930 and milrinone, whereas peak IIIb is also inhibited by rolipram when the cardiotonic sensitive PDE is inhibited by CI-930. Thus, cardiotonic-sensitive, cGMP-inhibitable, low Km cAMP PDE is present in both the soluble and particulate fractions of human cardiac left ventricular muscle of hearts from normal and cardiomyopathic subjects while the rolipram-sensitive PDE is present in the soluble fraction. The major differences in PDE activity of myopathic relative to normal left ventricular tissue are a reduced specific activity and Vmax of particulate PDE and one of the soluble peak III PDEs.
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PMID:Cellular distribution and pharmacological sensitivity of low Km cyclic nucleotide phosphodiesterase isozymes in human cardiac muscle from normal and cardiomyopathic subjects. 228 32

In conscious dogs, we examined the hypothesis that the effects of atrial natriuretic peptide (ANP) are mediated by cyclic GMP and tested whether stimulation of the intracellular pathway beyond the ANP receptor level still exerts ANP-like effects during tolerance to ANP in heart failure. We studied the hemodynamic, renal, and hormonal effects of the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP) in conscious dogs before and after induction of congestive heart failure by right ventricular pacing. In healthy dogs, 8-Br-cyclic GMP (1-100 micrograms/kg/min) dose-dependently decreased mean arterial pressure (MAP -19% by 100 micrograms/kg/min) and total peripheral resistance (TPR -22%) with no change in cardiac output (CO) and right atrial pressure, increased urine flow (UF 52%), and sodium excretion (UNaV 135%). Plasma renin (62%) and norepinephrine (NE 24%) were increased. In dogs with heart failure, 8-Br-cyclic GMP induced a similar arteriolar dilation (MAP -16%, TPR -23%) with no change in CO and preload. However, the effects on renal excretory function were abolished or markedly attenuated (UF -4%, UNaV 7%). Plasma renin (163%) and aldosterone (40%) were increased. Our findings support the hypothesis that the renal effects of ANP are mediated by cyclic GMP in vivo. The attenuation of renal effects of 8-Br-cyclic GMP in heart failure does not prove but is in agreement with the hypothesis that an intracellular defect beyond cyclic GMP production might be involved in the tolerance to ANP in heart failure.
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PMID:Hemodynamic, renal, and hormonal effects of 8-Br-cyclic GMP in conscious dogs with and without congestive heart failure. 247 97

We measured plasma concentrations of norepinephrine, cyclic AMP, cyclic GMP, atrial natriuretic peptides (ANP) and beta-adrenoceptor density (Bmax) and affinity (Kd) of lymphocytes in patients with congestive heart failure and correlated these parameters with symptoms and hemodynamic indices. Plasma concentration of norepinephrine, cyclic AMP, cyclic GMP and ANP significantly increased in patients with congestive heart failure. Plasma concentrations of norepinephrine were related to the severity of the heart failure, plasma cyclic AMP concentrations, and pulmonary artery pressures. Cyclic AMP concentrations fell rapidly after treatment of acute left ventricular failure. Peripheral blood lymphocytes were stimulated by isoproterenol, and cyclic AMP level in lymphocytes was assayed. In normal subjects the generation of cyclic AMP after stimulation decreased with age. The response of lymphocytes in patients of NYHA classes III and IV was significantly lower than in the normal age-matched controls. A significant correlation between plasma norepinephrine concentration and increase of lymphocyte cyclic AMP was demonstrated. From these results it was suggested that beta-adrenergic receptors in congestive heart failure were desensitized. Beta receptor numbers of lymphocytes significantly decreased in NYHA class III and IV, but did not decrease in class I and II. There was no significant difference in Kd associated with congestive heart 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. A significant correlation between the cyclic GMP and ANP concentration was found in patients with congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathophysiologic and prognostic considerations in circulatory insufficiency in congestive heart failure: receptor function. 254 Dec 67

Isolated calcium-tolerant rat ventricular cardiomyocytes were used to characterize the effects of atrial natriuretic peptide (ANP), Angiotensin II (AII) and their interaction on the myocardial contraction-/relaxation pattern free of interference from other types of cardiac cells. Binding of 125I-ANP showed a KD of 12 pM and approximately 600 binding sites per cell. At 37 degrees C (rate 140 bpm) ANP decreased the contraction maximum with an EC50 of about 70 pM, maximal decrease was 35%. ANP (10(-7) M) raised cellular cyclic-GMP from 0.76+/-0.12 to 1.32+/-0.13 pmole/10(6) cells (73%, p less than 0.05). Angiotensin II increased contractility by a maximum of 32% at 10(-7) M; the EC50 was 8 x 10(-10) M. AII markedly delayed relaxation (reduction of maximum relaxation velocity from 0.092 to 0.063 mm/s; p less than 0.05). ANP (10(-7) M) increased the effect of AII (10(-8) M) on contractility by 66% without changing relaxation parameters significantly. This unexpected interaction may be relevant in pathological conditions where both AII and ANP are stimulated, such as heart failure or secondary hypertension.
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PMID:Action of atrial natriuretic peptide and angiotensin II on the myocardium: studies in isolated rat ventricular cardiomyocytes. 255 Dec 88

Since atrial natriuretic factor (ANF) is a natriuretic and vasodilatory hormone, its mechanisms of action expectedly involve so-called negative pathways of cell stimulation, notably cyclic nucleotides. Indeed, the guanylate cyclase-cyclic GMP (cGMP) system appears to be the principal mediator of ANF's action. Specifically, particulate guanylate cyclase, a membrane glycoprotein, transmits ANF's effects, as opposed to the activation of soluble guanylate cyclase such agents as sodium nitroprusside. The stimulation of particulate guanylate cyclase by ANF manifests several characteristics. One of them is the functional irreversibility of stimulation with its apparent physiological consequences: the extended impact of ANF on diuresis and vasodilation in vivo lasts beyond the duration of increased plasma ANF levels and is accompanied by a prolonged elevation of cGMP. Another characteristic is the parallelism between guanylate cyclase stimulation and increases of cGMP in extracellular fluids. cGMP egression appears to be an active process, yet its physiological implications remain to be uncovered. In heart failure, cGMP continues to reflect augmented ANF levels, suggesting that in this disease, the lack of an ANF effect on sodium excretion is due to a defect distal to cGMP generation. In hypertension, where ANF levels are either normal or slightly elevated, probably secondary to high blood pressure, the ANF responsiveness of the particulate guanylate cyclase-cGMP system, the hypotensive effects, diuresis and natriuresis are exaggerated. The implications of this exaggerated responsiveness of the ANF-cGMP system in the pathophysiology of hypertension and its potential therapeutic connotations remain to be evaluated.
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PMID:Biochemical mechanisms of atrial natriuretic factor action. 257 29

The sequence of atrial natriuretic factor (ANF) has been determined, as well as the complete structure of the rat and human complementary DNA and gene. ANF and ANF messenger RNA are present not only in atria but also in ventricles. The circulating form of ANF has been identified as the C-terminal of the molecule, ANF (Ser 99-Tyr 126). The isolated secretory granules of rat atrial cardiocytes contain only pro-ANF (Asn 1-Tyr 126). An enzyme (IRCM-SP1) has been isolated from heart atria and ventricles. This enzyme is highly specific in cleaving ANF (Asn 1-Tyr 126), to yield ANF (103-126), (102-126), and (99-126). In target cells, ANF produces a rise in cyclic guanosine 3',5'-monophosphate (cGMP) due to activation of particulate guanylate cyclase, and inhibition of adenylate cyclase leading in some cases to a decrease in cyclic adenosine 3',5'-monophosphate (cAMP). ANF produces relaxation of rabbit and rat aortic strips, inhibits steroidogenesis in both zona glomerulosa and zona fasciculata cells, and inhibits the release of arginine vasopressin from the isolated rat hypothalamohypophysial preparation in vitro but decreases AVP release in vivo only at pharmacological doses. In all forms of experimental hypertension, plasma levels of ANF are increased and, at some time periods, atrial levels are also decreased. The ventricular levels of immunoreactive ANF are also increased in renal hypertension. Infusion of ANF by minipumps decreases the blood pressure near control levels in several models of experimental hypertension. In cardiomyopathic hamsters with heart failure, the atrial levels of immunoreactive ANF are decreased while the plasma and ventricular levels are increased.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The heart as an endocrine gland. 282 60

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

The muscle cells of cardiac atria contain many secretory granula with a prohormone of 126 amino acids (ANF(1-126)). Distension of the atria causes exocytosis of the granula with cleavage of the prohormone into the hormone ANF(99-126) or alpha-ANP and the N-terminal fragment ANF(1-98) with an as yet unknown role. The plasma concentration of the hormone in normal man is in the range of 10 pM (30 pg/ml) with a plasma half-life of several minutes and a release rate of 2-3 ng/kg per minute. The plasma concentration changes in parallel with the intake of sodium chloride and is elevated acutely by all interventions which increase the blood volume, or which cause its redistribution towards the cardiopulmonary compartment. Infusions of the hormone cause diuresis and natriuresis, inhibition of the renin-angiotensin-aldosterone system and of sympathetic activity and augmentation of tissue filtration. Thus, a hormonal feedback loop for cardiac unloading by limiting the plasma volume could be assumed. However, the ANF infusion rates necessary for eliciting these actions in man induce ANF plasma concentrations above physiological levels. On the other hand, a physiological role of the hormone in this regulation is suggested by observations during long-term administration of the hormone, which demonstrate actions of the hormone at physiological plasma levels. Furthermore, experiments with injection of ANF antibodies indicate a synergistic action of ANF, together with reflexes in response to atrial distension. ANF acts by activating specific high affinity membrane receptors, resulting in intracellular cGMP formation and cGMP release into plasma and urine. These ANF receptors are "down-regulated" by infusions of the hormone and by chronic volume expansion. In fetal circulation and in congestive heart failure, there is also augmented prohormone synthesis in the cardiac ventricles, which may then contribute to the release of the hormone. Although during cardiac failure the ANF plasma levels are augmented up to 30-fold, and the atrial prohormone content is reduced, there is no indication for an exhaustion of hormone synthesis or for resetting of stimulated hormone release. In addition to its role as a peripheral hormone for "cardiac unloading", ANF occurs in the central nervous system as a neuropeptide, which might also be involved in blood pressure and volume regulation.
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PMID:[Atrial natriuretic hormone in the human]. 296 72

In heart failure, ventricular function is influenced by modulation of pre- and afterload. It has been shown that the secretion of atrial natriuretic peptide (ANP) is increased in experimental preparations of heart failure and in patients with cardiac failure. Distension of myoendocrine cells of the atria is the major stimulus for the release of ANP. The possible beneficial effect of ANP in heart failure consists of unloading the heart by its vasodilatory, diuretic, and natriuretic properties. Intravenous application of high, pharmacological doses of ANP improves ventricular performance by a reduction of pre- and afterload, the renal effects however, are markedly attenuated. From animal experiments one may conclude that ANP may play an important role in early and moderate heart failure as a counterregulating mechanism of the renin-angiotensin-aldosterone system. In chronic severe heart failure vasoconstrictory, volume, and sodium-retaining mechanisms override the effects of ANP, deteriorating ventricular function by an inadequate increase of pre- and afterload. The attenuation of the effects of ANP in cardiac failure may be due to altered hemodynamics especially in the kidney, to a counterregulation of vasoconstrictory and volume-retaining neurohumoral factors, to a reduction of specific binding sites for ANP (receptor "down-regulation"), and to a possible intracellular defect beyond the formation of cGMP, the intracellular second messenger of ANP.
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PMID:[Conditions of secretion and peripheral effects of atrial natriuretic peptide in heart failure]. 297 95

To examine the interrelationship between human atrial natriuretic polypeptide (hANP) and cyclic 3'5'-guanosine monophosphate (cyclic GMP), plasma concentrations of these compounds were determined in 61 disease-free humans, as controls, and in 35 patients with congestive heart failure. Levels of plasma hANP (199.6 +/- 53.7 pg/ml) and cyclic GMP (12.6 +/- 1.7 pmol/ml) in patients with congestive heart failure were significantly higher than in the control subjects (hANP 57.1 +/- 2.8 pg/ml, cyclic GMP 5.2 +/- 0.3 pmol/ml). Although plasma hANP concentrations in the patients with congestive heart failure tended to increase with the severity of cardiac dysfunction, there was no significant correlation between the levels of plasma hANP and the grade of heart failure, classified according to the New York Heart Association. However, a significant correlation was found between plasma hANP and cyclic GMP concentrations in both the healthy subjects and the patients with congestive heart failure, and a weak positive correlation between plasma hANP and cyclic 3'5'-adenosine monophosphate (cyclic AMP) concentration in the patients with congestive heart failure. Thus, changes in plasma cyclic GMP concentration depend to some extent on the plasma concentrations of hANP.
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PMID:Relationship between atrial natriuretic polypeptide and cyclic 3'5'-guanosine monophosphate in human plasma. 303 37


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