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)

The natriuretic peptides are a group of structurally similar but genetically distinct peptides that have diverse actions in cardiovascular, renal, and endocrine homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are of myocardial cell origin and C-type natriuretic peptide (CNP) is of endothelial origin. ANP and BNP bind to the natriuretic peptide-A receptor (NPR-A), which, via 3',5'-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodilation, renin inhibition, antimitogenesis, and lusitropic properties. CNP lacks natriuretic actions but possesses vasodilating and growth-inhibiting actions via the guanylyl cyclase-linked natriuretic peptide-B receptor (NPR-B). All three peptides are cleared by the natriuretic peptide-C receptor (NPR-C) and are degraded by the ectoenzyme neutral endopeptidase 24.11 (NEP), both of which are widely expressed in the kidneys, lungs, and the vascular wall. Congestive heart failure (CHF) represents a pathological state in which the activation of the natriuretic peptides exceeds those of all other states. In this brief review, we will attempt to provide an update on important issues regarding natriuretic peptides in CHF, with a focus on their functional importance as a beneficial humoral response in asymptomatic left ventricular dysfunction (LVD), the mechanisms of natriuretic peptide hyporesponsiveness in severe heart failure, the diagnostic and prognostic significance of the natriuretic peptides in CHF, and the therapeutic potential of the natriuretic peptides in this multiorgan syndrome.
 ...
PMID:The natriuretic peptides in heart failure: diagnostic and therapeutic potentials. 1051 61

We investigated whether angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT1-receptor blockade (AT1-) would exert beneficial additive effects on coronary hemodynamics and on cardiac remodeling in post-myocardial infarction (MI) heart failure in rats. Wistar rats with MI were treated daily for 6 weeks with either trandolapril (0.1 mg/kg), losartan (3 mg/kg), or their combination, after which coronary hemodynamics (basal and at maximal vasodilation, fluospheres), systemic hemodynamics, and cardiac remodeling were investigated. Neither trandolapril nor losartan (both in nonantihypertensive doses) nor their combination (which significantly decreased blood pressure) proved to be effective at improving MI-induced impairments of basal coronary hemodynamics and of coronary flow reserve, and at preventing cardiac fibrosis development. In contrast, both trandolapril and losartan significantly improved the hemodynamic status [e.g., left ventricular end diastolic pressure: -27% and -39%, urinary cyclic guanosine monophosphate (GMP): -37%, and -26%, respectively] and slightly limited cardiac hypertrophy (-5% and -3%, respectively), and, in their combination, tended to exert additive effects on these three parameters (-49, -42, and -10%, respectively). Thus whereas the ACEI/AT1- combination tended to exert additive effects on systemic hemodynamics and cardiac hypertrophy in post-MI heart failure rats, no such effect was found for coronary hemodynamics, probably in relation to the lack of prevention of cardiac fibrosis. We conclude that an early (6 weeks) drug-induced improvement in coronary hemodynamics does not contribute to the long-term survival prolongation observed in this experimental model after either ACEI or AT1-.
 ...
PMID:Combined selective angiotensin II AT1-receptor blockade and angiotensin I-converting enzyme inhibition on coronary flow reserve in postischemic heart failure in rats. 1059 19

The endocrine function of the heart is to secrete Atrial and Brain natriuretic -peptides (ANP and BNP). These peptides are biologically active via particulate guanylate cyclases which generate cyclic GMP, the second intracellular messenger. A polysaccharide antagonist, HS-142-1 has been recently described by a Japanese Group. Cyclic GMP is partly secreted from the target cells into the extra cellular medium in which its accumulation is proportional to the concentration of the natriuretic peptide. Neutral Endopeptidase (NEP) is a zinc ectoenzyme involved in the catabolism of natriuretic peptides. NEP is absent in plasma but present on the surface of endothelial and smooth muscle cells. NEP is mainly expressed at the apical pole of the epithelial cells of the proximal tubule in the nephron. Chronic increase in volume and pressure within the cardiac cavities is associated with the oversecretion of natriuretic peptides. This chronic phenomenon involves the recruitment of all the cardiac myocytes to express natriuretic peptide genes. The clinical application of this hyperplasic phenomenon is congestive heart failure, in which the plasma levels of natriuretic peptides correlate with the level of the -hemodynamic stress. Therefore the plasma levels of natriuretic peptides are good pronostic markers in both experimental and human heart failure. The degree of congestive heart failure as well as the plasma levels of ANP and BNP are also -correlated with the plasma and urinary levels of cyclic GMP. The plasma level of -cyclic GMP is correlated with the endothelial concentration of cyclic GMP but not with the cyclic GMP concentration in smooth muscle cells. From these experimental data, we can conclude that plasma cyclic GMP originates from endothelial cells and is related to particulate guanylate cyclase activity. In contrast natriuretic peptides do not modulate vascular wall cyclic GMP content. The natriuretic action of ANP is probably due to the interaction of the filtered peptide with the particulate guanylate cyclase at the apical pole of the epithelial cells. The apparition of peptiduria associated with natriuresis during NEP inhibition provides evidence of the action of the peptide in the urinary compartment. It is also by a urinary pathway via the macula densa that ANP, and its potentiation by NEP inhibition, decreases renin secretion. The fact that plasma levels of ANP and plasma and urine levels of cyclic GMP correlate with the degree of salt retention in congestive heart failure, provides evidence for chronic desensitization of the system. An up-regulation of Na(+), K(+), 2Cl(-) expression associated with experimental congestive heart failure has recently been shown. Similarly, a modulation of the different sodium transporter systems along the nephron could be one of the counter-regulations leading to desensitization to natriuretic peptides. In conclusion, natriuretic peptides are true endocrine peptides, secreted by the heart, transported in the plasma, filtered by the glomeruli and active at the nephron level. The molecular effector of ANP and cyclic GMP in the epithelial cells is probably the G-kinase II, isoform phosphorylating the cystic fibrosis transmembrane conductance regulator (CFTR). The exact mechanism of desensitization remains to be elucidated.
 ...
PMID:[Functional compartmentation of the endocrine action of cardiac natriuretic peptides]. 1079 May 90

Omapatrilat, a novel vasopeptidase inhibitor, is a highly potent and selective inhibitor of neutral endopeptidase and angiotensin-converting enzyme; its therapeutic potential is being investigated for treatment of hypertension and heart failure. In the present study, the safety, tolerability, and hemodynamic effects of single oral doses of omapatrilat (1 to 50 mg) are compared with placebo in patients with heart failure. Patients with heart failure (New York Heart Association functional class II to IV) and a resting left ventricular ejection fraction < or = 40% were enrolled in a double-blind, placebo-controlled, sequential-panel study of single doses of omapatrilat of 1, 2.5, 5, 10, 25, or 50 mg, followed by hemodynamic assessment for 24 hours. At 4 to 6 hours after dosing, the 25- and 50-mg doses of omapatrilat, compared with placebo, reduced mean pulmonary capillary wedge pressure by approximately 6 mm Hg from 20 and 23 mm Hg at baseline to 14 and 16 mm Hg. The 50-mg omapatrilat dose maintained this effect compared with placebo with an approximately 2.5-mm Hg reduction in mean pulmonary capillary wedge pressure at 24 hours. Omapatrilat improved additional hemodynamic parameters, including cardiac index, systemic vascular resistance, stroke volume index, and mean arterial pressure. Additionally, by 2 hours after dosing with omapatrilat 25 and 50 mg, a trend in peak increases from baseline in plasma atrial natriuretic peptide (twofold) and cyclic guanosine monophosphate (nearly twofold) was observed. Moreover, omapatrilat was well tolerated. Thus, omapatrilat administered orally to patients with heart failure was safe and well tolerated and resulted in improved hemodynamic performance.
 ...
PMID:Effects of omapatrilat on hemodynamics and safety in patients with heart failure. 1156 90

Adrenomedullin (AM), identified from pheochromocytoma and having 52 amino acids, elicits a long-lasting vasodilatation and diuresis. AM is mainly mediated by the intracellular adenylate cyclase coupled with cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) -cyclic guanosine monophosphate (cGMP) pathway through its specific receptor. The calcitonin receptor-like receptor (CLCR) and receptor-activity modifying protein (RAMP) 2 or RAMP3 models have been proposed as the candidate receptor. AM is produced mainly in cardiovascular tissues in response to stimuli such as shear stress and stretch, hormonal factors and cytokines. Recently established AM knockout mice lines revealed that AM is essential for development of vitelline vessels of embryo. Plasma AM levels elevate in cardiovascular diseases such as heart failure, hypertension and septic shock, where AM may play protective roles through its characteristic biological activities. Human AM gene delivery improves hypertension, renal function, cardiac hypertrophy and nephrosclerosis in the hypertensive rats. AM decreases cardiac preload and afterload and improves cardiac contractility and diuresis in patients with heart failure and hypertension. Advances in gene engineering and receptor studies may contribute to further understandings of biological implication and therapeutic availability of AM.
 ...
PMID:A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides. 1175 55

The angiotensin AT(1) and AT(2) receptors have been cloned and characterised. Both are members of the serpentine receptor superfamily coupled to G proteins, but there is only 32% homology between the AT(1) and AT(2) receptors. The typical pharmacological features of AT(1) receptors are their selective affinity for biphenylimidazoles (typified by losartan) and their insensitivity to tetrahydroimidazopyridine (such as PD123319). In contrast, the AT(2) receptor has the opposite sensitivity for these two ligands. Genes located on chromosome 3 and X, respectively, encode the human AT(1) and AT(2) receptors. The signalling pathways of AT(1) and AT(2) are totally different. In addition to the classical signal transduction mechanisms (phospholipases C, D, A, voltage-dependent calcium channels and adenylate cyclase), the AT(1) receptor stimulates the phosphorylation of several tyrosine-containing proteins such as Jak 2, Stat 1 and mitogen-activated protein kinases. It also activates the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The AT(1) receptor is responsible for the majority of the effects of angiotensin II: vasoconstriction, sodium re-absorption, cell proliferation, extracellular matrix formation, inflammatory response and oxidative stress. The AT(2) receptor is expressed abundantly in fetal tissues but at low density in adults. It is, however, upregulated in various pathological circumstances such as heart failure. In contrast to the AT(1) receptor, the signalling pathway of the AT(2) receptor does not induce an increase in inositol triphosphate and diacylglycerate formation with calcium mobilisation. Activation of the AT(2) receptor stimulates an intracellular mechanism involving various Tyr (tyrosine) and Ser (serine)/Thr (threonine) phosphatases, nitric oxide/cyclic guanosine monophosphate (cGMP) and phospholipase A(2). The effect of the AT(2) receptor counterbalances that of the AT(1) receptor: inactivation of mitogen-activated protein kinase (MAP), antiproliferation, promotion of apoptosis, opening of delayed-rectifier K(+) channels, closing of T-type Ca(2+) channels, stimulation of nerve differentiation and regeneration. It has been hypothesised that stimulation of the AT(2) receptor is part of the mechanism of action of the AT(1) receptor antagonists.
 ...
PMID:[AT(1) and AT(2) angiotensin II receptors: key features]. 1203 84

Endothelial production of nitric oxide (nitrogen monoxide, NO) has become a major research area in vascular biology. Some of the most important effects that NO exerts in the vascular wall are potentially vasoprotective, because these effects maintain important physiological functions such as vasodilation, anticoagulation, leucocyte adhesion, smooth muscle proliferation, and the antioxidative capacity. During the last 2 decades it has become apparent that a variety of diseases are associated with an impairment of endothelium-dependent NO activity. One of the major causes is believed to be an increased production of reactive oxygen species, in particular superoxide, which have been shown to interfere with many steps of the NO--cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has been found in diverse conditions such as atherosclerosis, hypertension, diabetes, hypercholesterolemia, heart failure, and cigarette smoking. The aim of this review is to examine the cellular and molecular mechanisms whereby NO exerts potentially vasoprotective effects and to discuss pharmacologic approaches targeting the NO pathway in view of their potential to improve endothelial function and to reduce the progression of atherosclerotic vascular disease. We conclude that there is compelling evidence for vasoprotective actions of NO which are mediated by cGMP-dependent and cGMP-independent mechanisms. These effects may contribute to the beneficial effects of established drugs such as ACE inhibitors or statins. Unfortunately, clinical data on the effect of long-term treatment with nitrates on the progression of coronary artery disease are lacking. Finally, L-arginine or new activators of the NO pathway may become therapeutic options in the future.
 ...
PMID:Vasoprotection by nitric oxide: mechanisms and therapeutic potential. 1212 64

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
 ...
PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.
 ...
PMID:Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease. 1241 49

Endothelial dysfunction is associated with impairment of aerobic capacity in patients with heart failure and may play a role in the progression of disease. Impaired endothelium-dependent vasodilation in patients with heart failure can be attributed to decreased bioavailability of nitric oxide and attenuated responses to nitric oxide in vascular smooth muscle. Impaired vasodilation in response to nitric oxide derived from vascular endothelium or organic nitrates in vascular smooth muscle may be related in part to increased degradation of the second messenger cyclic guanosine monophosphate by type 5 phosphodiesterase. Sildenafil, a specific type 5 phosphodiesterase inhibitor currently approved for the treatment of erectile dysfunction, has been shown to acutely enhance endothelium-dependent vasodilation in patients with heart failure. Further studies are warranted to characterize the safety and efficacy of type 5 phosphodiesterase inhibition in the treatment of chronic heart failure.
 ...
PMID:Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure. 1255 72


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>