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)

Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.
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PMID:Natriuretic peptides and therapeutic applications. 1744 Aug 8

One of the clinical characteristics associated with septic shock is heart failure. Several lines of evidence indicate that functional consequences of heart failure in septic shock are linked to the activated NO-cyclic guanosine monophosphate (NO-cGMP) pathway. We have previously shown that the high-affinity cGMP export transporter, multidrug resistance protein 5 (MRP5), is expressed in the heart, which modulates intracellular concentrations and, hence, the effects of cGMP. Thus, modified expression of cardiac MRP5 in septic shock can alter cGMP concentrations and contribute to the development of heart failure. We therefore investigated MRP5 expression in the heart using two established murine models of septic shock (intraperitoneal LPS injection and surgical implantation of a stent into the ascending colon, resulting in a multibacterial peritonitis [CASP, colon ascendens stent peritonitis] in C57BL/6N mice, respectively; n = 38). Cardiac MRP5 was assessed by quantitative polymerase chain reaction and immunofluorescence. The protein was localized in the endothelial wall, smooth muscle, and cardiac myocytes. MRP5 mRNA expression was significantly reduced compared with controls both in the LPS (31.9 +/- 16.8 x 10(-4) vs. 54.1 +/- 14.8 x 10(-4), P = 0.025) and CASP model (18.3 +/- 9.4 x 10(-4) vs. 42.8 +/- 12.1 x 10(-4), P = 0.009; MRP5/glyceraldehyde 3-phosphate dehydrogenase copy numbers, respectively). In parallel, IL-6 plasma levels were significantly increased in both models. Incubation of cultured murine cardiomyocytes (HL1) with 5 ng/mL IL-6 resulted in decreased expression of MRP5 (54% of control), as did incubation of the cells with serum from septic mice (LPS serum, 22% of control; CASP serum, 11% of control). In conclusion, cardiac expression of the cGMP export transporter MRP5 is decreased in two murine models of septic shock, most likely by a transcriptional mechanism. Reduced cGMP export as a consequence of decreased MRP5 expression can attenuate heart failure in sepsis.
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PMID:Sepsis affects cardiac expression of multidrug resistance protein 5 (MRP5, ABCC5), an ABC-type CGMP export pump. 1758 84

The concept of the heart as an endocrine organ has been attractive since the discovery of atrial natriuretic peptide. This review focuses on the second discovered natriuretic peptide from the heart - B-type natriuretic peptide (BNP), widely used as a tool in the diagnosis of heart failure (HF). Controversy remains regarding its use as a therapeutic agent in HF. This article places into perspective some of the debate and provides insights into the therapeutics of BNP and the importance of its second messenger 3'5' cyclic guanosine monophosphate, which also is the second messenger for nitric oxide and is modulated by renal phosphodiesterases.
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PMID:B-type natriuretic peptide: beyond a diagnostic. 1876 Jul 56

Treatment of heart failure (HF) is a challenging task. An impaired nitric oxide pathway contributes to several abnormal cardiac and vascular phenotypes typical of the failing cardiovascular system. Inhibition of phosphodiesterase-5 (PDE5) is a new therapeutic strategy for overexpressing nitric oxide signaling by increasing the availability of cyclic guanosine monophosphate (cGMP). A number of background studies support the use of PDE5 inhibitors in HF. Treatment of pulmonary hypertension secondary to left ventricular dysfunction appears to be a primary target by virtue of the high PDE5 selectivity for the pulmonary circulation. Basic studies suggest that increased cGMP activity by PDE5 inhibition has potentially favorable direct myocardial effects that may block adrenergic, hypertrophic, and proapoptotic signaling. Furthermore, studies in humans have underscored the benefits of acute PDE5 inhibition on lung diffusion capacity, systemic endothelial function, muscle perfusion, and exercise performance. Despite promising initial data, larger controlled trials are necessary to define the safety, tolerability, and potential impact of PDE5 inhibitors on morbidity and mortality across the wide spectrum of patients with HF.
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PMID:Sildenafil and phosphodiesterase-5 inhibitors for heart failure. 1876 82

Preclinical data indicate that the nitric oxide-independent soluble guanylate cyclase activator cinaciguat (BAY 58-2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy-six healthy volunteers were included in this randomized, placebo-controlled study. Cinaciguat (50-250 microg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four-hour infusions (50-250 microg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150-250 microg/h), 4-hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose-proportionality with low interindividual variability. Plasma concentrations declined below 1.0 microg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.
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PMID:Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers. 1877 78

Cyclic guanosine 3', 5'-monophosphate (cGMP) plays an integral role in the control of vascular function. Generated from guanylate cyclases in response to the endogenous ligands, nitric oxide (NO) and natriuretic peptides (NPs), cGMP influences a number of vascular cell types and regulates vasomotor tone, endothelial permeability, cell growth and differentiation, as well as platelet and blood cell interactions. Reciprocal regulation of the NO-cGMP and NP-cGMP pathways is evident in the vasculature such that one cGMP generating system may compensate for the dysfunction of the other. Indeed, aberrant cGMP production and/or signalling accompanies many vascular disorders such as hypertension, atherosclerosis, coronary artery disease and diabetic complications. This chapter highlights the main vascular functions of cGMP, its role in disease and the resulting current and potential therapeutic applications. With respect to pulmonary hypertension, heart failure and erectile dysfunction, as well as cGMP signal transduction, the reader is specifically referred to other dedicated chapters.
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PMID:cGMP in the vasculature. 1908 40

Heart failure (HF) is a common disease that continues to be associated with high morbidity and mortality warranting novel therapeutic strategies. Cyclic guanosine monophosphate (cGMP) is the second messenger of several important signaling pathways based on distinct guanylate cyclases (GCs) in the cardiovascular system. Both the nitric oxide/soluble GC (NO/sGC) as well as the natriuretic peptide/GC-A (NP/GC-A) systems are disordered in HF, providing a rationale for their therapeutic augmentation. Soluble GC activation with conventional nitrovasodilators has been used for more than a century but is associated with cGMP-independent actions and the development of tolerance, actions which novel NO-independent sGC activators now in clinical development lack. Activation of GC-A by administration of naturally occurring or designer natriuretic peptides is an emerging field, as is the inhibition of enzymes that degrade endogenous NPs. Finally, inhibition of cGMP-degrading phosphodiesterases, particularly phosphodiesterase 5 provides an additional strategy to augment cGMP-signaling.
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PMID:Modulation of cGMP in heart failure: a new therapeutic paradigm. 1908 42

Drugs that inhibit cyclic nucleotide phosphodiesterase activity act to increase intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content. In total, 11 families of these enzymes-which differ with respect to affinity for cAMP and cGMP, cellular expression, intracellular localization, and mechanisms of regulation-have been identified. Inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases raise intracellular cAMP content in cardiac and vascular smooth muscle, with inotropic and, to a lesser extent, vasodilatory actions. These drugs have been used for many years in the treatment of patients with heart failure, but their long-term use has generally been shown to increase mortality through mechanisms that remain unclear. More recently, inhibitors of PDE5 cyclic nucleotide phosphodiesterases have been used as cGMP-raising agents in vascular smooth muscle. With respect to cardiovascular disease, there is evidence that these drugs are more efficacious in the pulmonary than in the systemic vasculature, for which reason they are used principally in patients with pulmonary hypertension. Effects attributable to inhibition of myocardial PDE5 activity are less well characterized. New information indicating that enzymes from the PDE1 family of cyclic nucleotide phosphodiesterases constitute the majority of cAMP- and cGMP-hydrolytic activity in human myocardium raises questions as to their role in regulating these signaling pathways in heart failure.
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PMID:Phosphodiesterase inhibition in heart failure. 1909 31

B-type natriuretic peptide (BNP) has emerged as a reliable biomarker in patients with congestive heart failure. The mature, biologically active B-type natriuretic peptide, BNP(1-32), is cleaved by corin from the 108 amino acid proBNP. However, in vivo as well as in vitro data demonstrated that this BNP(1-32) might be an ideal substrate for the endogenous aminopeptidase, dipeptidyl-peptidase IV (DPP IV). DPP IV removes the two amino terminal amino acids (Ser Pro) from BNP(1-32) to produce BNP(3-32), which has been detected in plasma of patients with congestive heart failure. The biological effects of BNP(3-32) remain undetermined. In cultured human cardiomyocytes and fibroblasts, equimolar concentrations of BNP(1-32) and BNP(3-32) both exert similar biological effects, as evidenced by their cGMP (cyclic guanylate monophosphate) generating capacity. However, in a canine model, intravenous BNP(3-32) infusion resulted in less natriuresis, diuresis, and vasodilation compared to intravenous infusion of BNP(1-32). The clinical relevance of these observations might be important for patients in whom the plasma BNP concentrations, measured by commercially available immunoassays, are high. Further studies exploring whether DPP IV inhibitors increase the bioavailability of BNP(1-32), delay the progression of heart failure, and increase the efficacy of exogenous administration of BNP(1-32) in decompensated heart failure are needed.
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PMID:Dipeptidyl-peptidase IV and B-type natriuretic peptide. From bench to bedside. 1932 4

Phosphodiesterase 5 (PDE5) selectively hydrolyzes cyclic guanosine monophosphate. Inhibitors of PDE5 were originally developed to treat angina pectoris, and currently have multiple therapeutic indications, including erectile dysfunction and pulmonary hypertension. Several lines of research have provided evidence to support various potential PDE5-dependent cellular mechanisms in the myocardium that are involved in the pathophysiology of heart failure and cardiac dysfunction. In this Review we provide a mechanistic overview of the pharmacological inhibition of PDE5 in the context of heart failure, and evaluate the evidence supporting the use of novel PDE5 inhibitors in the treatment of this condition.
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PMID:Phosphodiesterase 5 inhibition in heart failure: mechanisms and clinical implications. 1937 97


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