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)

CD-NP is a novel chimeric natriuretic peptide (NP) consisting of the 22-amino-acid (AA) human C-type natriuretic peptide (CNP), a venodilating peptide with limited renal actions and minimal effects on blood pressure, and the 15-AA C-terminus of Dendroaspis NP (DNP). The rationale for the design of CD-NP was to enhance the renal actions of CNP, the ligand for natriuretic peptide receptor-B, but without inducing excessive hypotension. Here we report the first-in-human studies for CD-NP, which represent the first successful clinical testing of a chimeric NP demonstrating in normal human volunteers that CD-NP possesses cyclic guanosine monophosphate-activating, natriuretic, and aldosterone-suppressing properties without inducing excessive hypotension, laying the foundation for additional studies on this first-in-class new cardiovascular therapeutic in human heart failure, which are now underway worldwide.
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PMID:Pharmacodynamics of a novel designer natriuretic peptide, CD-NP, in a first-in-human clinical trial in healthy subjects. 1939 84

Sildenafil is a selective inhibitor of type 5 phosphodiesterase, the main phosphodiesterase isoform responsible for hydrolysis of intracellular cyclic guanosine monophosphate in the pulmonary vasculature. It improves exercise capacity and quality of life in patients with systolic heart failure, especially in those who develop secondary pulmonary hypertension. It improves peak oxygen consumption, reduces minute ventilation/carbon dioxide output slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with heart failure and pulmonary hypertension. It improves flow-mediated maximal dilatation, ergoreflex on ventilation, and breathlessness both after 3 and 6 months of treatment. Sildenafil, by improving endothelial activity and muscle perfusion, improves signaling and ventilatory efficiencies, potentially indicating a novel approach in the therapeutic management of heart failure.
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PMID:Treating heart failure with sildenafil. 1962 92

The effect of carperitide, recombinant human atrial natriuretic peptide, on chronic heart failure (HF) has not been clarified. We investigated the beneficial effects of chronic carperitide treatment in rats with HF after experimental autoimmune myocarditis. A 28-day infusion of carperitide (n = 14) or vehicle (n = 14) was administrated to the rats 4 weeks after experimental autoimmune myocarditis induction. After 4 weeks, the myocardial levels of cyclic guanosine monophosphate (cGMP), left ventricular function, myocyte hypertrophy, interstitial fibrosis, myocardial capillary vessel density, and activity of one prominent substrate of cGMP, vasodilator-stimulated phosphoprotein (VASP) that may enhance angiogenesis, were measured. Carperitide treatment increased the myocardial levels of cGMP and attenuated the functional severity along with a decreased myocyte cross-sectional area, interstitial fibrosis, and an increased capillary to myocyte ratio. Furthermore, carperitide treatment enhanced the phosphorylation of VASP at Ser239, which was preferentially phosphorylated by cGMP-dependent protein kinase but not Ser157, which was preferentially phosphorylated by cyclic adenosine monophosphate-dependent protein kinase. Long-term carperitide treatment attenuates ventricular remodeling and ameliorates the progression of chronic HF. The effects of carperitide treatment are associated with increased neovascularization among the residual myocytes and an increase of VASP activation.
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PMID:Long-term carperitide treatment attenuates left ventricular remodeling in rats with heart failure after autoimmune myocarditis. 1966 89

Phosphodiesterase type-5 (PDE5) inhibitors are widely used as first-line therapy for erectile dysfunction (ED). Their efficacy and safety combined with an increasing understanding of cyclic guanosine monophosphate (cGMP)-regulated mechanisms, have triggered a number of attempts to determine their effects and potential benefits in non-urological conditions. In recent years, extensive and diverse preclinical and clinical evidence has been made available. PDE5 inhibition has shown collateral benefits for a multitude of risk factors or diseases associated with, or accompanying ED. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension and both sildenafil and tadalafil are approved for this indication. However, PDE5 inhibitors appear to have the potential of further expanding their indications. Importantly, accumulating data show that the therapeutic potential extends to the cardiovascular, gastrointestinal, cutaneous and nervous system and that these agents may be beneficial in a multitude of conditions such as Raynaud's phenomenon, heart failure, essential hypertension and stroke. PDE5 inhibitors are a conceptually attractive therapeutic class of agents with pleiotropic effects. The present review discusses recent findings regarding the effects of PDE5 inhibitors on non-urological conditions and highlights current and future clinical applications beyond ED.
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PMID:PDE5 inhibitors in non-urological conditions. 1986 Jun 98

In development by Nile Therapeutics Inc, under license from the Mayo Foundation, CD-NP is a chimeric natriuretic peptide in which the 15-amino acid C-terminal tail of Dendroaspis natriuretic peptide is fused to the 22-amino acid human C-type natriuretic peptide. The rationale for its design was to create a peptide with the beneficial cardiovascular and renal effects of native natriuretic peptides, but without a clinically significant hypotensive response. CD-NP is able to bind to all three natriuretic peptide receptors (NPR-A, NPR-B and NPR-C) and, therefore, is unique in being able to increase cyclic guanosine monophosphate production downstream of both NPR-A and NPR-B. Animal studies and human trials demonstrated that CD-NP is safe and improves cardiovascular and renal function without inducing significant levels of hypotension. Preliminary data also suggest improved renal function in human heart failure patients. Ongoing clinical trials are needed to further validate CD-NP as an effective treatment option for heart failure.
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PMID:CD-NP, a chimeric natriuretic peptide for the treatment of heart failure. 2017 49

Elevations in the plasma concentrations of natriuretic peptides correlate with increased severity of myxomatous mitral valve disease (MMVD) in dogs. This study correlates the severity of MMVD with the plasma concentrations of the biomarkers N-terminal fragment of the pro-brain-natriuretic peptide (NT-proBNP) and its second messenger, cyclic guanosine monophosphate (cGMP). Furthermore, the L-arginine:asymmetric dimethylarginine (ADMA) ratio was measured as an index of nitric oxide availability. The study included 75 dogs sub-divided into five groups based on severity of MMVD as assessed by clinical examination and echocardiography. Plasma NT-proBNP and cGMP concentrations increased with increasing valve dysfunction and were significantly elevated in dogs with heart failure. The cGMP:NT-proBNP ratio decreased significantly in dogs with heart failure, suggesting the development of natriuretic peptide resistance. Although the l-arginine:ADMA ratio decreased with increasingly severe MMVD, this was largely due to the older age of the dogs with heart failure.
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PMID:Brain-natriuretic peptide and cyclic guanosine monophosphate as biomarkers of myxomatous mitral valve disease in dogs. 2082 39

Endothelial dysfunction associated with decreased nitric oxide (NO) bioactivity is a major feature of vascular diseases such as atherosclerosis or diabetes. Sodium nitroprusside (SNP)-induced relaxation is entirely dependent on cyclic guanosine monophosphate (cGMP) and preserved in atherosclerosis, suggesting that smooth muscle response to NO donor is intact. However, NO gas activates both cGMP-dependent and -independent signal pathways in vascular smooth muscle cells, and oxidative stress associated with vascular diseases selectively impairs cGMP-independent relaxation to NO. Sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), which regulates intracellular Ca(2+) levels by pumping Ca(2+) into store, is a major cGMP-independent target for NO. Physiological levels of reactive nitrogen species (RNS) S-glutathiolate SERCA at Cys674 to increase its activity, and the augmentation of RNS in vascular diseases irreversibly oxidizes Cys674 or nitrates tyrosine residues at Tyr296-Tyr297, which are associated with loss of function. S-glutathiolation of various proteins by NO can explain redox-sensitive cGMP-independent actions, and oxidative inactivation of target proteins for NO can be associated with the pathogenesis of cardiovascular diseases. Oxidative inactivation of SERCA is also implicated with dysregulation of smooth muscle migration, promotion of platelet aggregation, and impairment of cardiac function, which can be implicated with restenosis, pathological angiogenesis, thrombosis, as well as heart failure. Analysis of posttranslational oxidative modifications of SERCA and the preservation of SERCA function can be novel strategies against cardiovascular diseases associated with oxidative stress.
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PMID:Modulation of vascular sarco/endoplasmic reticulum calcium ATPase in cardiovascular pathophysiology. 2093 2

Heart failure (HF) remains a major cause of morbidity and mortality in the United States despite recent advances in its treatment. The nitric oxide -soluble guanylate cyclase (sGC)-cyclic 3', 5'-guanosine monophosphate pathway is a key signaling cascade involved in many physiologic processes. Derangements of the cascade may play an important role in the pathophysiology of HF and other diseases. Organic nitrates, which derive their action from their metabolic conversion to nitric oxide, exploit this pathway therapeutically. They are a mainstay of treatment for acute HF, but the development of tolerance with chronic administration limits their long-term efficacy. The development of a novel class of sGC activators has shown in both animal and preliminary clinical trials to improve hemodynamics without tolerance, while preserving renal function in patients with HF. A phase II clinical program using the sGC activator cinaciguat (BAY 58-2667) is now in progress in patients with symptomatic HF to further evaluate the efficacy and safety of this treatment approach.
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PMID:Soluble guanylate cyclase activation with cinaciguat: a new approach to the treatment of decompensated heart failure. 2113 99

Phosphodiesterase type 5 inhibitors increase the intracellular level of cyclic guanosine monophosphate that is a potent nitric oxide dependent vasodilatation and antiproliferation agent. Unlike vardenafil and tadalafil which are prescribed in the erectile dysfunction, sildenafil is also used in a treatment of the pulmonary arterial hypertension, both congenital and acquired. The drug administration may let to various side effects such epistaxis, headache, flushing, eye problem including blurry vision, retinal hemorrhage and nonarteritic anterior ischemic optic neuropathy. It may be also complicated by high reduction of blood pressure and syncope especially in patients concomitantly treated with oral nitrate medications. High caution should be also taken in patients with a heart failure.
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PMID:[Cardiovascular complications of phosphodiesterase-5 inhibitors]. 2154 85

Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are frequently encountered in patients with advanced heart failure (HF). Both conditions aggravate prognosis and influence clinical decisions. Echocardiography is the screening tool of choice for pulmonary pressures and RV function, although invasive assessment of PH is necessary when advanced therapies are considered. Reversibility of PH in response to short-term pharmacologic treatment or even to long-term unloading after left ventricular assist device (LVAD) implantation is a favorable prognostic sign for both medically treated patients and heart transplant candidates. Although patients with severe PH secondary to HF have not derived benefit from pulmonary arterial hypertension therapies thus far, agents that modulate the cyclic guanosine monophosphate pathway, including phosphodiesterase 5A inhibitors, hold promise and are being actively investigated in advanced HF. Therapies that lead to reduction in left-sided pressures, including cardiac resynchronization and LVAD placement, also have a favorable effect on pulmonary pressures and RV function. However, no specific medical treatment for RV dysfunction exists to date, highlighting an important gap in the management of patients with advanced HF.
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PMID:Pulmonary hypertension and right ventricular function in advanced heart failure. 2179 Sep 69


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