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)

Nitric oxide is a key intercellular messenger in the human and animal bodies. The identification of nitric oxide (NO) as the endothelium-derived relaxing factor (EDRF) has driven an enormous effort to further elucidate the chemistry, biology and therapeutic actions of this important molecule. It has found that nitric oxide is involved in many disease states such as such as chronic heart failure, stroke, impotent (erectile dysfunction). The bioactivity of nitric oxide intrinsically linked to its diffusion from its site production to the sites of action. Accurate reliable in real time detection of NO in various biological systems is therefore crucial to understanding its biological role. However, the instability of NO in aqueous solution and its high reactivity with other molecules can cause difficulties for its measurement depending on the detection method employed. Although a variety of methods have been described to measure NO in aqueous environments, it is now generally accepted that electrochemical (amperometric) detection using NO-specific electrodes is the most reliable and sensitive technique available for real-time in situ detection of NO. In 1992 the first commercial NO electrode-based amperometric detection system was developed by WPI. The system has been used successfully for a number of years in a wide range of research applications, both in vitro and in vivo. Recently, many new electrochemical nitric sensors have been invented and commercialized. Here we describe some of the background principles in NO sensors design, methodology and their applications.
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PMID:Real time and in vivo monitoring of nitric oxide by electrochemical sensors--from dream to reality. 1535 68

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.
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PMID:Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. 1566 7

Erectile dysfunction (ED) increases in prevalence and severity because of aging processes and related organic, iatrogenic and social problems. Decline of testosterone (T) levels is observed with age and also in illnesses with a common basis of endothelial damage. The T deficiency may lead to decreased energy, mood depression, reduction of sexual desire, but no correlation has been reported between T level and severity of ED, which is mainly a neurovascular disease. In facts, inhibition of phosphodiesterase type 5 (PDE5) isoenzyme with sildenafil, tadalafil and vardenafil enhances vasodilatation in the corpus cavernosum and subsequent penile erection. Absolute pharmacological potency of PDE5 inhibitors is similar and non-selectivity defines the side-effects profile, while their elimination half-life explains not only the different duration of action, but also short and long-term tolerability. Efficacy of PDE5 inhibitors in younger patients is greater in respect to older subjects because of associated pathologies and the decline in hypothalamic-pituitary-gonadal function. T is essential in erectile function, controlling the expression and activity of PDE5 and therefore, androgen supplementation improves therapeutic response to PDE5 inhibitors in hypogonadal subjects. Since sexual behavior is a complex interplay of physical, psychological, and social factors, the possible effect of these drugs on androgen levels and brain function need to be deeply investigated. The ubiquitarious distribution of PDE5 and the availability of selective inhibitory molecules foster newer studies in the treatment of heart failure, pulmonary hypertension, inflammation, and depression. This new progress is certainly contributing to a better medical approach to sexuality and quality of life in aging people.
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PMID:New achievement and novel therapeutic applications of PDE5 inhibithors in older males. 1604 60

Patients with congestive heart failure (CHF) have specific factors that enhance the risk for erectile dysfunction (ED), such as low cardiac output and the use of drugs with vasodilator effect. ED can negatively affect interpersonal relationships and self-esteem, with significant impact on the quality of life. We hypothesized that the improvement of the sexual dysfunction would enhance the quality of life of individuals with systolic heart failure. This is a prospective study of 12 male CHF patients using a fixed dose of sildenafil during 1 month. Patients were included if they had left ventricular ejection fraction lower than 40% documented by echocardiography and International Index of Erectile Function (IIEF) score lower than 21. The effect of sildenafil in quality of life was evaluated by the Minnesota questionnaire. Improvement in ED was assessed using the IIEF. The mean IIEF5 score was 9.6 (+/-3.8) before the use of sildenafil and 19.3 (+/-4.3) after sildenafil (P = 0.0001). The mean Minnesota score was 28.75 (+/-21) before treatment and 12.75 (+/-10.1) after the intervention (P = 0.012). In conclusion, the sexual function improvement provided by sildenafil enhances quality of life in individuals with systolic heart failure.
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PMID:Sildenafil improves quality of life in men with heart failure and erectile dysfunction. 1612 Dec 7

Sildenafil is rarely used in patients with heart failure despite a high prevalence of erectile dysfunction, and the theoretic possibility that by increasing nitric oxide availability, it may improve left ventricular (LV) load and performance. This study aimed to determine the peak effects of sildenafil on LV load and performance in patients with heart failure caused by systolic LV dysfunction. Twenty patients with controlled LV failure and ejection fractions <35% received sildenafil 50 mg or a matching placebo when not receiving regular medication for > or =12 hours, in a randomized, placebo-controlled, double-blind, 2-way crossover fashion. Cardiac output was measured by Doppler echocardiography. The aortic pressure waveform was determined using generalized transfer function from radial artery applanation tonometry. Aortic and femoral arterial stiffness was determined as carotid-femoral and femoral-pedal pulse-wave velocity (PWV); wave reflection was measured as an augmentation index (AIx). Cardiac index increased significantly (by 0.37 L/min.m(2), p <0.0001), with the peak effect 60 minutes after sildenafil administration. Compared with the baseline value, total systemic resistance showed a reduction of 479 dynes.s.cm(-5) (p <0.0001). Aortic and lower limb PWV decreased significantly (by 0.89 and 1.14 m/s, respectively, p <0.0001 for both), as did AIx (by 3.6% absolute, p <0.0001); these remained significant after adjustment for mean pressure and heart rate changes. In conclusion, sildenafil improves cardiac performance because of a decrease in LV load, which is caused by decreases in peripheral resistance, in aortic and large artery stiffness, and in wave reflection from peripheral sites. This can explain the increase in cardiac output and in exercise capacity with sildenafil in patients with heart failure.
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PMID:Effect of sildenafil on cardiac performance in patients with heart failure. 1627 94

Phosphodiesterase 5 (PDE5) inhibitors have modest nitrate-like hemodynamic effects, lowering wedge pressure, pulmonary artery pressure, and systolic and diastolic arterial pressure. At rest, decreases in arterial pressure averaging 9/8 mm Hg may increase to 12/5 mm Hg as a result of the vasodilatory response, but no clinical adverse effects have been reported. On the background of increased vasoconstriction related to elevation of angiotensin II, a greater decrease may occur and be relevant to cardiovascular therapy, particularly if angiotensin II antagonists are coprescribed. Exercise studies in patients with ischemia identified no adverse event potential for sildenafil, vardenafil, and tadalafil. Another study showed sildenafil had an anti-ischemic effect, increasing time to limiting angina. Evidence supports the safety of these agents in patients with chronic stable coronary artery disease (CAD). With accumulating evidence of benefits on endothelial function and clinical improvements in pulmonary hypertension and heart failure, the hemodynamic and exercise effects of PDE5 inhibitors suggest an important therapeutic cardiovascular role, reinforcing their safety in the patient with CAD and erectile dysfunction.
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PMID:Hemodynamic and exercise effects of phosphodiesterase 5 inhibitors. 1638 64

Erectile dysfunction (ED) is highly prevalent in patients with chronic heart failure (CHF) and is among the most distressing symptoms in this patient population. Although the safety and efficacy of phosphodiesterase 5 (PDE5) inhibitors in the management of ED have been evaluated in many cardiovascular disease populations, scant data are available in patients with CHF. In published studies, the short-term safety and efficacy of sildenafil in patients with stable mild-to-moderate CHF with ED appears to be comparable to that observed in other populations with cardiovascular disease. Evidence is not available on the effects of vardenafil or tadalafil in CHF. In addition to their benefits in the treatment of ED, preliminary studies suggest that PDE5 inhibitors enhance endothelial function in patients with CHF and have beneficial effects on pulmonary hemodynamics and exercise capacity in patients with pulmonary hypertension. Additional studies are needed to determine the therapeutic potential of this class of agents in these disease states.
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PMID:Phosphodiesterase 5 inhibition in chronic heart failure and pulmonary hypertension. 1638 67

Erectile dysfunction (ED) is a highly prevalent and increasingly common, mainly vascular disorder. Most patients with chronic cardiovascular diseases experience decreased libido and frequency of sexual activity, as well as ED. Some unique organic and psychological factors contributing to ED have been identified in patients with underlying cardiovascular problems. Certain risk factors are common to the development of coronary artery disease, heart failure and ED, including diabetes mellitus, hypertension, smoking and dyslipidemia. Additionally, the use of medications such as beta blockers, digoxin and thiazide diuretics might eventually cause but more likely worsen sexual dysfunction. These unintended consequences can lead to medical noncompliance in misguided efforts to retain satisfactory sexual activity, and thereby worsen cardiovascular problems. Accordingly, it is important for physicians dealing with patients with cardiovascular diseases to address sexual concerns in their patients. After careful evaluation, most patients with stable cardiac disorders can resume sexual activity and/or can be treated for ED.
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PMID:Sex and the heart. 1639 42

Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n = 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n = 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 microg/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 +/- 2 versus 21 +/- 3 pmol/ml; P < 0.05) and urinary cGMP (4219 +/- 900 versus 1954 +/- 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 +/- 6 to 45 +/- 6 ml/min; P < 0.05) and that was not observed in group 2 (25 +/- 6 to 29 +/- 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 +/- 900 to 8600 +/- 1600 pmol/min; P < 0.05) as compared with group 2 (1954 +/- 300 to 3580 +/- 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.
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PMID:Maximizing the renal cyclic 3'-5'-guanosine monophosphate system with type V phosphodiesterase inhibition and exogenous natriuretic peptide: a novel strategy to improve renal function in experimental overt heart failure. 1692 3

Conventional drug screening has been targeted, in many cases, on cell surface receptors, e.g., G-Protein coupled receptors, to regulate cellular signaling and thus function. There is emerging evidence, however, that such targets can be expanded to effector enzymes of receptors because effector enzymes have multiple subtypes that differ in tissue distribution, and thus targeting such molecules may lead to organ-specific pharmacological regulation. An example is phosphodiesterase, which degrades cyclic nucleotides. Subtype-specific phosphodiesterase inhibitors, such as sildenafil citrate, a type 5 phosphodiesterase inhibitor, and milrinone, a type 3 phosphodiesterase inhibitor, are now widely used in the treatment of erectile dysfunction and heart failure, respectively. Adenylyl cyclase, which synthesizes cyclic AMP, has at least 9 isoforms that differ in tissue distribution. Transgenic mouse studies utilizing such isoforms have identified the roles of each isoform. Forskolin, a natural plant extract, was first identified as a general stimulator of adenylyl cyclase more than 20 years ago. Recently, 6-[3-(dimethylamino)propionyl]forskolin, a water-soluble forskolin derivative with high selectivity for type 5 (cardiac) adenylyl cyclase was developed and has been widely used in the treatment of acute heart failure. Adenine analogs or P-site inhibitors, which are classic, but not isoform-specific adenylyl cyclase inhibitors, are now utilized to develop isoform-specific inhibitors as well. Putting together, targeting adenylyl cyclase isoforms, either of isoform-specific stimulation or inhibition, may be a novel strategy to develop new drugs in the next decade.
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PMID:Drug therapy aimed at adenylyl cyclase to regulate cyclic nucleotide signaling. 1701 75


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