Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mendelian forms of hypertension have delivered a treasure trove of novel genes. To date, the molecular mechanisms of five such syndromes have been largely clarified, including glucocorticoid-remediable aldosteronism, Liddle's syndrome, apparent mineralocorticoid excess, an activating mutation of the mineralocorticoid receptor, and pseudohypoaldosteronism type 2. Each of these conditions features salt sensitivity with increased sodium and volume reabsorption by the kidney and low plasma renin activity. None of the gene loci for these syndromes has been convincingly linked to hypertension in the general population. We are investigating kindreds who have autosomal-dominant hypertension and brachydactyly. Affected persons invariably have both anomalies. The hypertension is severe and results in death at about age 50 years from stroke. The condition resembles essential hypertension, because renin, aldosterone, and norepinephrine responses are normal and no salt sensitivity is present. The response to antihypertensive drugs is general. Another feature is diminished baroreflex sensitivity with markedly impaired blood pressure buffering. Furthermore, the ventrolateral medulla may be compromised in these patients, because neurovascular anomalies are a regular finding. We mapped the gene(s) for this disease to chromosome 12p and narrowed the chromosomal region by studying more affected families. Interestingly, the same locus was recently mapped in Chinese families with essential hypertension. Our 3-centimorgan region contains genes encoding a phosphodiesterase, an ATP-dependent potassium channel, and its regulator the sulfonylurea receptor 2. Screening of the coding regions revealed that none of these candidate genes harbor obvious mutations; however, other genetic mechanisms may nevertheless compromise their function. Our study underscores the importance of regulatory physiology to the understanding of a complex genetic syndrome.
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PMID:Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology. 1295 13

In the present study, we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind. placebo-controlled crossover study. Diuretics were withdrawn, and a fixed sodium diet (100 mmol/day) was given to the patients for 5 days before both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by 99mTc-diethylenetriamine-pentaacetate and (131)I-hippuran clearances. In human nephrectomy specimens, PDE5 mRNA was expressed at similar levels in the cortex (n = 6) and inner medulla (n = 4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II, and aldosterone that did not differ on the 2 study days. Basal sodium excretion was similar at the 2 study days (median 17 and 18 mmol, respectively), and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma ANG II, and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min, and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 and 180 min. Plasma ANP concentration, GFR, and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.
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PMID:Inhibition of cGMP-specific phosphodiesterase type 5 reduces sodium excretion and arterial blood pressure in patients with NaCl retention and ascites. 1561 22

The ability of aldosterone to stimulate Na+ transport in a range of epithelial tissues has been known for many years. Early work suggested that aldosterone had a delayed action operating by transcriptional up-regulation of proteins such as the epithelial Na+ channel. However more recent data has suggested that the hormone has a short-term non-genomic action. In this paper we investigate short and long-term actions of aldosterone on Na+ transport in the rabbit urinary bladder. We have shown that aldosterone stimulates epithelial Na+ channel activity, as measured by the amiloride-sensitive short-circuit current over a 3.75 h period and that this action is potentiated by cAMP. Using reverse transcriptase-polymerase chain reaction we have shown that aldosterone and forskolin in combination up-regulate mRNA synthesis for the beta- and gamma-subunits of the epithelial Na+ channel. Using Western blotting we have shown in the case of the beta-subunit that a corresponding increase in channel protein occurs. We have also demonstrated that aldosterone in the presence of inhibitors of phosphodiesterase can stimulate the short-circuit current across rabbit bladder epithelium over a 20 min period. An explanation for the synergistic interaction between aldosterone and cAMP is provided. We have shown that aldosterone can increase cAMP levels within urothelial cells over a 4 min period. We propose that this represents a non-genomic action of the steroid hormone.
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PMID:Aldosterone stimulates active Na+ transport in rabbit urinary bladder by both genomic and non-genomic processes. 1576 41

Proteinuria (albuminuria) reflects dysfunction of the glomerular permeability barrier in which inflammatory cytokines play a key role. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses potent anti-inflammatory and immunomudulatory effects. This study evaluated the effectiveness of PTX to reduce proteinuria and inflammatory mediators in patients with proteinuric primary glomerular diseases. Seventeen patients with primary glomerular diseases, a persistent spot proteinuria exceeding 1.5 g/g creatinine (Cr) and a glomerular filtration rate between 24 and 115 ml/min/1.73 m(2) were treated with PTX 400 mg twice daily for 6 months. Before and after the treatment, serum Cr, plasma renin activity and aldosterone concentrations, plasma and urinary tumor necrosis factor (TNF)-alpha, interleukin-1beta and monocyte chemoattractant protein (MCP)-1, as well as urinary protein and Cr were measured. PTX significantly reduced urinary protein excretion, along with an increase of serum albumin. A significant correlation existed between the basal urinary protein/Cr and the basal urinary MCP-1/Cr ratios. PTX lowered the urinary MCP-1/Cr ratio, and the percent reduction of urinary protein/Cr ratio correlated directly with the precent decrease of urinary MCP-1/Cr ratio after PTX treatment. There was no significant change in blood pressure, renal function, biochemical parameters, plasma renin activity and aldosterone concentrations, or plasma TNF-alpha and MCP-1 levels during the study. In conclusion, administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion.
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PMID:Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. 1654 Oct 21

ACTH-stimulated aldosterone secretion can be inhibited by atrio-natriuretic peptide/cGMP. The mechanism behind this modulation has been reported to involve cGMP-dependent activation of phosphodiesterase 2 (PDE2) and hydrolysis of cAMP. Recently it was reported that activation of cGMP-dependent protein kinase II (cGKII) stimulated aldosterone secretion in rat zona glomerulosa cells. The zona glomerulosa of the murine adrenal cortex expresses cGKII and PDE2. We used mice with a homozygous inactivation of the cGKII gene to investigate in vivo the potential role of this kinase in aldosterone secretion. Basal plasma renin and aldosterone levels were similar in wild-type and cGKII(-/-) mice. In vivo injection of atrio-natriuretic peptide decreased ACTH-stimulated aldosterone secretion in wild-type mice, but had no effect in cGKII-deficient mice. These results support the view that cGKII modulates aldosterone secretion in the murine adrenal cortex.
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PMID:cGMP-dependent protein kinase II and aldosterone secretion. 1915 45

In spite of the advances in understanding the pathogenesis and approaches to the treatment of chronic heart failure, it remains one of the main causes of the patients invalidism and death, that makes the cardiologists all over the world develop new drugs for the treatment of the disease. The aim of the study was to show possible long-term use of enoximone, a new agent from the group of phosphodiesterase inhibitors, in doses of 75-150 mg a day in traditional combined pharmacotherapy of the patients with chronic heart failure. Thirty eight patients with chronic heart failure III-IV FC (NYHA) and 30% left ventrical efflux function were observed. The dynamics of the disease clinical signs, the heart hemodynamic and morphofunctional parameters, the heart bioelectric activity and the hospitalization frequency were investigated to estimate the therapy efficacy and safety. The use of enoximone in the traditional combined pharmacotherapy, including inhibitors of angiotensin-transforming enzymes, diuretics, beta-adrenoblockers and aldosterone antagonists, resulted in a reliable improvement as for the disease clinical signs, 17.8% increase of the left ventrical efflux function vs. the initial indices, less frequent hospitalization. The enoximone tolerability was good, no side effects requiring discontinuation of the drug use were recorded.
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PMID:[Potentialitis of phosphodiesterase inhibitors in management of patients with chronic heart failure complicating cardiac ischemia]. 1944 55

Cardiopulmonary exercise testing (CPX) is a well-recognized assessment technique in patients with HF. Ventilatory efficiency, aerobic capacity and heart rate recovery are several parameters obtained from CPX that accurately reflect physiologic function and provide robust prognostic information. Pharmacotherapy is a vital component to the management of patients with HF. Numerous pharmacologic interventions, such as ACE inhibition and beta-blockade have demonstrated significant physiologic and prognostic improvement in this population. Furthermore, a number of investigations demonstrating a positive change in the CPX response resulting from a pharmacologic intervention now exist. Because CPX variables reflect pathophysiologic processes differently, their response to a given pharmacologic is unique. For example, beta-blockade has been shown to significantly improve ventilatory efficiency, one of the most powerful prognostic markers obtained from CPX, while not altering aerobic capacity or heart rate recovery. Conversely, ACE and phosphodiesterase-5 inhibition appears to improve ventilatory efficiency and aerobic capacity. Given the prognostic value of CPX, gauging its improvement from pharmacotherapy may be advantageous in facilitating optimal titration of medications. A comprehensive review describing the physiologic and prognostic importance of CPX in the context of pharmacotherapy does not exist. This mini review will: 1. Identify key CPX variables obtained from CPX including aerobic capacity, ventilatory efficiency and heart rate recovery, 2. Describe the physiologic and prognostic significance of CPX in the heart failure population, and, 3. Summarize the present body of evidence addressing the change in CPX in response to different pharmacologic interventions including beta-blockade, renin-angiotensin-aldosterone axis inhibition and sildenafil.
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PMID:The impact of pharmacotherapy on the cardiopulmonary exercise test response in patients with heart failure: a mini review. 1948 8

Cilostazol (CILO), a selective inhibitor of phosphodiesterase 3 with potent antithrombotic property, has been shown to have a vasculoprotective effect in atherosclerosis animal models due to its potential anti-inflammatory and antioxidant actions. This study was undertaken to investigate whether CILO has in fact any vasculoprotective effects in aldosterone-induced hypertensive rats (Aldo-rats), and whether CILO affects Aldo-induced oxidative stress, nitric oxide (NO) production and pro-inflammatory gene expression. Treatment with CILO markedly ameliorated perivascular inflammatory changes in the coronary arterioles of Aldo-rats without affecting the systolic blood pressure and left ventricular weight. Treatment with CILO also prevented the increase in plasma levels of thiobarbituric acid-reactive substances, an oxidative stress marker, as well as decreased urinary NOx excretion in Aldo-rats. Furthermore, CILO almost completely inhibited a set of upregulated proinflammatory genes (ICAM-1, MCP-1, PDGF-A, osteopontin, MMP-2 and ACE), as well as NAD(P)H oxidase components (p22phox, gp91phox, p47phox) and Aldo-inducible genes (SGK-1 and NHE-1) in the aortic tissues from Aldo-rats. Taken together, this study showed for the first time that CILO prevented Aldo-induced vascular inflammation and injury without affecting the blood pressure, suggesting its vasculoprotective effect on Aldo-induced vascular injury independent of blood pressure.
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PMID:Vasculoprotective effect of cilostazol in aldosterone-induced hypertensive rats. 2001 1

The concept of modern medicine in treating chronic heart failure (CHF) has changed markedly in recent years. To improve the quality of life and prolong life, the treatment goal is no longer just temporary improvement of symptoms, more importantly, is to prevent and delay the occurrence and development of ventricular remodeling. Long-term chronic over-activation of sympathetic system, renin-angiotensin-aldosterone system and other neuroendocrine factors promotes myocardial remodeling, increases myocardial injury and deteriorates cardiac function. Despite short-term use can significantly improve the blood flow dynamics, long-term use of beta-adrenergic receptor stimulators and phosphodiesterase inhibitors does not prolong life, but increases the rate of sudden death caused by cardiac arrhythmia. Angiotensin converting enzyme inhibitors and beta-blockers have become the preferred drugs in treating chronic heart failure. In fact, after long-term use, beta-blockers can significantly improve ventricular remodeling, enhance ventricular function and reduce the incidence of sudden death of patients with CHF. In traditional Chinese medicine practice, short-term use of drugs for warming yang and reinforcing qi can improve symptoms of CHF, but long-term use may have adverse effects, for these medicines can stimulate sympathetic system. Early treatment with medicines of cold and cool property may be more favorable to patients with CHF, except the advanced patients who need special intervention. Eliminating heat and nourishing yin may play more active role in controlling the occurrence and development of CHF. Drugs with good efficacy and value in treating CHF may be developed from the Chinese herbal medicines with eliminating heat and nourishing yin property.
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PMID:[Progress in treatment of chronic heart failure in Western medicine and treatment strategies in traditional Chinese medicine]. 2008 51

The second messenger, cAMP, is one of the most important regulatory signals for control of steroidogenesis. This review focuses on current knowledge about regulation of cyclic nucleotides by phosphodiesterases (PDEs) in steroidogenic tissues. The first PDE known to directly regulate steroidogenesis was PDE2, the cGMP-stimulated PDE. PDE2 mediates ANP/cGMP-induced decreases in aldosterone production. Recently, the PDE8 family has been shown to control steroidogenesis in two tissues. Specifically, PDE8A regulates testosterone production by itself and in concert with additional IBMX-sensitive PDEs. PDE8B modulates basal corticosterone synthesis via acute and chronic mechanisms. In addition to cAMP-dependent pathways, cGMP signaling also can promote steroidogenesis, and PDE5 modulates this process. Finally, PDE mutations may lead to several human diseases characterized by abnormal steroid levels.
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PMID:The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis. 2196 40


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