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)

Primary pulmonary hypertension (PPH) is a rare but life-threatening disease. Median survival, from the time of diagnosis, is considered to be 2.8 years. However, therapeutic medical advances over the past 2 decades have resulted in significant improvements in quality of life and survival in patients with PPH. Because pulmonary vasoconstriction, endothelial cell proliferation, smooth muscle cell proliferation, and in situ thrombosis contribute to the development of this disease, treatment with vasodilators, anti-proliferative agents, and anticoagulants is recommended.Currently, oral administration of calcium channel antagonists and intravenous infusion of epoprostenol (prostacyclin) are established as treatment of PPH. Epoprostenol has vasoprotective effects including vasodilation, anti-platelet aggregation, and inhibition of smooth muscle cell proliferation. Interestingly, prostacyclin synthase deficiency in the lungs, and impaired prostacyclin production, have been linked to the development of pulmonary hypertension in this disease. As a result, continuous intravenous infusion of epoprostenol has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with PPH. The dramatic success of long-term intravenous prostacyclin is now leading to the development of epoprostenol analogs using newer drug delivery systems (oral beraprost, aerosolized iloprost, and subcutaneous treprostinil). In addition, promising drugs including endothelin antagonists and type V phosphodiesterase inhibitors have recently been developed. Furthermore, gene therapy with endothelial nitric oxide synthase gene or prostacyclin synthase gene may hold great promise in the treatment of PPH. Finally, accurate evaluation of disease severity and the efficacy of vasodilator therapy are important in the management of patients with PPH. In addition to invasive assessment by cardiac catheterization, we recommend repeated measurements of plasma brain natriuretic peptide, serum uric acid, and the distance walked in 6 minutes. These noninvasive parameters may be helpful as part of the evaluation of treatment in patients with PPH and, in particular, as a guide to the selection and timing for alternative therapies.
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PMID:Drug therapy of primary pulmonary hypertension. 1504 20

Activation of the intracellular cAMP-signaling pathway by either forskolin or the cAMP-mimetic dibutyryl cAMP significantly increased transcript levels of NPR-C in primary cultures of human aortic smooth muscle cells. The time course of the increase was rapid, with significant differences from control occurring within 3 h of treatment and reaching approximately 6 times control value after 24 h of exposure to 10 microM forskolin. Expression levels of the natriuretic peptide receptor B (NPR-B), but not the natriruetic peptide receptor A (NPR-A) were also increased by forskolin, rising to a level of approximately 2 times control at 96 h. NPR-B transcript levels in the presence of dibutyryl cAMP were unaltered by the protein kinase A (PKA) inhibitor KT-5720, suggesting a PKA-independent pathway to NPR-B up-regulation. In contrast, KT-5720 reduced NPR-C transcript to a lower level that was not significantly different from control. Partial re-differentiation of AOSMC by culture in growth factor-reduced matrix (Matrigel) did not significantly change NPR-C transcript levels compared with cells grown on plastic, and the dibutyryl cAMP-induced increase in NPR-C (approximately eight-nine-fold control value) was retained. The dibutyryl cAMP/forskolin effect on NPR-C transcript was not reproduced by the beta2-selective adrenergic agonist isoproterenol (10 microM), but was replicated by incubation with the phosphodiesterase inhibitor isobutylmethylxanthine (0.5 mM). Up-regulated NPR-B and NPR-C transcript levels were reflected, respectively, in a two-fold increase in CNP-stimulated cGMP and an increase in 125I-ANF binding competed by the NPR-C-specific natriuretic peptide, C-ANF(4-23) following a 4-day treatment with 0.125 mM dbcAMP. The present data suggest that elevation of cAMP in human vascular smooth muscle may potentiate the vasoactive effects of natriuretic peptides acting through the NPR-B and NPR-C receptors.
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PMID:Cyclic adenosine monophosphate (cAMP) increases natriuretic peptide receptor C (NPR-C) expression in human aortic smooth muscle cells. 1514 37

Most effects of the signaling molecule nitric oxide (NO) are mediated by the stimulation of NO-sensitive guanylyl cyclase (GC) and the subsequent intracellular increase in cGMP. Two isoforms of NO-sensitive GC have been identified to date that share regulatory properties but differ in their subcellular localization; the more ubiquitously expressed alpha1beta1 heterodimer, and the alpha2beta1 isoform mainly expressed in brain. New activators of NO-sensitive GC have been identified which may have beneficial pharmacological effects in cardiovascular diseases. In intact cells, NO-induced cGMP signaling not only depends on cGMP formation but is also critically determined by the activity of the enzyme responsible for cGMP degradation, e.g. phosphodiesterase 5 (PDE5). Sustained activation of PDE5 by cGMP has been identified as the mechanism responsible for the recently observed feedback inhibition within NO/cGMP signaling. Moreover, tuning of PDE5 activity may also represent a regulatory link to mediate cross talk between NO-induced and natriuretic peptide-induced cGMP signaling in general.
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PMID:NO-sensitive guanylyl cyclase and NO-induced feedback inhibition in cGMP signaling. 1576 23

Cyclic guanosine-3', 5'-monophosphate (cGMP)-dependent protein kinases (cGKs) are key enzymes of nitric oxide-cGMP and natriuretic peptide signalling cascades. These kinases mediate most of the effects of cGMP-elevating drugs, such as nitrates and phosphodiesterase inhibitors. cGKs modulate smooth muscle relaxation (e.g. the vasculature, gastrointestinal tract, bladder and penile), platelet aggregation, renin release, intestinal secretion, learning and memory. Furthermore, several cGK substrates have been identified. Isozyme-specific inhibitors and activators of cGK and its downstream substrates might act more specifically than upstream signalling activators, such as organic nitrates and phosphodiesterase inhibitors.
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PMID:cGMP-dependent protein kinases in drug discovery. 1589 27

Natriuretic peptides (NP) and the corresponding receptors are present in the rodent spinal cord. We have studied the structures which respond to atrial natriuretic peptide, brain natriuretic peptide, or C-type natriuretic peptide with an increased synthesis of cGMP. NP-responsive cGMP-producing structures were observed in laminae I-III, and X, and in addition in ependymal cells, astrocytes and a subpopulation of dorsal root ganglion cells. As the cGMP concentration is controlled by the rate of synthesis and the rate of breakdown by phosphodiesterases, we studied NP-responsive structures in spinal cord slices incubated in the presence of different phosphodiesterase inhibitors. We studied EHNA and BAY 60-7550 as selective PDE2 inhibitors, sildenafil as a selective PDE5 inhibitors, dipyridamole as a mixed type PDE5 and PDE10 inhibitor, rolipram as a PDE4 inhibitor, and SCH 81566 as a selective PDE9 inhibitor. Double immunostainings showed that cGMP-IR colocalized partial with the vesicular acetylcholine transporter molecule in lamina X, with Substance P in a subpopulation of neuronal fibers situated dorsolateral, and with a subpopulation of CGRP-IR dorsal root ganglion neurons. Colocalization of cGMP-IR was absent with parvalbumin, synaptophysin, and the vesicular transporter molecules for GABA and glutamate. It is concluded that NPs in the spinal cord are probably involved in integrating intersegmental sensory processing in the spinal cord although the greater part of the NP-responsive cGMP-producing fibers could not be characterized. PDE2, 5, and 9 are involved in regulating NP-stimulated cGMP levels in the spinal cord. NPs may have a role in regulating cerebrospinal fluid homeostasis.
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PMID:ANP-mediated cGMP signaling and phosphodiesterase inhibition in the rat cervical spinal cord. 1662 44

The phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, has been reported to produce sustained pulmonary vasodilatation in patients with pulmonary hypertension (PH). Recently, vardenafil, a more potent and selective PDE-5 inhibitor than sildenafil, has been approved for the treatment of erectile dysfunction. However, the long-term effects of oral vardenafil in patients with PH are unknown. We studied five consecutive patients with PH; one with primary pulmonary hypertension, two with chronic pulmonary thromboembolism, one with Eisenmenger syndrome (ventricular septal defect) and one with secondary pulmonary hypertension after a ventricular septal defect closure operation. In an acute hemodynamic trial, vardenafil (5 mg) significantly decreased both the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) with an increase in cardiac output. In a chronic hemodynamic trial, the maintenance dose of vardenafil (10 to 15 mg) for 3 months significantly decreased the PVR, but not the SVR, with a 20.7% reduction of the PVR/ SVR ratio. Plasma brain natriuretic peptide (BNP) levels were also significantly decreased after 3 months. This pilot study demonstrates that long-term oral vardenafil therapy may be a safe and effective treatment for patients with PH.
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PMID:Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension. 1675 46

Pharmacologic support of the failing neonatal heart to maintain cardiac output, which is vital for sufficient end organ perfusion, is a challenging task for the pediatric intensivist, especially since strategies which have been proven to be effective in adults cannot necessarily be extrapolated to neonates. The unique biochemical properties and structure of the neonatal heart, including the increased non-contractile tissue mass, a lower responsiveness to beta adrenergic agents and the heart rate dependent cardiac output with a limited ability to increase stroke volume, favor some of the new inotropes of the Ca+ sensitizer family. Focusing on the after load reduction, inodilators as phosphodiesterase inhibitors and human brain natriuretic peptide offer treatment options for the neonatal myocardium. Additionally, thyroxine and steroids have been investigated in neonates with low cardiac output after surgery for congenital heart disease. Gene therapy, in particular cardiac-selective gene transfer, might offer perspectives for future support for the neonatal heart. This text reviews some of the most recent pharmacologic strategies targeting the failing myocardium in the critically ill newborn and infant.
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PMID:New inotropic pharmacologic strategies targeting the failing myocardium in the newborn and infant. 1684 28

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

Idiopathic pulmonary arterial hypertension is a disease involving small muscular pulmonary arteries and arterioles. Treatment with prostacyclin analogs and endothelin receptor antagonists is the cornerstone of therapy in these patients. Recent evidence suggests that phosphodiesterase-5 inhibitors such as sildenafil may improve functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Despite these advances, pulmonary arterial hypertension remains a deadly and progressive disease and it has been suggested that combination therapy aimed at multiple targets may produce a greater improvement while minimizing adverse effects. We report three patients who declined after initial improvement on bosentan and subsequently showed an improvement in their functional capacity and brain natriuretic peptide (BNP) with the addition of sildenafil. This benefit has been sustained over a mean follow-up period of 19 (range 12-24) months.
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PMID:Long-term results after addition of sildenafil in idiopathic PAH patients on bosentan. 1692 86

Survival rates in pulmonary arterial hypertension (PAH) associated with rheumatic diseases, in particular connective tissue diseases such as systemic sclerosis, are even lower than in idiopathic PAH. These low survival rates highlight the need for early diagnosis and treatment in these patients. Transthoracic Doppler-echocardiography is most often used for diagnostic screening of patients at risk. Other screening tests are serum pro-brain-natriuretic peptide (pro-BNP) and diffusion capacity for carbon monoxide (DLCO), which appear to be changed early in the course of the PAH associated with connective tissue diseases. The diagnosis needs to be confirmed by right heart catheterization, which is recommended in all patients with suspected PAH. Besides the conventional background therapy, a number of specific therapies have been evaluated in randomized controlled trials in the recent years. These therapies include prostacyclins and prostacyclin analogues, endothelin-receptor antagonists and phosphodiesterase-5 inhibitors. Response to treatment can be measured by exercise capacity (e.g. 6 min walk distance) and pro-BNP, although certain aspects of validation for these outcome measures are lacking in PAH associated with connective tissue diseases.
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PMID:Pulmonary arterial hypertension and rheumatic diseases--from diagnosis to treatment. 1698 Jul 19


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