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

---

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

Cyclic AMP affects microvascular smooth muscle contraction and growth. Therefore, it is important to elucidate mechanisms regulating cyclic AMP production in microvascular smooth muscle. In this study, we determined whether several signal transduction pathways regulate receptor-induced cyclic AMP in isolated preglomerular microvessels and microvascular smooth muscle cells. Preglomerular microvessels were incubated with isoproterenol (beta-adrenoceptor agonist) and with and without U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), 1-butanol (phospholipase D inhibitor), CGP77675 (c-src inhibitor), HA1077 (Rho kinase inhibitor), Y27632 (Rho kinase inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), dipenyleneiodonium (NADPH oxidase inhibitor), or Tempol (superoxide dismutase mimetic). Cultured preglomerular microvascular smooth muscle cells were incubated with isoproterenol or forskolin (direct activator of adenylyl cyclase) and with or without U73122, C(2)-ceramide (phospholipase D inhibitor), or PP1 [src family inhibitor, 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine]. All studies were conducted with 3-isobutyl-1-methylxanthine (broad-spectrum phosphodiesterase inhibitor) to eliminate changes in cyclic AMP degradation. In microvessels isoproterenol-induced cyclic AMP was not affected by Y27632, HA1007, LY294002, dipenylene-iodonium, or Tempol; was increased by U73122 and GF109203X; and was decreased by 1-butanol and CGP77675. In cells, U73122 increased and C(2)-ceramide and PP1 decreased isoproterenol-induced cyclic AMP. Forskolin-induced cyclic AMP was not altered. These results indicate that receptor-mediated activation of adenylyl cyclase is 1) not modulated by Rho kinase, phosphatidylinositol-3-kinase, NADPH oxidase, or superoxide; 2) is attenuated by phospholipase C and protein kinase C; and 3) is augmented by phospholipase D and src. Phospholipase C, phospholipase D, and src modulate receptor-induced cyclic AMP by affecting beta-adrenoreceptor/G protein/adenylyl cyclase coupling rather than by directly affecting adenylyl cyclase activity.
...
PMID:Modulation of cyclic AMP production by signal transduction pathways in preglomerular microvessels and microvascular smooth muscle cells. 1508 74

Signaling molecules play a critical role in the pathophysiology of airway diseases. Recent evidence shows that cyclic ADP-ribose (cADPr), an endogenous activator of the ryanodine receptor channel in mammalian cells, modulates agonist-induced calcium responses in airway smooth muscle (ASM) cells. In addition, cADPr-mediated calcium release appears to play an important role in the "non-specific" increased ASM responsiveness to contractile agonists in cytokine-treated cells, a characteristic finding of asthma. Furthermore, other signaling molecules such as Rho/Rho kinase and phosphodiesterase also contribute to bronchial hyperresponsiveness. Thus, a better understanding of these signaling molecules that alter calcium signaling and contractility of ASM might provide new insight into novel therapeutic targets for the control of bronchial hyperresponsiveness.
...
PMID:Bronchial hyperresponsiveness: insights into new signaling molecules. 1514 Apr 13

Current research on the development of new medical treatments of erectile dysfunction (ED) fall essentially into two main types of approaches: (1) the traditional strategy based on compounds acting to induce an erection on demand, without modifying the underlying pathologic alterations that lead to ED; and (2) more novel agents not inducing an erectile response but aiming for a long-term correction of either the defect in cavernosal tissue integrity responsible for functional impairment, or the impairment per se of the cavernosal tissue function. In the first approach, new phosphodiesterase inhibitors (either more potent and specific than the clinically available ones or harboring nitric oxide-releasing structures), soluble guanylate cyclase activators, Rho kinase inhibitors, as well as centrally active agents stimulating hypothalamic dopamine or melanocortin receptors, combinations of different types of drugs, and new facilitators of tissue uptake of active agents, are being investigated and some may soon be applied clinically. In the second approach, the first type of correction comprises regulators of endogenous cell number and integrity and extracellular matrix turnover (inhibitors of apoptosis and fibrosis, neurotrophic and angiogenic factors), testosterone, and tissue and cell explants (nerve and smooth muscle grafting, adult pluripotent cells), whereas the second includes in vivo gene therapy with different genes and vectors, and ex vivo gene therapy, combining gene transfer with stem cell implants. This second approach requires extensive laboratory research prior to clinical translation but may provide a means to cure ED. The current status and future directions of these strategies are discussed.
...
PMID:Therapy of erectile dysfunction: potential future treatments. 1514 97

Inhibition of the type 5 phosphodiesterase and inhibition of Rho kinase are both effective in reducing pulmonary hypertension (PH). Here we investigate whether Rho kinase inhibition is involved in the beneficial effect of the type 5 phosphodiesterase inhibitor sildenafil on PH. Chronic hypoxia-induced PH in rats is associated with an increase in RhoA activity in pulmonary artery that was maximal after 2 days (10.7+/-0.9-fold increase, n=6, P<0.001). The activity of Rho kinase assessed by measuring the level of myosin phosphatase target subunit 1 (MYPT1) phosphorylation was also increased (5.7+/-0.8-fold over control, n=8). Chronic fasudil (30 mg kg(-1) day(-1); 14 days) and sildenafil (25 mg kg(-1) day(-1); 14 days) treatments reduced PH and pulmonary cardiovascular remodelling, and inhibited the MYPT1 phosphorylation in pulmonary artery from hypoxic rats by 82.3+/-3% (n=4) and by 76.6+/-2% (n=4), respectively. The inhibitory effect of sildenafil (10 microM) on MYPT1 phosphorylation was demonstrated by the loss of actin stress fibres in vascular smooth muscle cells. However, in vitro kinase assays indicated that sildenafil had no direct inhibitory action on Rho kinase activity. Sildenafil treatment induced increased RhoA phosphorylation and association to its cytosolic inhibitory protein, guanine dissociation inhibitor (GDI) in pulmonary artery.We propose that sildenafil inhibits RhoA/Rho kinase-dependent functions in pulmonary artery through enhanced RhoA phosphorylation and cytosolic sequestration by GDI. The inhibition of intracellular events downstream of RhoA thus participates in the beneficial effect of sildenafil on PH.
...
PMID:Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension. 1620 23

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED is a highly prevalent health problem with considerable impact on the quality of life of men and their partners. Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors is effective in a wide range of individuals, it is not efficacious in all patients. The failure of PDE5 inhibitors happens mainly in men with diabetes, non-nerve sparing radical prostatectomy, and high disease severity. Therefore, improved therapies based on a better understanding of the fundamental issues in erectile physiology and pathophysiology have recently been proposed. Here, we summarize studies on ED treatment using gene and stem cell therapies. Adenoviral-mediated intracavernosal transfer of therapeutic genes, such as endothelial nitric oxide synthase (eNOS), calcitonin gene-related peptide (CGRP), superoxide dismutase (SOD), and RhoA/Rho kinase and mesenchymal stem cell-based cell and gene therapy strategy for the treatment of age- and diabetes-related ED are the focus of this review.
...
PMID:Gene and stem cell therapy for erectile dysfunction. 1639 45

Hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension present a common and formidable clinical problem for practicing thoracic, transplant, and trauma surgeons. The recent discovery of efficacious drugs that are selective for the pulmonary vasculature has brought about the potential for very powerful therapeutic agents. Inhaled nitric oxide (NO) therapy has already found broad clinical utility, yet its use is limited by potential toxicities. Rho kinase (ROK) has been discovered to play a very central role in the formation of hypoxia induced pulmonary hypertension, and the advent of very specific ROK inhibitors has shown positive clinical results. Finally, phosphodiesterase-5 inhibitors have been found to selectively vasodilate the pulmonary vasculature in the midst of HPV. The purposes of this review are to: 1) discuss the advantages and disadvantages of inhaled preparations of NO; 2) address experimental alternatives to inhaled preparations of NO to treat HPV; 3) explore potential therapeutic avenues associated with inhibition of Rho-kinase; and, 4) examine the use of phosphodiesterase-5 (PDE-5) inhibitors and combination therapy in the treatment of HPV.
...
PMID:Experimental therapies for hypoxia-induced pulmonary hypertension during acute lung injury. 1655 66

The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the treatment of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, PDE5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of PDE5 inhibitor failure. Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Treatment failure may cause considerable distress. If dose titration, more attempts and continuous dosing of PDE5 inhibitors (taken on a daily basis) fail to resolve the initial PDE5 inhibitor failure, clinicians need to consider alternative treatments. These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Combination therapy like prostaglandin E(1) (PGE(1)) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT(2) antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide (NO) donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of PDE5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of PDE5 inhibitors may be maintained. Targeting the risk factors of ED (similar to those for arteriosclerosis) in the early stages of the disease may prevent the development or decrease the severity of ED.
...
PMID:The management of phosphodiesterase-5 (PDE5) inhibitor failure. 1661 Nov 51

Pulmonary arterial hypertension is a progressive, fatal disease. Current treatments including prostanoids, endothelin-1 (ET-1) antagonists, and phosphodiesterase (PDE) inhibitors, have sought to address the pulmonary vascular endothelial dysfunction and vasoconstriction associated with the condition. These treatments may slow the progression of the disease but do not afford a cure. Future treatments must target more directly the structural vascular changes that impair blood flow through the pulmonary circulation. Several novel therapeutic targets have been proposed and are under active investigation, including soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-HT2B receptors, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, Rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. Tyrosine kinase inhibitors, statins, 5-HT2B receptor antagonists, EPCs and soluble guanylyl cyclase activators are among the most advanced, having produced encouraging results in animal models, and human trials are underway. This review summarises the current research in this area and speculates on their likely success.
...
PMID:Therapeutic targets in pulmonary arterial hypertension. 1901 Mar 50

Epithelial-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-beta1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-beta1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-beta1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and alpha-smooth muscle actin. Interestingly, TGF-beta1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-beta1-stimulated cells. Most importantly, treatment of TGF-beta1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-beta1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-beta1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.
...
PMID:Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition: the role of phosphodiesterase 4. 1975 79

Activation of the thromboxane prostanoid (TP) receptor produces potent vasoconstriction, which contributes to the increased vascular tone and blood pressure. The present study was designed to examine the hypothesis that stimulation of prostanoid TP receptors impairs endothelium-independent relaxations to cyclic AMP-elevating agents via increasing the activity of phosphodiesterases (PDEs). Rat carotid arteries without endothelium were isolated and suspended in myograph for the measurement of changes in isometric tension; the tissue content of cyclic AMP was assayed by enzyme immunoassay kit; and prostanoid TP receptor was detected in vascular wall by immunohistochemistry and Western blot. In phenylephrine-contracted rings without endothelium, relaxations induced by isoprenaline (receptor-mediated) and forskolin (receptor-independent) were markedly reduced by the presence of a prostanoid TP receptor agonist, U46619; the attenuated relaxations were prevented by acute treatment with S18886, the selective prostanoid TP receptor antagonist, but not by protein kinase C inhibitors. The reduced relaxations were partially restored by IBMX (non-selective PDE inhibitor), cilostazol (PDE3 inhibitor), rolipram (PDE4 inhibitor) or by Y27632 (Rho kinase inhibitor), but not by T0156 (PDE5 inhibitor). U46619 diminished isoprenaline- or forskolin-stimulated rise in cyclic AMP and this effect was inhibited by cilostazol, rolipram or Y27632. The present results suggest that activation of prostanoid TP receptors impairs cyclic AMP-dependent vasorelaxations partly via PDE- and RhoA/Rho kinase-dependent mechanisms. Inhibitors of PDEs and Rho kinase may be useful in the treatment of cardiovascular complications.
...
PMID:Prostanoid TP receptor-mediated impairment of cyclic AMP-dependent vasorelaxation is reversed by phosphodiesterase inhibitors. 2009 81


1 2 3 Next >>

---