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Pde5 inhibition

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https://www.readbyqxmd.com/read/29773995/hypoxia-reoxygenation-of-rat-renal-arteries-impairs-vasorelaxation-via-modulation-of-endothelium-independent-sgc-cgmp-pkg-signaling
#1
Diana Braun, Christa Zollbrecht, Stefanie Dietze, Rudolf Schubert, Stefan Golz, Holger Summer, Pontus B Persson, Mattias Carlström, Marion Ludwig, Andreas Patzak
Ischemia/reperfusion injury holds a key position in many pathological conditions such as acute kidney injury and in the transition to chronic stages of renal damage. We hypothesized that besides a reported disproportional activation of vasoconstrictor response, hypoxia/reoxygenation (H/R) adversely affects endothelial dilatory systems and impairs relaxation in renal arteries. Rat renal interlobar arteries were studied under isometric conditions. Hypoxia was induced by application of 95% N2 , 5% CO2 for 60 min to the bath solution, followed by a 10 min period of reoxygenation (95% O2 , 5% CO2 )...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29743944/repurposing-drugs-in-oncology-redo-selective-pde5-inhibitors-as-anti-cancer-agents
#2
Pan Pantziarka, Vidula Sukhatme, Sergio Crispino, Gauthier Bouche, Lydie Meheus, Vikas P Sukhatme
Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of cancers...
2018: Ecancermedicalscience
https://www.readbyqxmd.com/read/29735634/evaluation-of-sildenafil-and-tadalafil-for-reversing-constriction-of-fetal-arteries-in-a-human-placenta-perfusion-model
#3
Robert B Walton, Luckey C Reed, Sarah M Estrada, Stacey S Schmiedecke, Diana L Villazana-Kretzer, Peter G Napolitano, Nicholas Ieronimakis
Fetal growth restriction resulting from reduced placental blood perfusion is a major cause of neonatal morbidity and mortality. Aside from intense surveillance and early delivery, there is no treatment for fetal growth restriction. A potential treatment associated with placental vasoconstriction is the class of PDE5 (phosphodiesterase type 5) inhibitors such as sildenafil, which is known to cross the placenta. In contrast, tadalafil, a more potent and selective PDE5 inhibitor has not been studied in pregnancy or experimental models of fetal growth restriction...
May 7, 2018: Hypertension
https://www.readbyqxmd.com/read/29724712/mutations-of-the-pde5a-gene-confer-a-survival-advantage-in-patients-with-colon-cancer
#4
Steven Lehrer, Peter H Rheinstein, Kenneth Rosenzweig
Sildenafil is a small molecule that inhibits PDE5. The study of Islam et al validates PDE5 as a colon cancer chemoprevention target in mice (2), as did a second mouse study (3). Our analysis of TCGA data corroborates this finding in humans. Further studies are needed to determine whether sildenafil or other PDE5 inhibitors might be colon cancer preventives or treatments.
May 3, 2018: Cancer Prevention Research
https://www.readbyqxmd.com/read/29694963/treatment-of-macular-degeneration-with-sildenafil-results-of-a-two-year-trial
#5
D Jackson Coleman, Winston Lee, Stanley Chang, Ronald H Silverman, Harriet O Lloyd, Suzanne Daly, Stephen H Tsang
OBJECTIVE: To evaluate PDE5/6 inhibition with sildenafil to reduce choroidal ischemia and treat age-related macular degeneration. METHODS: Sildenafil was prescribed to treat participants with macular degenerations or macular dystrophies measured by spectral-domain optical coherence tomography, color fundus photography, enhanced depth imaging, and best-corrected visual acuity. RESULTS: No change in calcified drusen was noted. Vitelliform-type soft drusen were not substantially changed...
April 25, 2018: Ophthalmologica. Journal International D'ophtalmologie
https://www.readbyqxmd.com/read/29687019/phosphodiesterase-5-inhibition-potentiates-cerebrovascular-reactivity-in-chronic-traumatic-brain-injury
#6
Kimbra Kenney, Franck Amyot, Carol Moore, Margalit Haber, L Christine Turtzo, Christian Shenouda, Erika Silverman, Yunhua Gong, Bao-Xi Qu, Leah Harburg, Eric M Wassermann, Hanzhang Lu, Ramon Diaz-Arrastia
Background: Traumatic cerebrovascular injury (TCVI), a common consequence of traumatic brain injury (TBI), presents an attractive therapeutic target. Because phosphodiesterase-5 (PDE5) inhibitors potentiate the action of nitric oxide (NO) produced by endothelial cells, they are candidate therapies for TCVI. This study aims to: (1) measure cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and change in CVR after a single dose of sildenafil (ΔCVR) in chronic TBI compared to uninjured controls; (2) examine the safety and tolerability of 8-week sildenafil administration in chronic symptomatic moderate/severe TBI patients; and as an exploratory aim, (3) assess the effect of an 8-week course of sildenafil on chronic TBI symptoms...
April 2018: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29668326/effects-of-aging-and-exercise-training-on-leg-hemodynamics-and-oxidative-metabolism-in-the-transition-from-rest-to-steady-state-exercise-role-of-cgmp-signaling
#7
Peter Piil, Tue Smith Jørgensen, Jon Egelund, Nicolai Rytter, Lasse Gliemann, Jens Bangsbo, Ylva Hellsten, Michael Nyberg
Aging is associated with slower skeletal muscle O2 uptake (VO2 ) kinetics; however, the mechanisms underlying this effect of age are unclear. Also, the effects of exercise training in elderly on the initial vascular and metabolic response to exercise remain to be elucidated. We measured leg hemodynamics and oxidative metabolism in the transition from rest to steady state exercise engaging the knee-extensor muscles in young (n=15, 25{plus minus}1 years) and older (n=15, 72{plus minus}1 years) subjects before and after a period of aerobic high-intensity exercise training...
April 18, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29667180/pde5-inhibitors-pharmacology-and-clinical-applications-20-years-after-sildenafil-discovery
#8
REVIEW
K-E Andersson
The discovery of the nitric oxide/cyclic cGMP pathway was the basis for our understanding of many normal physiological functions and the pathophysiology of several diseases. Since the discovery and introduction of sildenafil, inhibitors of phosphodiesterase isoenzymes type 5 (PDE5) have been first-line therapy for erectile dysfunction (ED). The success of sildenafil in the treatment of ED stimulated research in the field of PDE5 inhibition and led to many new applications, such as treatment of lower urinary symptoms (LUTS), and pulmonary arterial hypertension, which are now approved indications...
April 17, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29665366/3-7-bis-2-hydroxyethyl-icaritin-a-potent-inhibitor-of-phosphodiesterase-5-prevents-monocrotaline-induced-pulmonary-arterial-hypertension-via-no-cgmp-activation-in-rats
#9
Tao-Hua Lan, Xiao-Ling Chen, Yun-Shan Wu, Hui-Liang Qiu, Jun-Zhe Li, Xin-Min Ruan, Dan-Ping Xu, Dong-Qun Lin
Pulmonary arterial hypertension (PAH) is a chronic progressive disease which leads to elevated pulmonary arterial pressure and right heart failure. 3,7-Bis(2-hydroxyethyl)icaritin (ICT), an icariin derivatives, was reported to have potent inhibitory activity on phosphodiesterase type 5 (PDE5) which plays a crucial role in the pathogenesis of PAH. The present study was designed to investigate the effects of ICT on monocrotaline (MCT)-induced PAH rat model and reveal the underlying mechanism. MCT-induced PAH rat models were established with intragastric administration of ICT (10, 20, 40mg/kg/d), Icariin (ICA) (40mg/kg/d) and Sildenafil (25mg/kg/d)...
April 14, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29660387/long-term-inhibition-of-pde5-ameliorates-aging-induced-changes-in-rat-testis
#10
Srdjan J Sokanovic, Ivan Capo, Marija M Medar, Silvana A Andric, Tatjana S Kostic
NO-cGMP signaling pathway has been implicated in reduction of testicular steroidogenesis during aging. Here we analyzed the effect of PDE5 inhibition on old testicular phenotype formation. The old phenotype exhibited low testosterone and increased nitrite levels in circulation, increased cGMP accumulation in testicular interstitial fluid (TIF), progressive atrophy of testicular seminiferous tubules and enlargement of interstitial area followed by rise in blood vessel density and slight increase in the number of Leydig cells and macrophages...
April 13, 2018: Experimental Gerontology
https://www.readbyqxmd.com/read/29621314/sildenafil-ameliorates-right-ventricular-early-molecular-derangement-during-left-ventricular-pressure-overload
#11
Yousuke Imai, Taro Kariya, Masaki Iwakiri, Yoshitsugu Yamada, Eiki Takimoto
Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined...
2018: PloS One
https://www.readbyqxmd.com/read/29616790/novel-tadalafil-derivatives-ameliorates-scopolamine-induced-cognitive-impairment-in-mice-via-inhibition-of-acetylcholinesterase-ache-and-phosphodiesterase-5-pde5
#12
Wei Ni, Huan Wang, Xiaokang Li, Xinyu Zheng, Manjiong Wang, Jian Zhang, Qi Gong, Dazheng Ling, Fei Mao, Haiyan Zhang, Jian Li
On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability...
April 17, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29566267/tadalafil-attenuates-hypotonicity-induced-ca-2-influx-via-trpv2-and-trpv4-in-primary-rat-bladder-urothelial-cell-cultures
#13
Xiao Dong, Hiroshi Nakagomi, Tatsuya Miyamoto, Tatsuya Ihara, Satoru Kira, Norifumi Sawada, Takahiko Mitsui, Masayuki Takeda
AIMS: To investigate the localization of phosphodiesterase 5 (PDE5) and the molecular mechanism underlying the effect of the PDE5 inhibitor tadalafil in signal transduction in the bladder urothelium. METHODS: PDE5 expression in rat bladder tissues and cultured primary rat bladder urothelial cells was evaluated using immunochemistry and western blot assays. Ca2+ influx in cells exposed to isotonic solution, hypotonic solution, a selective transient receptor potential vanilloid 2 (TRPV2) channel agonist (cannabidiol), a selective TRPV4 channel agonist (GSK1016790A), a TRP cation channel melastatin 7 (TRPM7) channel agonist (PIP2), or a purinergic receptor agonist (ATP) in the presence or absence of 10 µM tadalafil was evaluated using calcium imaging techniques...
March 22, 2018: Neurourology and Urodynamics
https://www.readbyqxmd.com/read/29551532/effect-of-ginger-paullinia-cupana-muira-puama-and-l-citrulline-singly-or-in-combination-on-modulation-of-the-inducible-nitric-oxide-no-cgmp-pathway-in-rat-penile-smooth-muscle-cells
#14
Monica G Ferrini, Eduardo Garcia, Andrea Abraham, Jorge N Artaza, Sabine Nguyen, Jacob Rajfer
INTRODUCTION: COMP-4 is a natural compound-based dietary supplement consisting of the combination of ginger, Paullinia cupana, muira puama and l-citrulline, which when given long-term has been shown in the aged rat to a) upregulate iNOS in the penile smooth muscle cells (SMC), b) reverse the corporal SMC apoptosis and fibrosis associated with corporal veno-occlusive dysfunction (CVOD), and c) improve resulting erectile function. To elucidate the mechanism of how COMP-4 and its individual components modulate the iNOS-cGMP pathway, an in vitro study was conducted using a rat corporal primary SMC culture to determine its effect on NOS, soluble guanylate cyclase (sGC), cGMP and the phosphodiesterase 5 enzyme (PDE5)...
June 1, 2018: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/29549279/phosphodiesterase-type-4-inhibition-enhances-nitric-oxide-and-hydrogen-sulfide-mediated-bladder-neck-inhibitory-neurotransmission
#15
Ángel Agis-Torres, Paz Recio, María Elvira López-Oliva, María Pilar Martínez, María Victoria Barahona, Sara Benedito, Salvador Bustamante, Miguel Ángel Jiménez-Cidre, Albino García-Sacristán, Dolores Prieto, Vítor S Fernandes, Medardo Hernández
Nitric oxide (NO) and hydrogen sulfide (H2 S) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples...
March 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29545395/prevention-of-pkg-1%C3%AE-oxidation-suppresses-antihypertrophic-antifibrotic-effects-from-pde5-inhibition-but-not-sgc-stimulation
#16
Taishi Nakamura, Guangshuo Zhu, Mark J Ranek, Kristen Kokkonen-Simon, Manling Zhang, Grace E Kim, Kenichi Tsujita, David A Kass
BACKGROUND: Stimulation of sGC (soluble guanylate cyclase) or inhibition of PDE5 (phosphodiesterase type 5) activates PKG (protein kinase G)-1α to counteract cardiac hypertrophy and failure. PKG1α acts within localized intracellular domains; however, its oxidation at cysteine 42, linking homomonomers, alters this localization, impairing suppression of pathological cardiac stress. Because PDE5 and sGC reside in separate microdomains, we speculated that PKG1α oxidation might also differentially influence the effects from their pharmacological modulation...
March 2018: Circulation. Heart Failure
https://www.readbyqxmd.com/read/29491258/discovery-of-2-e-2-7-fluoro-3-methylquinoxalin-2-yl-vinyl-6-pyrrolidin-1-yl-n-tetrahydro-2h-pyran-4-yl-pyrimidin-4-amine-hydrochloride-as-a-highly-selective-pde10a-inhibitor
#17
Yoichi Kadoh, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Kenji Omori, Jun Kotera, Takashi Sasaki, Tamaki Kobayashi, Hiroyuki Taniguchi, Yumi Watanabe, Koki Kojima, Toshiaki Sakamoto, Toshiyuki Himiyama, Eiji Kawanishi
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5...
2018: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29488328/phosphodiesterase-pde5-inhibition-assay-for-rapid-detection-of-erectile-dysfunction-drugs-and-analogs-in-sexual-enhancement-products
#18
Michael F Santillo, Mapa S T Mapa
Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase-5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based on measuring inhibition of PDE5 activity, the pharmacological mechanism shared among the adulterants. Initially, the assay reaction scheme was established and characterized, followed by analysis of 9 representative PDE5 inhibitors (IC50 , 0...
February 28, 2018: Drug Testing and Analysis
https://www.readbyqxmd.com/read/29462984/mathematical-modelling-of-nitric-oxide-cyclic-gmp-cyclic-amp-signalling-in-platelets
#19
Rune Kleppe, Inge Jonassen, Stein Ove Døskeland, Frode Selheim
Platelet activation contributes to normal haemostasis but also to pathologic conditions like stroke and cardiac infarction. Signalling by cGMP and cAMP inhibit platelet activation and are therefore attractive targets for thrombosis prevention. However, extensive cross-talk between the cGMP and cAMP signalling pathways in multiple tissues complicates the selective targeting of their activities. We have used mathematical modelling based on experimental data from the literature to quantify the steady state behaviour of nitric oxide (NO)/cGMP/cAMP signalling in platelets...
February 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29438213/new-no-donor-ncx-1443-therapeutic-effects-on-pulmonary-hypertension-in-the-sad-mouse-model-of-sickle-cell-disease
#20
Shariq Abid, Kanny Kebe, Amal Houssaïni, Françoise Tomberli, Elisabeth Marcos, Emilie Bizard, Marielle Breau, Aurelien Parpaleix, Claire-Marie Tissot, Bernard Maitre, Larissa Lipskaia, Genevieve Derumeaux, Elena Bastia, Armand Mekontso-Dessap, Serge Adnot
Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416, and was similarly reduced by daily NCX1443 gavage...
February 8, 2018: Journal of Cardiovascular Pharmacology
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