scholarly journals Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

2021 ◽  
Vol 22 (4) ◽  
pp. 1929
Author(s):  
Daniela Mokra ◽  
Juraj Mokry
Keyword(s):  
Length Of Hospital Stay ◽  
Phosphodiesterase Inhibitors ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Pharmacological Action ◽  
Lung Damage ◽  
Lung Protective Ventilation ◽  
Ventilatory Parameters ◽  
Pde Inhibitors ◽  
Supportive Interventions

Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial–endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.

Involvement of Cyclic Adenosine Monophosphate in the Regulation of Pupal Color Adaptation of the Butterfly, Inachis io

1997 ◽  
Vol 52 (3-4) ◽  
pp. 255-258 ◽  
Author(s):  
Gerhard Starnecker
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Intracellular Camp ◽  
Dependent Manner ◽  
Color Adaptation ◽  
Yellow Color ◽  
Pde Inhibitors ◽  
Inachis Io ◽  
Yellow Coloration ◽  
Entire Central Nervous System

AbstractIn the butterfly Inachis io, a pupal melanization reducing factor (PMRF) which is located throughout the entire central nervous system controls the intensity of pigmentation of pupal cuticle depending on the background color of the pupation site. PMRF does not only reduce melanization but, in addition, enhances lutein incorporation in a dose-dependent manner to form pupae with yellow color on bright backgrounds.The present paper reports on the effects on pupal pigmentation caused by cyclic nucleo­ tides and phosphodiesterase (PDE) inhibitors which prevent degradation of cyclic nucleo­ tides. The injection of cAMP did not alter pupal coloration whereas its membrane-permeable analog dibutyryl-cAMP mimicked dose-dependently PMRF activity. Thus, pupae of reduced melanization and, in addition, enhanced yellow coloration were formed. This indicates that an increased intracellular cAMP level is capable of mediating PMRF effect. Also, the injection of the PDE inhibitor isobutylmethylxanthine (IBMX) caused dose-dependently pupae of reduced melanization and enhanced lutein incorporation.Theophylline (another PDE inhibitor) was only slightly effective (23% inhibition of melanization) at the highest dose compared to IBMX. The injection of cGMP and its analog dibutyryl-cGMP exhibited no melanization reducing effect.Extracts of abdominal ganglia (AG) which contained PMRF activity caused significantly brighter pupae when injected in combination with IBMX. However, this stimulation by IBMX became no longer effective at higher AG doses. Therefore, the present results are suggestive of an involvement of cAMP as a second messenger in the action of PMRF on pupal color adaptation.

scholarly journals Contribution of BKCa channels to vascular tone regulation by PDE3 and PDE4 is lost in heart failure

2018 ◽  
Vol 115 (1) ◽  
pp. 130-144 ◽  
Author(s):  
Sarah Idres ◽  
Germain Perrin ◽  
Valérie Domergue ◽  
Florence Lefebvre ◽  
Susana Gomez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Coronary Arteries ◽  
Vascular Tone ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Bkca Channel ◽  
Adrenergic Stimulation ◽  
Bkca Channels ◽  
Α Subunit ◽  
Pde Inhibitors

Abstract Aims Regulation of vascular tone by 3′,5′-cyclic adenosine monophosphate (cAMP) involves many effectors including the large conductance, Ca2+-activated, K+ (BKCa) channels. In arteries, cAMP is mainly hydrolyzed by type 3 and 4 phosphodiesterases (PDE3, PDE4). Here, we examined the specific contribution of BKCa channels to tone regulation by these PDEs in rat coronary arteries, and how this is altered in heart failure (HF). Methods and results Concomitant application of PDE3 (cilostamide) and PDE4 (Ro-20-1724) inhibitors increased BKCa unitary channel activity in isolated myocytes from rat coronary arteries. Myography was conducted in isolated, U46619-contracted coronary arteries. Cilostamide (Cil) or Ro-20-1724 induced a vasorelaxation that was greatly reduced by iberiotoxin (IBTX), a BKCa channel blocker. Ro-20-1724 and Cil potentiated the relaxation induced by the β-adrenergic agonist isoprenaline (ISO) or the adenylyl cyclase activator L-858051 (L85). IBTX abolished the effect of PDE inhibitors on ISO but did not on L85. In coronary arteries from rats with HF induced by aortic stenosis, contractility and response to acetylcholine were dramatically reduced compared with arteries from sham rats, but relaxation to PDE inhibitors was retained. Interestingly, however, IBTX had no effect on Ro-20-1724- and Cil-induced vasorelaxations in HF. Expression of the BKCa channel α-subunit, of a 98 kDa PDE3A and of a 80 kDa PDE4D were lower in HF compared with sham coronary arteries, while that of a 70 kDa PDE4B was increased. Proximity ligation assays demonstrated that PDE3 and PDE4 were localized in the vicinity of the channel. Conclusion BKCa channels mediate the relaxation of coronary artery induced by PDE3 and PDE4 inhibition. This is achieved by co-localization of both PDEs with BKCa channels, enabling tight control of cAMP available for channel opening. Contribution of the channel is prominent at rest and on β-adrenergic stimulation. This coupling is lost in HF.

CYCLIC ADENOSINE MONOPHOSPHATE-PHOSPHODIESTERASE INHIBITORS REDUCE SKELETAL MUSCLE PROTEIN CATABOLISM IN SEPTIC RATS

Shock ◽  
2007 ◽  
Vol 27 (6) ◽  
pp. 687-694 ◽  
Author(s):  
Eduardo Carvalho Lira ◽  
Fl??via Aparecida Graca ◽  
Dawit Albieiro P. Goncalves ◽  
Neusa M. Zanon ◽  
Amanda Martins Baviera ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Protein ◽  
Phosphodiesterase Inhibitors ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Protein Catabolism ◽  
Skeletal Muscle Protein

Possible Involvement of Cyclic Adenosine Monophosphate–independent Mechanism in the Positive Chronotropic Effect of Norepinephrine in the Isolated Guinea Pig Right Atrium

2001 ◽  
Vol 95 (2) ◽  
pp. 437-444 ◽  
Author(s):  
Mieko Asada ◽  
Masayuki Endou
Keyword(s):  
Guinea Pig ◽  
Positive Inotropic Effect ◽  
Phosphodiesterase Inhibitors ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Inotropic Effect ◽  
Dependent Manner ◽  
Chronotropic Effect ◽  
Beating Rate ◽  
Positive Chronotropic Effect

Background Although both positive chronotropic and inotropic effects of beta-adrenergic stimulation are thought to be mediated by cyclic adenosine 3'5'-monophosphate, phosphodiesterase III inhibitors such as amrinone and milrinone potentiate the positive inotropic effect of catecholamines with minimum influence on the heart rate in clinical setting. The aim of the current study was to compare the positive chronotropic effect of norepinephrine with that of forskolin to elucidate whether cyclic adenosine monophosphate is relevant to the chronotropic effect of norepinephrine. Methods Concentration-response curves for the positive chronotropic effects of norepinephrine and forskolin on the spontaneously beating right atria of guinea pigs were determined in the absence and presence of phosphodiesterase inhibitors or ion channel inhibitors. In some experiments, the left atria driven electrically were used to determine the positive inotropic effect of norepinephrine. Results Norepinephrine and forskolin increased the beating rate in a concentration-dependent manner. The positive chronotropic effect of forskolin was potentiated by amrinone and 3-isobutyl-1-methylxanthine, whereas the positive chronotropic effect of norepinephrine was not potentiated by the phosphodiesterase inhibitors. In contrast, the positive inotropic effect of norepinephrine was potentiated by amrinone. The hyperpolarization-activated inward current inhibitor cesium chloride and L-type voltage-dependent Ca2+ current inhibitor verapamil suppressed the chronotropic effect of norepinephrine, whereas these inhibitors did not affect the chronotropic effect of forskolin. Conclusion Norepinephrine increases the spontaneously beating rate by a different mechanism from that of forskolin, suggesting that cyclic adenosine monophosphate is causally unrelated to the positive chronotropic effect of norepinephrine in the guinea pig heart.

scholarly journals A Homogeneous Fluorescent Assay for cAMP-Phosphodiesterase Enzyme Activity

2011 ◽  
Vol 17 (3) ◽  
pp. 409-414 ◽  
Author(s):  
Ling Tian ◽  
Rongsheng E. Wang ◽  
Ying Fei ◽  
Yie-Hwa Chang
Keyword(s):  
Enzyme Activity ◽  
High Throughput Screening ◽  
Cyclic Adenosine Monophosphate ◽  
Cost Effective ◽  
Adenosine Monophosphate ◽  
Rat Tissues ◽  
Camp Phosphodiesterase ◽  
Kinetic Measurements ◽  
Phosphodiester Bond ◽  
Pde Inhibitors

Cyclic adenosine monophosphate–phosphodiesterases (cAMP-PDEs) regulate the cellular level of cAMP by selectively catalyzing the hydrolysis of the phosphodiester bond in the cAMP molecule. They play important roles in modulating cellular and physiological functions. There is a growing interest in the study of cAMP-PDEs as therapeutic targets. We describe a novel method for measuring the enzyme activity of cAMP-PDEs that is based on a homogeneous fluorescence assay employing a cAMP-dependent DNA-binding protein (CAP). We demonstrate that the assay is quick and robust compared to traditional methods and is expected to be cost-effective for high-throughput screening of cAMP-PDE inhibitors. The usefulness of the assay is demonstrated by measuring IC50 values of three nonselective PDE inhibitors and by kinetic measurements of cAMP-PDEs from various rat tissues.

Diabetic Theory in Anti-Alzheimer’s Drug Research and Development. Part 2: Therapeutic Potential of cAMP-Specific Phosphodiesterase Inhibitors

2020 ◽  
Vol 27 ◽  
Author(s):  
Agnieszka Jankowska ◽  
Maciej Pawłowski ◽  
Grażyna Chłoń-Rzepa
Keyword(s):  
Emotional Processing ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Phosphodiesterase Inhibitors ◽  
Adenosine Monophosphate ◽  
In Vivo Studies ◽  
Age Related ◽  
Pde Inhibitors

: Alzheimer’s Disease (AD) is one of the most prevalent age-related neurodegenerative diseases that affect the cognition, behavior, and daily activities of individuals. Studies indicate that this disease is characterized by several pathological mechanisms, including the accumulation of amyloid beta peptide, hyperphosphorylation of tau protein, impairment of cholinergic neurotransmission, and increase in inflammatory responses within the central nervous system. Chronic neuroinflammation associated with AD is closely related to disturbances in metabolic processes, including insulin release and glucose metabolism. As AD is also called type III diabetes, diverse compounds having antidiabetic effects have been investigated as potential drugs for its symptomatic and disease-modifying treatment. In addition to insulin and oral antidiabetic drugs, scientific attention has been paid to cyclic-3′,5′-adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) inhibitors that can modulate the concentration of glucose and related hormones, and exert beneficial effects on memory, mood, and emotional processing. In this review, we present the most recent reports focusing on the involvement of cAMPspecific PDE4, PDE7, and PDE8 in glycemic and inflammatory response controls as well as the potential utility of the PDE inhibitors in the treatment of AD. Besides the results of in vitro and in vivo studies, the review also presents recent reports from clinical trials.

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