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The Beneficial Effect of Omega-3 PUFA and L-Arginine on Endothelial Nitric Oxide (NO) Bioavailability
Published in Robert Fried, Richard M. Carlton, Flaxseed, 2023
Robert Fried, Richard M. Carlton
Vasodilation results from muscle cell relaxation, and, as is true of any signaling pathway, there must be a way to terminate the action of the signal: cGMP is converted into GMP by a specific phosphodiesterase (PDE). There are ten families of PDEs: PDE1–10. The major PDE in vascular smooth muscle is type 5. Viagra® (Sildenafil) is a specific inhibitor of PDE type 5. By blocking the breakdown of cGMP, Viagra acts to prolong the effects of cGMP, thus slowing the degradation of NO and so maintaining cavernosal blood inflow.
Introduction
Published in Amritpal Singh Saroya, Reverse Pharmacology, 2018
As far as cosmetic application is concerned, cyclic nucleotide phosphodiesterase 4 (PDE4) was the most promising candidate. The others PDE1, 2, 3, 5 and 6 subtypes were not retained, which clearly indicates for a selectivity for PDE4. Investigatory tests with 6 subtypes of phosphodiesterase demonstrated a significant selectivity for phosphodiesterase 4 subtype. Evaluation of e-viniferin on the secretion of markers of inflammation confirmed the selectivity (Do et al. 2005).
Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Stimulated by the Ca2+-calmodulin complex, this isoenzyme has at least seven isoforms, a number of which are found in the brain. The two major isoforms, Iα and Iβ, have different affinities for cAMP and cGMP. PDE Iα acts preferentially on cGMP, whereas PDE Iβ has equal potency on both substrates. In the presence of Ca2+-calmodulin, the enzymes are activated, causing 2–4-fold reduction of the Km. Selective inhibitors include the phenothiazines, such as trifluoroperazine, W-7 and the ginsenosides from ginseng (Panax quinquefolium) root. As the inhibition can be overcome by calmodulin, it appears that these agents are serving as calmodulin antagonists and probably bind to the calmodulin binding site. Vinpocetin and 8-methoxy-methyl-3-isobutyl-1-methylxanthine, however, inhibit the hydrolytic site on PDE I selectively, rather than the calmodulin binding site (Thompson 1991). These inhibitors relax airway and vascular smooth muscle and are also possible inhibitors of platelet aggregation (Nicholson et al. 1991).
PDE1 inhibitors: a review of the recent patent literature (2008-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Mei-Ling Le, Mei-Yan Jiang, Chuan Han, Yi-Yi Yang, Yinuo Wu
The inhibition of PDE1 can efficiently activate the NO/cGMP/PKG and cAMP/PKA signals by upregulating the levels of cAMP and cGMP. In addition, the ability of binding of Ca2+/calmodulin leads to the mechanism of PDE1 having some cross-talk of the Ca2+ and cyclic nucleotide signaling [32]. Researches showed that the inhibition of PDE1 can increase the levels of cAMP and cGMP in the brain, leading to the phosphorylation and activation of the transcription factors cAMP responsive element-binding protein (CREB) and serum response factor (SRF), promoting the neuronal survival and memory consolidation [33–36]. In cardiac fibroblasts, the inhibition of PDE1A attenuates isoproterenol-induced interstitial fibrosis in mice, alleviating the phenylephrine-induced cardiac myocyte hypertrophy and regulating collagen synthesis [21,37]. The depletion of PDE1C showed protective effects on cardiac myocyte hypertrophy in a PKA-dependent manner [38]. In the liver fibrosis, the inhibition of PDE1 ameliorates the fibrosis through regulating the cAMP/CREB/TLR4 signaling [39].
Topical roflumilast for the treatment of psoriasis
Published in Expert Review of Clinical Immunology, 2023
Anastasia Drakos, Ron Vender, Tiago Torres
Phosphodiesterases (PDEs) are a class of enzymes responsible for the hydrolysis and subsequent inactivation of cyclic nucleotides [14–16]. They assist in the regulation of signal transduction pathways by inhibiting the action of intracellular second messengers, 3,’5’-cyclic adenosine monophosphate (cAMP) and 3,’5’-cyclic guanosine monophosphate (cGMP). There are 11 families of phosphodiesterase enzymes, PDE1-PDE11. PDE4 is specific to cAMP and is implicated in a number of inflammatory responses as the main PDE expressed in immune cells and keratinocytes [14–16].
Clinical pharmacology of cardiac cyclic AMP in human heart failure: too much or too little?
Published in Expert Review of Clinical Pharmacology, 2023
Since its seminal discovery in the late 1950's by Earl Sutherland and colleagues, prompting him to coin the term ‘second messenger’ for such molecules that form inside the cell in response to an extracellular signal (‘first messenger’), cyclic 3', 5'-adenosine monophosphate (cAMP) has been found to play central roles in almost every signaling pathway inside every cell type [1]. This Nobel prize-awarded discovery laid the foundation for the signal transduction field. cAMP is synthesized from adenosine triphosphate (ATP) at the cell membrane by specific enzymes, the adenylyl cyclases (ACs), which, however, lack extracellular segments and do not bind extracellular molecules [2]. In the following decades, additional Nobel prize-awarded work by Alfred Gilman and Martin Rodbell but also by Bob Lefkowitz, Brian Kobilka, and others elucidated how ACs get activated by extracellular stimuli, i.e. that the stimulus binds to, and activates a specific plasma membrane-residing heptahelical receptor, which, in turn, activates one of several guanine nucleotide-binding (G) proteins residing nearby at the cell membrane. One of these G proteins, Gs, binds and activates AC after its interaction with the receptor (a G protein – coupled receptor, GPCR) [3–8]. G proteins are heterotrimers of a, b, and g subunits, with a subunit either stimulating AC activity (Gas) or inhibiting it (Galphai), resulting in increased or decreased intracellular cAMP levels, respectively [2,3]. Certain Gbg subunits (a dimer that functions as a monomer) can also modulate AC activity [2]. Ten mammalian AC isoforms exist, nine cell membrane-bound (AC1–9) and one soluble (cytosolic AC10, responding to bicarbonate instead of the cell membrane-embedded GPCR) [2]. cAMP signals are transduced by several effector proteins with which they directly interact, including protein kinase A (PKA or cAMP-dependent protein kinase), the exchange protein directly activated by cAMP (Epac), cyclic nucleotide – gated (CNG) ion channels, and the Popeye domain-containing (POPDC) proteins [9–13]. At least 11 different types of phosphodiesterase (PDE1–11) exist in mammalian cells, responsible for termination of cAMP action. Three of them (PDE5, −6, −9) degrade exclusively cyclic 3', 5'-guanosine monophosphate (cGMP), while the other eight terminate the life of cAMP in cells (PDE4, −7, and −8 are cAMP-specific; PDE1, −2, −3, −10, and −11 have dual cAMP/cGMP specificity) [14–16]. Importantly, PDEs are encoded by multiple genes with multiple splice variants or alternative promoters, so the number of PDE isoforms in mammals is quite vast (over 100 functional PDE isoforms have been identified to date) [14–16]. Finally, cAMP and cGMP crosstalk to each other directly via PDE activity regulation, e.g. cGMP modulates certain cAMP terminating PDE activity and vice versa [14–16].