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      Imaging of PDE2- and PDE3-Mediated cGMP-to-cAMP Cross-Talk in Cardiomyocytes

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          Abstract

          Cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are important second messengers that regulate cardiovascular function and disease by acting in discrete subcellular microdomains. Signaling compartmentation at these locations is often regulated by phosphodiesterases (PDEs). Some PDEs are also involved in the cross-talk between the two second messengers. The purpose of this review is to summarize and highlight recent findings about the role of PDE2 and PDE3 in cardiomyocyte cyclic nucleotide compartmentation and visualization of this process using live cell imaging techniques.

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          Most cited references150

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          The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.

          Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.
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            Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.

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              Advances in targeting cyclic nucleotide phosphodiesterases.

              Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.
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                Author and article information

                Journal
                J Cardiovasc Dev Dis
                J Cardiovasc Dev Dis
                jcdd
                Journal of Cardiovascular Development and Disease
                MDPI
                2308-3425
                19 January 2018
                March 2018
                : 5
                : 1
                : 4
                Affiliations
                [1 ]Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; n.pavlaki@ 123456uke.de
                [2 ]German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
                Author notes
                [* ]Correspondence: v.nikolaev@ 123456uke.de ; Tel.: +49-40-7410-51391
                Article
                jcdd-05-00004
                10.3390/jcdd5010004
                5872352
                29367582
                daf81b25-a203-405a-9b71-1d207ebad9b6
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 December 2017
                : 17 January 2018
                Categories
                Review

                camp,cgmp,phosphodiesterase,fret,imaging,cross-talk
                camp, cgmp, phosphodiesterase, fret, imaging, cross-talk

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