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• W2135914024 abstract "HomeHypertensionVol. 41, No. 3Does Sildenafil Indirectly Inhibit Phosphodiesterase 3 in Vascular Smooth Muscle? Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBDoes Sildenafil Indirectly Inhibit Phosphodiesterase 3 in Vascular Smooth Muscle? Donald H. Maurice Donald H. MauriceDonald H. Maurice Career Investigator, Heart and Stroke Foundation of Ontario, Associate Professor of Pharmacology and Toxicology, Queen’s University, Kingston, Ontario, Canada, E-mail Search for more papers by this author Originally published10 Feb 2003https://doi.org/10.1161/01.HYP.0000054979.81019.0AHypertension. 2003;41:e2Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 10, 2003: Previous Version 1 To the Editor:I read with great interest the recent report by Schalcher et al, entitled “Interaction of Sildenafil With cAMP-Mediated Vasodilation In Vivo.”1 The data presented deals with a potentially important issue and, given the increasing interest in using phosphodiesterase 5 (PDE5) inhibitors for various conditions, in addition to erectile dysfunction, are also timely. As a researcher studying the role of cyclic nucleotide phosphodiesterases (PDEs) in cardiovascular tissues, I would like to take this opportunity to comment on some of the statements made in the discussion of these data. First, since a considerable literature describing the importance of interactions between cGMP and cAMP hydrolyzing PDEs has accumulated in recent years, the finding that sildenafil and cAMP-dependent vasodilators interacted to regulate forearm blood flow (FBF) in this study should, perhaps, not have been described as “unexpected.”2 In earlier work, Dr Richard Haslam and I reported that cGMP elevating agents (for example nitroprusside) increased cAMP through a cGMP-dependent inhibition of the cAMP-hydrolyzing phosphodiesterase 3 (PDE3) in blood platelets and arterial smooth muscle.3–5 This effect of cGMP on cAMP hydrolysis in these cells allowed a marked synergistic increase in platelet or smooth muscle cAMP when activators of adenylyl cyclase and guanylyl cyclase were used together, as well as a cAMP-dependent synergistic inhibition of blood platelet aggregation and arterial smooth muscle contraction. More recently, similar reports have described this effect in cardiac myocytes and mesangial cells,6,7 perhaps indicating that interactions between cGMP and cAMP are important in several cell types and challenging the concept that the cAMP and cGMP signaling cascades operate as parallel and independent systems. Second, although the interaction between sildenafil and isoprenaline, an activator of adenylyl cyclase, described by Schalcher and colleagues is consistent with a role for PDE3 in mediating the interaction between the compounds on forearm blood flow (FBF), the documented interaction with milrinone, a PDE3 inhibitor, is not. Indeed, if sildenafil and milrinone ultimately each had their effects by inhibiting PDE3, their combination would have been sub-additive, not additive, as reported in Figure 2. In contrast, presentation of this same data after controlling for the basal effect of sildenafil on flow, as depicted in Figure 3, is consistent with an effect of a sildenafil-mediated, cGMP-dependent inhibition of PDE3. Perhaps an inhibitor of adenylyl cyclase activity would be helpful in clarifying the issue of mechanism. Third, while Schalcher and colleagues correctly state that PDE5 is not expressed in cardiac myocytes, they suggest that sildenafil could potentially inhibit cardiac PDE3 indirectly by increasing plasma cGMP levels. Since plasma cGMP accumulates as a result of its extrusion from cells and would not be taken up from the circulation by cardiac myocytes, or any other cell, this possible indirect effect of sildenafil on cardiac PDE3 in highly unlikely to occur.1 Schalcher C, Schad K, Brunner-La Rocca HP, Schindler R, Oechslin E, Scharf C, Suetsch G, Bertel O, Kiowski W. Interaction of sildenafil with cAMP-mediated vasodilation in vivo. Hypertension. 2002; 40: 763–767.LinkGoogle Scholar2 Lugnier C. Cyclic nucleotide phosphodiesterase families in intracellular signaling and diabetes. Adv Exp Med Biol. 2001; 498: 253–261.CrossrefMedlineGoogle Scholar3 Maurice DH, Haslam RJ. Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP. Mol Pharmacol. 1990; 37: 671–681.MedlineGoogle Scholar4 Maurice DH, Haslam RJ. Nitroprusside enhances isoprenaline-induced increases in cAMP in rat aortic smooth muscle. Eur J Pharmacol. 1990; 191: 471–475.CrossrefMedlineGoogle Scholar5 Maurice DH, Crankshaw D, Haslam RJ. Synergistic actions of nitrovasodilators and isoprenaline on rat aortic smooth muscle. Eur J Pharmacol. 1991; 192: 235–242.CrossrefMedlineGoogle Scholar6 Kirstein M, Rivet-Bastide M, Hatem S, Benardeau A, Mercadier JJ, Fischmeister R. Nitric oxide regulates the calcium current in isolated human atrial myocytes. J Clin Invest. 1995; 95: 794–802.CrossrefMedlineGoogle Scholar7 Sandner P, Kornfeld M, Ruan X, Arendshorst WJ, Kurtz A. Nitric oxide/cAMP interactions in the control of rat renal vascular resistance. Circ Res. 1999; 84: 186–192.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Quadir S, Cottone P and Sabino V (2019) Role of Sigma Receptors in Alcohol Addiction, Frontiers in Pharmacology, 10.3389/fphar.2019.00687, 10 March 2003Vol 41, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/01.HYP.0000054979.81019.0APMID: 12623968 Originally publishedFebruary 10, 2003 PDF download Advertisement SubjectsCell Signaling/Signal TransductionCongenital Heart DiseaseEndothelium/Vascular Type/Nitric OxidePharmacologySmooth Muscle Proliferation and Differentiation" @default.
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