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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases

Author(s): Javier Blanco-Rivero and Fabiano E. Xavier*

Volume 26, Issue 30, 2020

Page: [3633 - 3651] Pages: 19

DOI: 10.2174/1381612826666200403172736

Price: $65


Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

Keywords: Phosphodiesterases, endothelial dysfunction, cardiovascular diseases, phosphodiesterase inhibitors, cyclic GMP, cyclic AMP.

Organization WH. Health statistics and information systems 2016.
Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol (Oxf) 2017; 219(1): 22-96.
[] [PMID: 26706498]
Park KH, Park WJ. Endothelial dysfunction: clinical implications in cardiovascular disease and therapeutic approaches. J Korean Med Sci 2015; 30(9): 1213-25.
[] [PMID: 26339159]
Netherton SJ, Maurice DH. Vascular endothelial cell cyclic nucleotide phosphodiesterases and regulated cell migration: implications in angiogenesis. Mol Pharmacol 2005; 67(1): 263-72.
[] [PMID: 15475573]
Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 2009; 122(3): 216-38.
[] [PMID: 19306895]
Bobin P, Belacel-Ouari M, Bedioune I, et al. Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective. Arch Cardiovasc Dis 2016; 109(6-7): 431-43.
[] [PMID: 27184830]
Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007; 76: 481-511.
[] [PMID: 17376027]
Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 2011; 91(2): 651-90.
[] [PMID: 21527734]
Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995; 268(4 Pt 1): C799-822.
[] [PMID: 7733230]
Mundiña-Weilenmann C, Vittone L, Rinaldi G, Said M, de Cingolani GC, Mattiazzi A. Endoplasmic reticulum contribution to the relaxant effect of cGMP- and cAMP-elevating agents in feline aorta. Am J Physiol Heart Circ Physiol 2000; 278(6): H1856-65.
[] [PMID: 10843882]
Akata T. Cellular and molecular mechanisms regulating vascular tone. Part 1: basic mechanisms controlling cytosolic Ca2+ concentration and the Ca2+-dependent regulation of vascular tone. J Anesth 2007; 21(2): 220-31.
[] [PMID: 17458652]
Zieba BJ, Artamonov MV, Jin L, et al. The cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac, induces smooth muscle relaxation by down-regulation of RhoA activity. J Biol Chem 2011; 286(19): 16681-92.
[] [PMID: 21454546]
Roberts OL, Kamishima T, Barrett-Jolley R, Quayle JM, Dart C. Exchange protein activated by cAMP (Epac) induces vascular relaxation by activating Ca2+-sensitive K+ channels in rat mesenteric artery. J Physiol 2013; 591(20): 5107-23.
[] [PMID: 23959673]
García-Morales V, Luaces-Regueira M, Campos-Toimil M. The cAMP effectors PKA and Epac activate endothelial NO synthase through PI3K/Akt pathway in human endothelial cells. Biochem Pharmacol 2017; 145: 94-101.
[] [PMID: 28912066]
Griffith TM. Endothelial control of vascular tone by nitric oxide and gap junctions: a haemodynamic perspective. Biorheology 2002; 39(3-4): 307-18.
[PMID: 12122246]
Edwards G, Félétou M, Weston AH. Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch 2010; 459(6): 863-79.
[] [PMID: 20383718]
Chaytor AT, Taylor HJ, Griffith TM. Gap junction-dependent and independent EDHF-type relaxations may involve smooth muscle cAMP accumulation. Am J Physiol Heart Circ Physiol 2002; 282(4): H1548-55.
[] [PMID: 11893592]
Münzel T, Feil R, Mülsch A, Lohmann SM, Hofmann F, Walter U. Physiology and pathophysiology of vascular signaling controlled by guanosine 3′,5′-cyclic monophosphate-dependent protein kinase. Circulation 2003; 108(18): 2172-83.
[] [PMID: 14597579]
Cary SP, Winger JA, Derbyshire ER, Marletta MA. Nitric oxide signaling: no longer simply on or off. Trends Biochem Sci 2006; 31(4): 231-9.
[] [PMID: 16530415]
Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev 2006; 27(1): 47-72.
[] [PMID: 16291870]
Kwan HY, Huang Y, Yao XQ, Leung FP. Role of cyclic nucleotides in the control of cytosolic Ca2+ levels in vascular endothelial cells. Clin Exp Pharmacol Physiol 2009; 36(9): 857-66.
[] [PMID: 19413591]
Cornwell TL, Arnold E, Boerth NJ, Lincoln TM. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP dependent protein kinase by cGMP. Am J Physiol 1994; 267(5 Pt 1): C1405-13.
[] [PMID: 7977701]
Eckly-Michel A, Martin V, Lugnier C. Involvement of cyclic nucleotide-dependent protein kinases in cyclic AMP-mediated vasorelaxation. Br J Pharmacol 1997; 122(1): 158-64.
[] [PMID: 9298542]
Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 2006; 109(3): 366-98.
[] [PMID: 16102838]
Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75(4): 725-48.
[] [PMID: 7480160]
Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999; 83(5A): 3C-12.
[] [PMID: 10078537]
Giachini FR, Lima VV, Carneiro FS, Tostes RC, Webb RC. Decreased cGMP level contributes to increased contraction in arteries from hypertensive rats: role of phosphodiesterase 1. Hypertension 2011; 57(3): 655-63.
[] [PMID: 21282562]
Laursen M, Beck L, Kehler J, et al. Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats. Br J Pharmacol 2017; 174(15): 2563-75.
[] [PMID: 28548283]
Noguera MA, Ivorra MD, Lugnier C, D’Ocon P. Role of cyclic nucleotide phosphodiesterase isoenzymes in contractile responses of denuded rat aorta related to various Ca2+ sources. Naunyn Schmiedebergs Arch Pharmacol 2001; 363(6): 612-9.
[] [PMID: 11414656]
Khammy MM, Dalsgaard T, Larsen PH, et al. PDE1A inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries. Br J Pharmacol 2017; 174(22): 4186-98.
[] [PMID: 28910498]
Sonnenburg WK, Mullaney PJ, Beavo JA. Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. J Biol Chem 1991; 266(26): 17655-61.
[PMID: 1654333]
Yang Q, Paskind M, Bolger G, et al. A novel cyclic GMP stimulated phosphodiesterase from rat brain. Biochem Biophys Res Commun 1994; 205(3): 1850-8.
[] [PMID: 7811274]
Rosman GJ, Martins TJ, Sonnenburg WK, Beavo JA, Ferguson K, Loughney K. Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3′,5′-cyclic nucleotide phosphodiesterase. Gene 1997; 191(1): 89-95.
[] [PMID: 9210593]
Zaccolo M, Movsesian MA. cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res 2007; 100(11): 1569-78.
[] [PMID: 17556670]
Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006; 58(3): 488-520.
[] [PMID: 16968949]
Murray F, Patel HH, Suda RY, et al. Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1. Am J Physiol Lung Cell Mol Physiol 2007; 292(1): L294-303.
[] [PMID: 16980375]
Surapisitchat J, Jeon KI, Yan C, Beavo JA. Differential regulation of endothelial cell permeability by cGMP via phosphodiesterases 2 and 3. Circ Res 2007; 101(8): 811-8.
[] [PMID: 17704206]
Haynes J Jr, Killilea DW, Peterson PD, Thompson WJ. Erythro-9- (2-hydroxy-3-nonyl)adenine inhibits cyclic-3′,5′-guanosine monophosphate- stimulated phosphodiesterase to reverse hypoxic pulmonary vasoconstriction in the perfused rat lung. J Pharmacol Exp Ther 1996; 276(2): 752-7.
[PMID: 8632346]
Bubb KJ, Trinder SL, Baliga RS, et al. Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension. Circulation 2014; 130(6): 496-507.
[] [PMID: 24899690]
Reinhardt RR, Chin E, Zhou J, et al. Distinctive anatomical patterns of gene expression for cGMP-inhibited cyclic nucleotide phosphodiesterases. J Clin Invest 1995; 95(4): 1528-38.
[] [PMID: 7706458]
Liu H, Maurice DH. Expression of cyclic GMP-inhibited phosphodiesterases 3A and 3B (PDE3A and PDE3B) in rat tissues: differential subcellular localization and regulated expression by cyclic AMP. Br J Pharmacol 1998; 125(7): 1501-10.
[] [PMID: 9884079]
Manganiello VC, Degerman E. Cyclic nucleotide phosphodiesterases (PDEs): diverse regulators of cyclic nucleotide signals and inviting molecular targets for novel therapeutic agents. Thromb Haemost 1999; 82(2): 407-11.
[PMID: 10605731]
Mitome-Mishima Y, Miyamoto N, Tanaka R, et al. Differences in phosphodiesterase 3A and 3B expression after ischemic insult. Neurosci Res 2013; 75(4): 340-8.
[] [PMID: 23471014]
MacKeil JL, Brzezinska P, Burke-Kleinman J, et al. Phosphodiesterase 3B (PDE3B) antagonizes the anti-angiogenic actions of PKA in human and murine endothelial cells. Cell Signal 2019; 62: 109342.
[] [PMID: 31176020]
Belacel-Ouari M, Zhang L, Hubert F, et al. Influence of cell confluence on the cAMP signalling pathway in vascular smooth muscle cells. Cell Signal 2017; 35: 118-28.
[] [PMID: 28389413]
Sun B, Li H, Shakur Y, et al. Role of phosphodiesterase type 3A and 3B in regulating platelet and cardiac function using subtype selective knockout mice. Cell Signal 2007; 19(8): 1765-71.
[] [PMID: 17482796]
Kanlop N, Chattipakorn S, Chattipakorn N. Effects of cilostazol in the heart. J Cardiovasc Med (Hagerstown) 2011; 12(2): 88-95.
[] [PMID: 21200326]
Suzuki K, Uchida K, Nakanishi N, Hattori Y. Cilostazol activates AMP-activated protein kinase and restores endothelial function in diabetes. Am J Hypertens 2008; 21(4): 451-7.
[] [PMID: 18369362]
Park SY, Lee JH, Kim CD, et al. Cilostazol suppresses superoxide production and expression of adhesion molecules in human endothelial cells via mediation of cAMP-dependent protein kinase mediated maxi-K channel activation. J Pharmacol Exp Ther 2006; 317(3): 1238-45.
[] [PMID: 16547169]
Movsesian MA, Kukreja RC. Phosphodiesterase inhibition in heart failure. Handb Exp Pharmacol 2011; 204(204): 237-49.
[] [PMID: 21695643]
Fertig BA, Baillie GS. PDE4-Mediated cAMP Signalling. J Cardiovasc Dev Dis 2018; 5(1): E8.
[] [PMID: 29385021]
Houslay MD. PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol Biol 2001; 69: 249-315.
[] [PMID: 11550796]
Komas N, Lugnier C, Stoclet JC. Endothelium-dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors. Br J Pharmacol 1991; 104(2): 495-503.
[] [PMID: 1665741]
Rabe KF, Tenor H, Dent G, Schudt C, Nakashima M, Magnussen H. Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 1994; 266(5 Pt 1): L536-43.
[PMID: 7515580]
Bian H, Zhang J, Wu P, et al. Differential type 4 cAMP-specific phosphodiesterase (PDE4) expression and functional sensitivity to PDE4 inhibitors among rats, monkeys and humans. Biochem Pharmacol 2004; 68(11): 2229-36.
[] [PMID: 15498513]
Growcott EJ, Spink KG, Ren X, Afzal S, Banner KH, Wharton J. Phosphodiesterase type 4 expression and anti-proliferative effects in human pulmonary artery smooth muscle cells. Respir Res 2006; 7: 9.
[] [PMID: 16423283]
Lugnier C, Komas N. Modulation of vascular cyclic nucleotide phosphodiesterases by cyclic GMP: role in vasodilatation. Eur Heart J 1993; 14(Suppl. I): 141-8.
[PMID: 8293765]
Wagner RS, Smith CJ, Taylor AM, Rhoades RA. Phosphodiesterase inhibition improves agonist-induced relaxation of hypertensive pulmonary arteries. J Pharmacol Exp Ther 1997; 282(3): 1650-7.
[PMID: 9316883]
Pauvert O, Salvail D, Rousseau E, Lugnier C, Marthan R, Savineau JP. Characterisation of cyclic nucleotide phosphodiesterase isoforms in the media layer of the main pulmonary artery. Biochem Pharmacol 2002; 63(9): 1763-72.
[] [PMID: 12007579]
Lehrke M, Kahles F, Makowska A, et al. PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner. J Mol Cell Cardiol 2015; 81: 23-33.
[] [PMID: 25640159]
Corbin JD, Turko IV, Beasley A, Francis SH. Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem 2000; 267(9): 2760-7.
[] [PMID: 10785399]
Mullershausen F, Friebe A, Feil R, Thompson WJ, Hofmann F, Koesling D. Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling. J Cell Biol 2003; 160(5): 719-27.
[] [PMID: 12604588]
Loughney K, Hill TR, Florio VA, et al. Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP specific 3′,5′-cyclic nucleotide phosphodiesterase. Gene 1998; 216(1): 139-47.
[] [PMID: 9714779]
Stacey P, Rulten S, Dapling A, Phillips SC. Molecular cloning and expression of human cGMP-binding cGMP-specific phosphodiesterase (PDE5). Biochem Biophys Res Commun 1998; 247(2): 249-54.
[] [PMID: 9642111]
Keravis T, Komas N, Lugnier C. Cyclic nucleotide hydrolysis in bovine aortic endothelial cells in culture: differential regulation in cobblestone and spindle phenotypes. J Vasc Res 2000; 37(4): 235-49.
[] [PMID: 10965223]
Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 2005; 289(2): L196-206.
[] [PMID: 15792963]
Wang J, Bingaman S, Huxley VH. Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases. Am J Physiol Heart Circ Physiol 2010; 298(4): H1146-54.
[] [PMID: 20139324]
Zamorano-León JJ, Olivier C, de Las Heras N, et al. Vardenafil improves penile erection in type 2 diabetes mellitus patients with erectile dysfunction: role of tropomyosin. J Sex Med 2013; 10(12): 3110-20.
[] [PMID: 24112450]
Mercapide J, Santiago E, Alberdi E, Martinez-Irujo JJ. Contribution of phosphodiesterase isoenzymes and cyclic nucleotide efflux to the regulation of cyclic GMP levels in aortic smooth muscle cells. Biochem Pharmacol 1999; 58(10): 1675-83.
[] [PMID: 10535760]
Lugnier C, Schoeffter P, Le Bec A, Strouthou E, Stoclet JC. Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. Biochem Pharmacol 1986; 35(10): 1743-51.
[] [PMID: 2423089]
Schoeffter P, Lugnier C, Demesy-Waeldele F, Stoclet JC. Role of cyclic AMP- and cyclic GMP-phosphodiesterases in the control of cyclic nucleotide levels and smooth muscle tone in rat isolated aorta. A study with selective inhibitors. Biochem Pharmacol 1987; 36(22): 3965-72.
[] [PMID: 2825708]
Lewis GD, Semigran MJ. Type 5 phosphodiesterase inhibition in heart failure and pulmonary hypertension. Curr Heart Fail Rep 2004; 1(4): 183-9.
[] [PMID: 16036043]
Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003; 92(9A): 9M-18.
[] [PMID: 14609619]
Kumar M, Bhattacharya V. Cilostazol: a new drug in the treatment intermittent claudication. Recent Pat Cardiovasc Drug Discov 2007; 2(3): 181-5.
[] [PMID: 18221117]
Kim SM, Jung JM, Kim BJ, Lee JS, Kwon SU. Cilostazol mono and combination treatments in ischemic stroke: an updated systematic review and meta-analysis. Stroke 2019; 50(12): 3503-11.
[] [PMID: 31607242]
Vasquez EC, Gava AL, Graceli JB, et al. Novel therapeutic targets for phosphodiesterase 5 inhibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis. Curr Pharm Biotechnol 2016; 17(4): 347-64.
[] [PMID: 26696017]
Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res 2009; 32(8): 1103-8.
[] [PMID: 19727602]
Rajavashisth TB, Andalibi A, Territo MC, et al. Induction of endothelial cell expression of granulocyte and macrophage colony stimulating factors by modified low-density lipoproteins. Nature 1990; 344(6263): 254-7.
[] [PMID: 1690354]
Libby P, Aikawa M, Kinlay S, Selwyn A, Ganz P. Lipid lowering improves endothelial functions. Int J Cardiol 2000; 74(Suppl. 1): S3-10.
[] [PMID: 10856767]
Lusis AJ. Atherosclerosis. Nature 2000; 407(6801): 233-41.
[] [PMID: 11001066]
Libby P. Inflammation in atherosclerosis. Nature 2002; 420(6917): 868-74.
[] [PMID: 12490960]
Huang R, Mills K, Romero J, et al. Comparative effects of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on carotid artery intima-media thickness progression: a network meta-analysis. Cardiovasc Diabetol 2019; 18(1): 14.
[] [PMID: 30700294]
Erdogan A, Luedders DW, Muenz BM, et al. Sildenafil inhibits the proliferation of cultured human endothelial cells. Int J Biomed Sci 2007; 3(2): 93-6.
[PMID: 23675029]
Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, Vardenafil, increases circulating progenitor cells in humans. Int J Impot Res 2005; 17(4): 377-80.
[] [PMID: 15829988]
Foresta C, De Toni L, Di Mambro A, Garolla A, Ferlin A, Zuccarello D. The PDE5 inhibitor sildenafil increases circulating endothelial progenitor cells and CXCR4 expression. J Sex Med 2009; 6(2): 369-72.
[] [PMID: 18823318]
Favot L, Keravis T, Holl V, Le Bec A, Lugnier C. VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors. Thromb Haemost 2003; 90(2): 334-43.
[] [PMID: 12888882]
Balarini CM, Leal MA, Gomes IB, et al. Sildenafil restores endothelial function in the apolipoprotein E knockout mouse. J Transl Med 2013; 11: 3.
[] [PMID: 23289368]
Takahashi S, Oida K, Fujiwara R, et al. Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. J Cardiovasc Pharmacol 1992; 20(6): 900-6.
[] [PMID: 1282592]
Kubota Y, Kichikawa K, Uchida H, et al. Pharmacologic treatment of intimal hyperplasia after metallic stent placement in the peripheral arteries. An experimental study. Invest Radiol 1995; 30(9): 532-7.
[] [PMID: 8537210]
Liu Y, Shakur Y, Yoshitake M, Kambayashi Ji J. Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake. Cardiovasc Drug Rev 2001; 19(4): 369-86.
[] [PMID: 11830753]
Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, et al. Cilostazol for Restenosis Trial (CREST) Investigators. Coronary stent restenosis in patients treated with cilostazol. Circulation 2005; 112(18): 2826-32.
[] [PMID: 16246948]
Tani T, Uehara K, Sudo T, Marukawa K, Yasuda Y, Kimura Y. Cilostazol, a selective type III phosphodiesterase inhibitor, decreases triglyceride and increases HDL cholesterol levels by increasing lipoprotein lipase activity in rats. Atherosclerosis 2000; 152(2): 299-305.
[] [PMID: 10998457]
Lee JH, Oh GT, Park SY, et al. Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-α formation in low-density lipoprotein receptor-null mice fed high cholesterol. J Pharmacol Exp Ther 2005; 313(2): 502-9.
[] [PMID: 15734902]
Okutsu R, Yoshikawa T, Nagasawa M, et al. Cilostazol inhibits modified low-density lipoprotein uptake and foam cell formation in mouse peritoneal macrophages. Atherosclerosis 2009; 204(2): 405-11.
[] [PMID: 19108834]
Sallustio F, Rotondo F, Di Legge S, Stanzione P. Cilostazol in the management of atherosclerosis. Curr Vasc Pharmacol 2010; 8(3): 363-72.
[] [PMID: 20180773]
Zhao L, Mason NA, Morrell NW, et al. Sildenafil inhibits hypoxia induced pulmonary hypertension. Circulation 2001; 104(4): 424-8.
[] [PMID: 11468204]
Barradas MA, Jagroop A, O’Donoghue S, Jeremy JY, Mikhailidis DP. Effect of milrinone in human platelet shape change, aggregation and thromboxane A2 synthesis: an in vitro study. Thromb Res 1993; 71(3): 227-36.
[] [PMID: 8267765]
Kariyazono H, Nakamura K, Shinkawa T, Yamaguchi T, Sakata R, Yamada K. Inhibition of platelet aggregation and the release of Pselectin from platelets by cilostazol. Thromb Res 2001; 101(6): 445-53.
[] [PMID: 11323002]
Schrör K. The pharmacology of cilostazol. Diabetes Obes Metab 2002; 4(Suppl. 2): S14-9.
[] [PMID: 12180353]
Ishikawa M, Cooper D, Russell J, et al. Molecular determinants of the prothrombogenic and inflammatory phenotype assumed by the postischemic cerebral microcirculation. Stroke 2003; 34(7): 1777-82.
[] [PMID: 12775881]
Wesley MC, McGowan FX, Castro RA, Dissanayake S, Zurakowski D, Dinardo JA. The effect of milrinone on platelet activation as determined by TEG platelet mapping. Anesth Analg 2009; 108(5): 1425-9.
[] [PMID: 19372315]
Kondo K, Umemura K, Miyaji M, Nakashima M. Milrinone, a phosphodiesterase inhibitor, suppresses intimal thickening after photochemically induced endothelial injury in the mouse femoral artery. Atherosclerosis 1999; 142(1): 133-8.
[] [PMID: 9920514]
Biondi-Zoccai GG, Lotrionte M, Anselmino M, et al. Systematic review and meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary intervention. Am Heart J 2008; 155(6): 1081-9.
[] [PMID: 18513523]
Sharma H, Lencioni M, Narendran P. Cardiovascular disease in type 1 diabetes. Cardiovasc Endocrinol Metab 2019; 8(1): 28-34.
[] [PMID: 31646295]
Nagaoka T, Shirakawa T, Balon TW, Russell JC, Fujita-Yamaguchi Y. Cyclic nucleotide phosphodiesterase 3 expression in vivo: evidence for tissue-specific expression of phosphodiesterase 3A or 3B mRNA and activity in the aorta and adipose tissue of atherosclerosis-prone insulin-resistant rats. Diabetes 1998; 47(7): 1135-44.
[] [PMID: 9648839]
Netherton SJ, Jimmo SL, Palmer D, et al. Altered phosphodiesterase 3-mediated cAMP hydrolysis contributes to a hypermotile phenotype in obese JCR:LA-cp rat aortic vascular smooth muscle cells: implications for diabetes-associated cardiovascular disease. Diabetes 2002; 51(4): 1194-200.
[] [PMID: 11916944]
Matsumoto T, Kobayashi T, Kamata K. Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats. Am J Physiol Heart Circ Physiol 2003; 285(1): H283-91.
[] [PMID: 12793980]
Matsumoto T, Wakabayashi K, Kobayashi T, Kamata K. Functional changes in adenylyl cyclases and associated decreases in relaxation responses in mesenteric arteries from diabetic rats. Am J Physiol Heart Circ Physiol 2005; 289(5): H2234-43.
[] [PMID: 15894571]
Matsumoto S, Hanai T, Uemura H, Levin RM. Effects of chronic treatment with vardenafil, a phosphodiesterase 5 inhibitor, on female rat bladder in a partial bladder outlet obstruction model. BJU Int 2009; 103(7): 987-90.
[] [PMID: 19021615]
Kumar A, Kumar A, Jaggi AS, Singh N. Efficacy of Cilostazol a selective phosphodiesterase-3 inhibitor in rat model of Streptozotocin diabetes induced vascular dementia. Pharmacol Biochem Behav 2015; 135: 20-30.
[] [PMID: 25987325]
Tsukamoto Y, Nagata E, Fukuyama N, et al. Cilostazol protects against microvascular brain injury in a rat model of type 2 diabetes. Neurosci Res 2017; 117: 48-53.
[] [PMID: 27939902]
Morishita R, Higaki J, Hayashi SI, et al. Role of hepatocyte growth factor in endothelial regulation: prevention of high D-glucose-induced endothelial cell death by prostaglandins and phosphodiesterase type 3 inhibitor. Diabetologia 1997; 40(9): 1053-61.
[] [PMID: 9300242]
Omi H, Okayama N, Shimizu M, et al. Cilostazol inhibits high glucose-mediated endothelial-neutrophil adhesion by decreasing adhesion molecule expression via NO production. Microvasc Res 2004; 68(2): 119-25.
[] [PMID: 15313121]
Tseng SY, Chao TH, Li YH, et al. Cilostazol improves high glucose-induced impaired angiogenesis in human endothelial progenitor cells and vascular endothelial cells as well as enhances vasculoangiogenesis in hyperglycemic mice mediated by the adenosine monophosphate-activated protein kinase pathway. J Vasc Surg 2016; 63(4): 1051-62.e3.
[] [PMID: 25595409]
Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care 2002; 25(8): 1336-9.
[] [PMID: 12145231]
Deyoung L, Chung E, Kovac JR, Romano W, Brock GB. Daily use of sildenafil improves endothelial function in men with type 2 diabetes. J Androl 2012; 33(2): 176-80.
[] [PMID: 21680809]
Aversa A, Greco E, Bruzziches R, Pili M, Rosano G, Spera G. Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res 2007; 19(2): 200-7.
[] [PMID: 16943794]
Aversa A, Vitale C, Volterrani M, et al. Chronic administration of Sildenafil improves markers of endothelial function in men with Type 2 diabetes. Diabet Med 2008; 25(1): 37-44.
[] [PMID: 18199130]
Santi D, Locaso M, Granata AR, et al. Could chronic Vardenafil administration influence the cardiovascular risk in men with type 2 diabetes mellitus? PLoS One 2018; 13(6)e0199299
[] [PMID: 29953477]
Venneri MA, Giannetta E, Panio G, et al. Chronic inhibition of pde5 limits pro-inflammatory monocyte-macrophage polarization in streptozotocin-induced diabetic mice. PLoS One 2015; 10(5)e0126580
[] [PMID: 25961566]
Ahn GJ, Sohn YS, Kang KK, et al. The effect of PDE5 inhibition on the erectile function in streptozotocin-induced diabetic rats. Int J Impot Res 2005; 17(2): 134-41.
[] [PMID: 15578039]
Schäfer A1, Fraccarollo D, Pförtsch S, et al. Improvement of vascular function by acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes mellitus. Br J Pharmacol 2008; 153: 886-93.
Radovits T, Bömicke T, Kökény G, et al. The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus. Br J Pharmacol 2009; 156(6): 909-19.
[] [PMID: 19298393]
Bierhaus A, Stern DM, Nawroth PP. RAGE in inflammation: a new therapeutic target? Curr Opin Investig Drugs 2006; 7(11): 985-91.
[PMID: 17117586]
Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Vardenafil, an inhibitor of phosphodiesterase-5, blocks advanced glycation end product (AGE)-induced up-regulation of monocyte chemoattractant protein-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression via elevation of cGMP. Clin Exp Med 2011; 11(2): 131-5.
[] [PMID: 20803229]
Flammer AJ, Lüscher TF. Three decades of endothelium research: from the detection of nitric oxide to the everyday implementation of endothelial function measurements in cardiovascular diseases. Swiss Med Wkly 2010; 140: w13122.
[] [PMID: 21120736]
Félétou M, Köhler R, Vanhoutte PM. Endothelium-derived vasoactive factors and hypertension: possible roles in pathogenesis and as treatment targets. Curr Hypertens Rep 2010; 12(4): 267-75.
[] [PMID: 20532699]
Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol 2002; 40(3): 505-10.
[] [PMID: 12142118]
Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs 2002; 62(2): 265-84.
[] [PMID: 11817973]
Stegbauer J, Friedrich S, Potthoff SA, et al. Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension. PLoS One 2013; 8(11)e80674
[] [PMID: 24260450]
Tawar U, Kotlo K, Jain S, Shukla S, Setty S, Danziger RS. Renal phosphodiesterase 4B is activated in the Dahl salt-sensitive rat. Hypertension 2008; 51(3): 762-6.
[] [PMID: 18227403]
Jackson EK, Mi Z. Regulation of renovascular adenosine 3′,5′-cyclic monophosphate in spontaneously hypertensive rats. Hypertension 2009; 54(2): 270-7.
[] [PMID: 19528365]
Cheng D, Ren J, Gillespie DG, Mi Z, Jackson EK. Regulation of 3′,5′-cAMP in preglomerular smooth muscle and endothelial cells from genetically hypertensive rats. Hypertension 2010; 56(6): 1096-101.
[] [PMID: 20975032]
Oyama N, Yagita Y, Kawamura M, et al. Cilostazol, not aspirin, reduces ischemic brain injury via endothelial protection in spontaneously hypertensive rats. Stroke 2011; 42(9): 2571-7.
[] [PMID: 21799161]
Masi S, Uliana M, Virdis A. Angiotensin II and vascular damage in hypertension: Role of oxidative stress and sympathetic activation. Vascul Pharmacol 2019; 115: 13-7.
[] [PMID: 30707954]
Alvarez E, Rodiño-Janeiro BK, Ucieda-Somoza R, González-Juanatey JR. Pravastatin counteracts angiotensin II-induced upregulation and activation of NADPH oxidase at plasma membrane of human endothelial cells. J Cardiovasc Pharmacol 2010; 55(2): 203-12.
[] [PMID: 20010434]
Shi MQ, Su FF, Xu X, et al. Cilostazol suppresses angiotensin II-induced apoptosis in endothelial cells. Mol Med Rep 2016; 13(3): 2597-605.
[] [PMID: 26862035]
Chalupsky K, Cai H. Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 2005; 102(25): 9056-61.
[] [PMID: 15941833]
Yugar-Toledo JC, Ferreira-Melo SE, Consolim-Colombo FM, Irigoyen MC, Coelho OR, Moreno H Jr. Cyclic guanosine monophosphate phosphodiesterase-5 inhibitor promotes an endothelium NO-dependent-like vasodilation in patients with refractory hypertension. Nitric Oxide 2007; 16(3): 315-21.
[] [PMID: 17276107]
Attinà TM, Malatino LS, Maxwell SR, Padfield PL, Webb DJ. Phosphodiesterase type 5 inhibition reverses impaired forearm exercise-induced vasodilatation in hypertensive patients. J Hypertens 2008; 26(3): 501-7.
[] [PMID: 18300861]
Verri V, Brandão AA, Tibirica E. Penile microvascular endothelial function in hypertensive patients: effects of acute type 5 phosphodiesterase inhibition. Braz J Med Biol Res 2018; 51(3)e6601
[] [PMID: 29340522]
Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase type 5 inhibition in hypertension. Hypertension 2006; 48(4): 622-7.
[] [PMID: 16940217]
Yaguas K, Bautista R, Quiroz Y, et al. Chronic sildenafil treatment corrects endothelial dysfunction and improves hypertension. Am J Nephrol 2010; 31(4): 283-91.
[] [PMID: 20110668]
Teixeira-da-Silva JJ, Nunes-Moreira HS, Silva CO, et al. Chronic administration of sildenafil improves endothelial function in spontaneously hypertensive rats by decreasing COX-2 expression and oxidative stress. Life Sci 2019; 225: 29-38.
[] [PMID: 30940538]
Leal MAS, Aires R, Pandolfi T, et al. Sildenafil reduces aortic endothelial dysfunction and structural damage in spontaneously hypertensive rats: Role of NO, NADPH and COX-1 pathways. Vascul Pharmacol 2020; 124: 106601.
[] [PMID: 31689530]
Guimarães DA, Rizzi E, Ceron CS, Pinheiro LC, Gerlach RF, Tanus-Santos JE. Atorvastatin and sildenafil lower blood pressure and improve endothelial dysfunction, but only atorvastatin increases vascular stores of nitric oxide in hypertension. Redox Biol 2013; 1: 578-85.
[] [PMID: 24363994]
Fahning BM, Dias AT, Oliveira JP, et al. Sildenafil improves vascular endothelial structure and function in renovascular hypertension. Curr Pharm Biotechnol 2015; 16(9): 823-31.
[] [PMID: 26059106]
Dias AT, Cintra AS, Frossard JC, et al. Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension. J Transl Med 2014; 12: 250.
[] [PMID: 25223948]
Dias AT, Leal MAS, Zanardo TC, et al. Beneficial morphofunctional changes promoted by sildenafil in resistance vessels in the angiotensin ii-induced hypertension model. Curr Pharm Biotechnol 2018; 19(6): 483-94.
[] [PMID: 29938618]
Wortel RC, Mizrachi A, Li H, et al. Sildenafil protects endothelial cells from radiation-induced oxidative stress. J Sex Med 2019; 16(11): 1721-33.
[] [PMID: 31585804]
Foresta C, Ferlin A, De Toni L, et al. Circulating endothelial progenitor cells and endothelial function after chronic Tadalafil treatment in subjects with erectile dysfunction. Int J Impot Res 2006; 18(5): 484-8.
[] [PMID: 16541115]
Martínez-Revelles S, Avendaño MS, García-Redondo AB, et al. Reciprocal relationship between reactive oxygen species and cyclooxygenase-2 and vascular dysfunction in hypertension. Antioxid Redox Signal 2013; 18(1): 51-65.
[] [PMID: 22671943]
Alvarez Y, Briones AM, Balfagón G, Alonso MJ, Salaices M. Hypertension increases the participation of vasoconstrictor prostanoids from cyclooxygenase-2 in phenylephrine responses. J Hypertens 2005; 23(4): 767-77.
[] [PMID: 15775781]
Xavier FE, Aras-López R, Arroyo-Villa I, et al. Aldosterone induces endothelial dysfunction in resistance arteries from normotensive and hypertensive rats by increasing thromboxane A2 and prostacyclin. Br J Pharmacol 2008; 154(6): 1225-35.
[] [PMID: 18500359]
Kim J, Lee YR, Lee CH, et al. Mitogen-activated protein kinase contributes to elevated basal tone in aortic smooth muscle from hypertensive rats. Eur J Pharmacol 2005; 514(2-3): 209-15.
[] [PMID: 15910808]
Aguado A, Rodríguez C, Martínez-Revelles S, et al. HuR mediates the synergistic effects of angiotensin II and IL-1β on vascular COX-2 expression and cell migration. Br J Pharmacol 2015; 172(12): 3028-42.
[] [PMID: 25653183]
Touyz RM, Deschepper C, Park JB, et al. Inhibition of mitogen-activated protein/extracellular signal-regulated kinase improves endothelial function and attenuates Ang II-induced contractility of mesenteric resistance arteries from spontaneously hypertensive rats. J Hypertens 2002; 20(6): 1127-34.
[] [PMID: 12023682]
Zusman RM, Morales A, Glasser DB, Osterloh IH. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 1999; 83(5A): 35C-44C.
[] [PMID: 10078541]
Jackson G, Benjamin N, Jackson N, Allen MJ. Effects of sildenafil citrate on human hemodynamics. Am J Cardiol 1999; 83(5A): 13C-20C.
[] [PMID: 10078538]
Cipolla MJ, Liebeskind DS, Chan SL. The importance of comorbidities in ischemic stroke: Impact of hypertension on the cerebral circulation. J Cereb Blood Flow Metab 2018; 38(12): 2129-49.
[] [PMID: 30198826]
Abdullahi W, Tripathi D, Ronaldson PT. Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection. Am J Physiol Cell Physiol 2018; 315(3): C343-56.
[] [PMID: 29949404]
Horai S, Nakagawa S, Tanaka K, et al. Cilostazol strengthens barrier integrity in brain endothelial cells. Cell Mol Neurobiol 2013; 33(2): 291-307.
[] [PMID: 23224787]
Omote Y, Deguchi K, Kono S, et al. Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation. J Neurosci Res 2014; 92(3): 369-74.
[] [PMID: 24375726]
Rosenberg GA. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 2009; 8(2): 205-16.
[] [PMID: 19161911]
Hase Y, Okamoto Y, Fujita Y, et al. Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia. Exp Neurol 2012; 233(1): 523-33.
[] [PMID: 22173318]
Fukuoka T, Hayashi T, Hirayama M, Maruyama H, Tanahashi N. Cilostazol inhibits platelet-endothelial cell interaction in murine microvessels after transient bilateral common carotid artery occlusion. J Stroke Cerebrovasc Dis 2014; 23(5): 1056-61.
[] [PMID: 24135235]
Ueno H, Koyama H, Mima Y, et al. Comparison of the effect of cilostazol with aspirin on circulating endothelial progenitor cells and small-dense LDL cholesterol in diabetic patients with cerebral ischemia: a randomized controlled pilot trial. J Atheroscler Thromb 2011; 18(10): 883-90.
[] [PMID: 21701082]
Belayev L, Busto R, Ikeda M, et al. Protection against blood-brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: a quantitative study. Brain Res 1998; 787(2): 277-85.
[] [PMID: 9518648]
Kraft P, Schwarz T, Göb E, et al. The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis. Exp Neurol 2013; 247: 80-90.
[] [PMID: 23570902]
Hu S, Cao Q, Xu P, Ji W, Wang G, Zhang Y. Rolipram stimulates angiogenesis and attenuates neuronal apoptosis through the cAMP/cAMP-responsive element binding protein pathway following ischemic stroke in rats. Exp Ther Med 2016; 11(3): 1005-10.
[] [PMID: 26998028]
Chen J, Yu H, Zhong J, et al. The phosphodiesterase-4 inhibitor, FCPR16, attenuates ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion and reperfusion. Brain Res Bull 2018; 137: 98-106.
[] [PMID: 29155261]
Zhang R, Wang L, Zhang L, et al. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 2003; 92(3): 308-13.
[] [PMID: 12595343]
Li L, Jiang Q, Zhang L, et al. Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res 2007; 1132(1): 185-92.
[] [PMID: 17188664]
Zhang L, Zhang Z, Zhang RL, et al. Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res 2006; 1118(1): 192-8.
[] [PMID: 16959227]
Choi SM, Kim JE, Kang KK. Chronic treatment of DA-8159, a new phosphodiesterase type V inhibitor, attenuates endothelial dysfunction in stroke-prone spontaneously hypertensive rat. Life Sci 2006; 78(11): 1211-6.
[] [PMID: 16214180]
Barodka VM, Joshi BL, Berkowitz DE, Hogue CW Jr, Nyhan D. Review article: implications of vascular aging. Anesth Analg 2011; 112(5): 1048-60.
[] [PMID: 21474663]
El Assar M, Angulo J, Vallejo S, Peiró C, Sánchez-Ferrer CF, Rodríguez-Mañas L. Mechanisms involved in the aging-induced vascular dysfunction. Front Physiol 2012; 3: 132.
[] [PMID: 22783194]
Bautista Niño PK, Durik M, Danser AH, et al. Phosphodiesterase 1 regulation is a key mechanism in vascular aging. Clin Sci (Lond) 2015; 129(12): 1061-75.
[] [PMID: 26464516]
Ota H, Eto M, Kano MR, et al. Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arterioscler Thromb Vasc Biol 2008; 28(9): 1634-9.
[] [PMID: 18556572]
Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci USA 2007; 104(37): 14855-60.
[] [PMID: 17785417]
Moreira HS, Lima-Leal GA, Santos-Rocha J, Gomes-Pereira L, Duarte GP, Xavier FE. Phosphodiesterase-3 inhibitor cilostazol reverses endothelial dysfunction with ageing in rat mesenteric resistance arteries. Eur J Pharmacol 2018; 822: 59-68.
[] [PMID: 29355555]
Sarela AI, Mihaimeed FMA, Batten JJ, Davidson BR, Mathie RT. Hepatic and splanchnic nitric oxide activity in patients with cirrhosis. Gut 1999; 44(5): 749-53.
[] [PMID: 10205218]
Wiest R, Groszmann RJ. Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance. Semin Liver Dis 1999; 19(4): 411-26.
[] [PMID: 10643626]
Shah V, García-Cardeña G, Sessa WC, Groszmann RJ. The hepatic circulation in health and disease: report of a single-topic symposium. Hepatology 1998; 27(1): 279-88.
[] [PMID: 9425948]
Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002; 35(2): 478-91.
[] [PMID: 11826425]
Shah V, Lyford G, Gores G, Farrugia G. Nitric oxide in gastrointestinal health and disease. Gastroenterology 2004; 126(3): 903-13.
[] [PMID: 14988844]
McCuskey RS. Morphological mechanisms for regulating blood flow through hepatic sinusoids. Liver 2000; 20(1): 3-7.
[] [PMID: 10726955]
Lee KC, Yang YY, Huang YT, et al. Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability. Clin Sci (Lond) 2010; 119(1): 45-55.
[] [PMID: 20132096]
Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017; 121: 27-42.
[] [PMID: 28506744]
Shah V, Wiest R, Garcia-Cardena G, Cadelina G, Groszmann RJ, Sessa WC. Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension. Am J Physiol 1999; 277(2): G463-8.
[PMID: 10444461]
Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol 2003; 38(Suppl. 1): S54-68.
[] [PMID: 12591186]
Tsai MH, Iwakiri Y, Cadelina G, Sessa WC, Groszmann RJ. Mesenteric vasoconstriction triggers nitric oxide overproduction in the superior mesenteric artery of portal hypertensive rats. Gastroenterology 2003; 125(5): 1452-61.
[] [PMID: 14598261]
Wiest R, Shah V, Sessa WC, Groszmann RJ. NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. Am J Physiol 1999; 276(4): G1043-51.
[PMID: 10198349]
Ginès P, Cárdenas A, Arroyo V, Rodés J. Management of cirrhosis and ascites. N Engl J Med 2004; 350(16): 1646-54.
[] [PMID: 15084697]
Garcia-Tsao G. Portal hypertension. Curr Opin Gastroenterol 2005; 21(3): 313-22.
[] [PMID: 15818152]
Abdel Kawy HS. Cilostazol attenuates cholestatic liver injury and its complications in common bile duct ligated rats. Eur J Pharmacol 2015; 752: 8-17.
[] [PMID: 25666386]
Loureiro-Silva MR, Iwakiri Y, Abraldes JG, Haq O, Groszmann RJ. Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers. J Hepatol 2006; 44(5): 886-93.
[] [PMID: 16545481]
Deibert P, Schumacher YO, Ruecker G, et al. Effect of vardenafil, an inhibitor of phosphodiesterase-5, on portal haemodynamics in normal and cirrhotic liver -- results of a pilot study. Aliment Pharmacol Ther 2006; 23(1): 121-8.
[] [PMID: 16393289]
Lee KC, Yang YY, Wang YW, et al. Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients. Hepatol Res 2008; 38(12): 1186-93.
[] [PMID: 18631254]
Bremer HC, Kreisel W, Roecker K, et al. Phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension: a case report. J Med Case Reports 2007; 1: 46.
[] [PMID: 17623085]
Deibert P, Bremer H, Roessle M, Kurz-Schmieg AK, Kreisel W. PDE-5 inhibitors lower portal and pulmonary pressure in portopulmonary hypertension. Eur Respir J 2007; 29(1): 220-1.
[] [PMID: 17197488]
Cheng CH, Wang YC, Wu TH, et al. Sildenafil monotherapy to treat portopulmonary hypertension before liver transplant. Transplant Proc 2019; 51(5): 1435-8.
[] [PMID: 31079941]
Colle I, De Vriese AS, Van Vlierberghe H, Lameire NH, DeVos M. Systemic and splanchnic haemodynamic effects of sildenafil in an in vivo animal model of cirrhosis support for a risk in cirrhotic patients. Liver Int 2004; 24(1): 63-8.
[] [PMID: 15102002]
Wang YW, Lin HC, Yang YY, Hou MC, Lee SD. Sildenafil decreased pulmonary arterial pressure but may have exacerbated portal hypertension in a patient with cirrhosis and portopulmonary hypertension. J Gastroenterol 2006; 41(6): 593-7.
[] [PMID: 16868809]
Clemmesen JO, Giraldi A, Ott P, Dalhoff K, Hansen BA, Larsen FS. Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis. World J Gastroenterol 2008; 14(40): 6208-12.
[] [PMID: 18985812]

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