{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:15:58Z","timestamp":1791090958495,"version":"4.1.0"},"reference-count":122,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2011,1,31]],"date-time":"2011-01-31T00:00:00Z","timestamp":1296432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurourology and Urodynamics"],"published-print":{"date-parts":[[2011,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The PDE5 inhibitor tadalafil is investigation for the treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Several clinical studies of tadalafil and other PDE5 inhibitors have reported significant symptom reduction but limited urinary flow rate improvement. This manuscript reviews the published literature describing the pathophysiology of male LUTS, with an emphasis on mechanisms that may be modulated or improved by phosphodiesterase type 5 (PDE5) inhibition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Literature (through March 2010) was obtained via Medline searches and from the individual reviewers files. Articles were selected for review based on describing in vitro, preclinical, or clinical studies of pathological processes contributing to LUTS, or possible effects of PDE5 inhibition in the lower urinary tract.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Major mechanisms contributing to LUTS include: reduced nitric oxide\/cyclic guanosine monophosphate signaling; increased RhoA kinase pathway activity; autonomic overactivity; increased bladder afferent activity; and pelvic ischemia. Tadalafil and other PDE5 inhibitors have demonstrated beneficial effects on smooth muscle relaxation, smooth muscle and endothelial cell proliferation, nerve activity, and tissue perfusion that may impact LUTS in men.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The pathophysiology of male LUTS is complex and not completely understood. LUTS may occur independently of BPH or secondary to BPH but in both cases involve obstructive or irritative mechanisms with substantial pathophysiological overlap. While the precise mechanism remains unclear, inhibition of PDE5 seems to have an effect on several pathways that may impact LUTS. Neurourol. Urodynam. 30:292\u2013301, 2011. \u00a9 2011 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/nau.20999","type":"journal-article","created":{"date-parts":[[2011,1,31]],"date-time":"2011-01-31T15:26:31Z","timestamp":1296487591000},"page":"292-301","source":"Crossref","is-referenced-by-count":175,"title":["Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: Pathophysiology and mechanism(s) of action"],"prefix":"10.1002","volume":"30","author":[{"given":"Karl\u2010Erik","family":"Andersson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"de Groat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin T.","family":"McVary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom F.","family":"Lue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Maggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus G.","family":"Roehrborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Jacques","family":"Wyndaele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Melby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Viktrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,1,31]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2003.08.015"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-4295(02)02243-4"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2006.02.018"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2006.09.019"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-4295(01)01298-5"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11934-002-0095-3"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2003.09.030"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2009.07.044"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2008.03.109"},{"key":"e_1_2_7_11_2","unstructured":"AUA Practice Guidelines Committee.AUA guideline on management of benign prostatic hyperplasia.http:\/\/www.auanet.org\/content\/guidelines\u2010and\u2010quality\u2010care\/clinical\u2010guidelines\/main\u2010reports\/bph\u2010management\/chapt_3_appendix.pdf 2003."},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa030656"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2008.08.062"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2006.06102.x"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2008.01.075"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2006.10.055"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2006.11.037"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2008.06.079"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2009.08822.x"},{"key":"e_1_2_7_20_2","article-title":"Tadalafil administered once daily for treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: A 1\u2010year study","author":"Donatucci C","year":"2010","journal-title":"BJU Int"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2009.11.014"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-008-0303-y"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/nau.20485"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2009.08418.x"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2006.06501.x"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1838(96)00139-7"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0045(19970915)33:1<1::AID-PROS1>3.0.CO;2-P"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)65621-2"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1838(94)00160-L"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-005-1151-3"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-005-0146-4"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1998.275.2.F226"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.90301.2008"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-007-0454-y"},{"key":"e_1_2_7_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)37208-7"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1995.tb16379.x"},{"key":"e_1_2_7_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2006.06217.x"},{"key":"e_1_2_7_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00304075"},{"key":"e_1_2_7_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00457-X"},{"key":"e_1_2_7_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2007.11.008"},{"key":"e_1_2_7_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2005.12.050"},{"key":"e_1_2_7_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2009.01511.x"},{"key":"e_1_2_7_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2010.03.110"},{"key":"e_1_2_7_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/PL00007088"},{"key":"e_1_2_7_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003450100221"},{"key":"e_1_2_7_46_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-1079"},{"key":"e_1_2_7_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2009.08651.x"},{"key":"e_1_2_7_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2008.06.060"},{"key":"e_1_2_7_49_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2008.07555.x"},{"key":"e_1_2_7_50_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2009.08438.x"},{"key":"e_1_2_7_51_2","doi-asserted-by":"publisher","DOI":"10.1006\/pmed.2000.0643"},{"key":"e_1_2_7_52_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007174102953"},{"key":"e_1_2_7_53_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1992.tb09273.x"},{"key":"e_1_2_7_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)67420-4"},{"key":"e_1_2_7_55_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.2000.279.3.R1112"},{"key":"e_1_2_7_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2009.09.074"},{"key":"e_1_2_7_57_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.53.3.467"},{"key":"e_1_2_7_58_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2009.01249.x"},{"key":"e_1_2_7_59_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00378.2002"},{"key":"e_1_2_7_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/83258"},{"key":"e_1_2_7_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.10170"},{"key":"e_1_2_7_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-4356(01)00351-1"},{"key":"e_1_2_7_63_2","doi-asserted-by":"publisher","DOI":"10.1080\/080370599438365"},{"key":"e_1_2_7_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2009.04.025"},{"key":"e_1_2_7_65_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.21041"},{"key":"e_1_2_7_66_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.ju.0000173072.73702.64"},{"key":"e_1_2_7_67_2","first-page":"79","article-title":"The autonomic nervous system function in benign prostatic hyperplasia","volume":"47","author":"Thor PJ","year":"2006","journal-title":"Folia Med Cracov"},{"key":"e_1_2_7_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2007.04.048"},{"key":"e_1_2_7_69_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod51.1.99"},{"key":"e_1_2_7_70_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod44.6.1171"},{"key":"e_1_2_7_71_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0045(1998)8 <2::AID-PROS2>3.0.CO;2-U"},{"key":"e_1_2_7_72_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1939-4640.2000.tb03276.x"},{"key":"e_1_2_7_73_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.1998.275.4.R1366"},{"key":"e_1_2_7_74_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-79090-7_4"},{"key":"e_1_2_7_75_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903100309"},{"key":"e_1_2_7_76_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115488"},{"key":"e_1_2_7_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(01)66664-3"},{"key":"e_1_2_7_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2008.01.069"},{"key":"e_1_2_7_79_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpuro0408"},{"key":"e_1_2_7_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2005.12.018"},{"key":"e_1_2_7_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2006.07.015"},{"key":"e_1_2_7_82_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2005.05777.x"},{"key":"e_1_2_7_83_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2006.06400.x"},{"key":"e_1_2_7_84_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11934-002-0051-2"},{"key":"e_1_2_7_85_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.10279"},{"key":"e_1_2_7_86_2","first-page":"1936","article-title":"Expression of hypoxia\u2010inducible factor 1alpha in human normal, benign, and malignant prostate tissue","volume":"116","author":"Du Z","year":"2003","journal-title":"Chin Med J (Engl)"},{"key":"e_1_2_7_87_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2006.03.038"},{"key":"e_1_2_7_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)68236-5"},{"key":"e_1_2_7_89_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)68995-1"},{"key":"e_1_2_7_90_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2007.03.096"},{"key":"e_1_2_7_91_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2007.07310.x"},{"key":"e_1_2_7_92_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2007.07339.x"},{"key":"e_1_2_7_93_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2009.05.045"},{"key":"e_1_2_7_94_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2006.06735.x"},{"key":"e_1_2_7_95_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)64843-4"},{"key":"e_1_2_7_96_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2006.12.011"},{"key":"e_1_2_7_97_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.10084"},{"key":"e_1_2_7_98_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ucl.2007.09.012"},{"key":"e_1_2_7_99_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.21027"},{"key":"e_1_2_7_100_2","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/S0022-5347(18)35422-3","article-title":"The impact of acute or chronic inflammation in baseline biopsy on the risk of clinical progression of BPH: Results from the MTOPS Study [Abstract 1286]","volume":"173","author":"Roehrborn CG","year":"2005","journal-title":"J Urol"},{"key":"e_1_2_7_101_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2009.00972.x"},{"key":"e_1_2_7_102_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2009.235"},{"key":"e_1_2_7_103_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.01.144"},{"key":"e_1_2_7_104_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-002-0248-5"},{"key":"e_1_2_7_105_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2008.11.041"},{"key":"e_1_2_7_106_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2007.10.051"},{"key":"e_1_2_7_107_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1442-2042.2007.01874.x"},{"key":"e_1_2_7_108_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2008.08.062"},{"key":"e_1_2_7_109_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2001.86.1.304"},{"key":"e_1_2_7_110_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00207.2009"},{"key":"e_1_2_7_111_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2008.08324.x"},{"key":"e_1_2_7_112_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2007.07.048"},{"key":"e_1_2_7_113_2","first-page":"271","article-title":"Effect of chronic ischemia on bladder structure and function","volume":"539","author":"Azadzoi KM","year":"2003","journal-title":"Adv Exp Med Biol"},{"key":"e_1_2_7_114_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-005-0026-2"},{"key":"e_1_2_7_115_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2004.10.002"},{"key":"e_1_2_7_116_2","doi-asserted-by":"publisher","DOI":"10.1080\/10799890802176626"},{"key":"e_1_2_7_117_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2008.07587.x"},{"key":"e_1_2_7_118_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.ju.0000064923.29954.7e"},{"key":"e_1_2_7_119_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11547-009-0449-8"},{"key":"e_1_2_7_120_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2005.06.040"},{"key":"e_1_2_7_121_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2009.01558.x"},{"key":"e_1_2_7_122_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2009.01.030"},{"key":"e_1_2_7_123_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0304264101"}],"container-title":["Neurourology and Urodynamics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fnau.20999","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fnau.20999","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/nau.20999","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T14:57:48Z","timestamp":1696690668000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/nau.20999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,1,31]]},"references-count":122,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2011,3]]}},"alternative-id":["10.1002\/nau.20999"],"URL":"https:\/\/doi.org\/10.1002\/nau.20999","archive":["Portico"],"relation":{},"ISSN":["0733-2467","1520-6777"],"issn-type":[{"value":"0733-2467","type":"print"},{"value":"1520-6777","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,1,31]]}}}