Mekhoa ea Phoso ea Penile le Motheo oa Phekolo ea Meriana ea Erectile Dysfunction (2011)

1. Li-Synthases tsa Nitric-Oxide Lenaneong.

Karolo ea bohlokoa ea NO boikhathollong ba CC ea mesifa le li-vasculature e amoheloa ka bongata.Andersson le Wagner, 1995; Andersson, 2001; Musicki le Burnett, 2006; Musicki et al., 2009). Ho bonahala ho se na lipelaelo mabapi le boteng ba li -NNOS methapong ea ho hlapela le ho fela ha tsona kahare ho CC, le makaleng a methapo ea methapo ea methapo le methapo ea methapo ho bahanyetsi ba methapo e tebileng ea thapo ea thota.Andersson, 2001). Ka bobeli methapo (nNOS) le endothelium (eNOS) ea CC e kanna ea ba mohloli oa NO. Menehelo e lekanyelitsoeng ea mefuta e fapaneng ea NOS ho erection ha e e-so theoe.

Phapang ea nNOS (penile nNOS) e tšoauoe e le li-isoforms tse peli tse fapaneng ka ho khetheha botoneng ba panya le sebopeho, foromo ea bolelele bo bolelele ba α le mofuta oa β oa splice o haellang mofuta oa N-terminal postynaptic density 95 / disc-large / zona sebaka sa occludens, sa bohlokoa bakeng sa tšebelisano-'mele le protheine. Bopaki bo fana ka maikutlo a hore phapang ea α splice e sebetsa ho NO sebopeho litsing tsa methapo, athe karolo e sebetsang ea of ​​variant ka vivo ha e hlake ebile e kanna ea se kholo (Magee et al., 1996; Gonzalez-Cadavid et al., 1999, 2000). Liphumano tsa Hurt et al. (2006) o netefalitse hore mefuta e meng e sebelisitsoeng ea liNNOS ke babuelli ba mantlha ba kutloisiso ea penile. Lits'ila tse haellang ka bobeli ba eNOS le liNNOS li na le litšebelisano, li bontša boits'oaro bo tloaelehileng ba ho ikatisa, 'me li arabela ka mokhoa o matla ho tsosa motlakase oa methapo ea kutlo. Re ile ra makatsoa ke ho fumana hore lisele tse ikhethileng tsa khoebo tse tsoang liphoofolong tse hlaha le tse tlositsoeng NOS li bonts'a likarabo tse ts'oanang le ts'usumetso ea motlakase (Burnett et al., 1996; Hurt et al., 2006). Lithuto tse sebetsang li ts'ehetsa ho hlaha le bohlokoa ba eNOS liseleng tsa ho hlatsoetsa batho (Andersson le Wagner, 1995; Musicki le Burnett, 2006), mme ho bonahala eka ho joalo le ka rat (Cartledge et al., 2000b) le toeba (Mizusawa et al., 2001) CC.

Le ha kopano lipakeng tsa NOS isoenzymes e ntse e le taba ea ho ithuta, bopaki bo teng bo supa mohlaleng (Feie. 4) moo NNOS e qalang karabelo ea erectile, e ntan'o ba e ts'oaroang le ho eketsoa ke ts'ebetso ea eNOS (e qetellang e hlahisoa ke khatello ea shear) (Hurt et al., 2002, 2006; Musicki le Burnett, 2006; Bivalacqua et al., 2007b; Musicki et al., 2009). eNOS e na le karolo ea bohlokoahali karabelong ea erectile, mme ts'ebetso ea eona le endothelial NO bioavailability li laoloa ke mekhoa e mengata ea kamora ho fetolela ea phetolelo, joalo ka phosphorylation, ts'ebelisano ea eNOS le liprotheine tse tataisang le litsela tsa contractile, le liketso tsa mefuta e sebetsang ea oksijene (ROS) . Mechine ena e laola likarabo tsa INOS tse pakeng tsa maemo a 'mele' me e fana ka mekhoa e fapaneng eo ho se nang phetoho ea letho ea NO e ka fetoloang ho eona ka lipina tsa vasculogenic erectile dysfunction (ED).

   

Sheba tlhahiso e kholoanyane:   

• Leqepheng lena
• Ka fensetere e ncha

Setšoantšo sa 4.   

Tšebelisano pakeng tsa nNOS le eNOS. Bopaki bo ntseng bo le teng bo supa mohloling oo ho oonaNNOS e qalang karabelo ea erectile, e ntan'o bolokoa le ho eketsoa ke ts'ebetso ea eNOS (e qetellang e hlahisoa ke khatello ea shear). [E fetotsoe ho tsoa ho Hurt KJ, Musicki B, Palese MA, Crone JK, Becker RE, Moriarity JL, Snyder SH, le Burnett AL (2002) phosphorylation e itšetlehileng ka Akt ea endothelial nitric-oxide synthase Mediates penile erection. Proc Natl Acad Sci USA 99:4061-4066. Tokelo ea Copyright © 2002 Setsi sa Naha sa Mahlale, USA. E sebelisoa ka tumello.].

Tšusumetso ea li-androgens ts'ebetsong ea erectile e kanna ea hokahanngoa le tsela ea NO / cGMP (Andersson, 2001) le haeba ho bontšitsoe litsela tse sa itšetleheng ka NO.Reilly et al., 1997; Mills le Lewis, 1999; Mill et al., 1999). Ho tsamaisoa ha likhoto le kalafo ka antiandrogen flutamide ho fokolitse mosebetsi oa penile NOS (Chamness et al., 1995; Lugg et al., 1996; Penson et al., 1996).

Ha ho bapisoa le likhoto tse nyane, methapo e nang le NOS, polelo ea NOS mRNA, le ts'ebetso ea NOS li fokotsehile liphoofolong tsa khale (Garban et al., 1995; Carrier et al., 1997; Dahiya et al., 1997). ED e amanang le, ho etsa mohlala, lefu la tsoekere le fumanoe le amahanngoa le litaba tse fokotsehileng tsa NNOS le tšebetso ho CC ea ratVernet et al., 1995; Autieri et al., 1996; Rehman et al., 1997). Ho batho, lefu la tsoekere la "lefu la tsoekere" le khothalelitsoe ho amana le litlamorao tsa lihlahisoa tsa pheletso ea glycation kamorao ho sebopeho sa NO (Seftel et al., 1997). Cartarant et al. (2000a) e fumanoe litatsong tse tsoang glycosylated hemoglobin ea motho ea nyenyefatsang mesifa ea CC e khathollang ka meloko ea li-anions tsa superoxide le ts'ebetso ea extracellular ea NO.

Angulo et al. (2006), ho lekola tšusumetso ea ts'ebetso ea PKC mabapi le molumo o bonolo oa mesifa ho li-tiske tse tsoang ho banna ba lefu la tsoekere le ba nondiabetic ba nang le ED, o fumane hore ts'ebeliso e feteletseng ea PKC ho lefu la tsoekere e ikarabella bakeng sa tumellano e ntlafalitsoeng le ho fokotsa boikhathollo bo itšetlehileng ka INOS ba mesifa ea CC ea motho.

2. Likarolo tsa Guanylyl.

Li-GCs, tse nang le li-membrane-bind (membrate, pGC) le solofle isoforms (sGC), li hlahisitsoe ka mefuta eohle ea sele (Lucas et al., 2000). Li-GC li hlohlelletsoa ke NO, li-peptide tsa natriuretic, le ligands tse ling tsa endo native (mohlala, CO). CO, e hlahisoang ka ho senyeha hoa heme oxygenase-mediated ea heme ea cellular, e boetse e ntlafatsa sGC, empa e le tlase haholo ho feta NO (Friebe et al., 1996).

Kim et al. (1998) tlhahiso e bonts'itseng tlhahiso ea cGMP ke pGC kahar'a li-membrane tsa CC tsa mmutla le rat e hlohlellelitsoeng ke mofuta oa C-mofuta oa natriuretic peptide 1-22 (CNP), atria natriuretic peptide 1-28 (ANP), le brain natriuretic peptide 1-26 (BNP). Ntle le moo, CNP, empa eseng ANP, e lokisitse litokisetso tse ikhethileng tsa rabi CC. Aizawa et al. (2008) e ile ea etsa lipatlisiso ka litlamorao tsa ANP, BNP, le CNP ka khatello ea methapo le methapo ea mali methapong ea methapo e sa sebetseng. Ba fumane hore likarabo tsa erectile li ka qalisoa ke ANP, ka BNP, mme ha e sebetse hantle ke CNP. ANP le BNP li na le tšebelisano e phahameng ho GC-A, li fana ka maikutlo a hore li-receptor tsena li kentse letsoho likarabo.

Küthe et al. (2003) o ithutile polelo ea GC-B, e amohelang CNP ho CC ea motho. Lingoloa tsa mRNA li fumanoe li kenyelelitsoe ho GC-B, mme polelo e netefalitsoe maemong a protheine ka immunohistochemistry e bonts'ang GC-B ho CC le lisele tsa methapo ea methapo ea methapo. CNP e eketsehile kahare cGMP. Lithutong tsa ho hlapela ka litho tsa 'mele ka li-strip tsa CC tsa mesifa, CNP e ile ea baka boikhathollo ba mesifa. Ho fihletsoe qeto ea hore CNP le li-receptor tsa eona li kanna tsa ba le karolo ho kenyeng tšebetsong ea penile. Kameho e phomotsang ea ANP le uroguanylin li bontšitsoe ka marang-rang a CC ea motho ke Sousa et al. (2010). Ba fumane hore uroguanylin e nchafalitse methapo ke GC le K_CaMechine e itšetlehileng ka "mocha" mme e khothalelitse hore li-receptors tsa natriuretic peptide ke liphofu tse ka ba teng ntlafatsong ea lithethefatsi tse ncha bakeng sa kalafo ea ED. Leha ho le joalo, botoneng, sGC mohlomong ke "receptor" ea bohlokoa ka ho fetisisa ea NO joalo ka molek'hule e bolelang. Enzyme, e thusang ho fetoloa ha GTP ho cGMP, e na le likarolo tse peli tse fapaneng mme e na le sehlopha sa heme sa maiketsetso se sebetsanang le 400-fold activation ka NO. Nimmegeers et al. (2008) e lekotse bohlokoa ba tšebetsong ba sGCcy₁β₁ isoform in CC ho tloha bannaGG₁(- / -) le litoeba tsa mofuta oa hlaha. Ho phomola ho ea ho endo native NO (ho tloha ka acetylcholine, bradykinin, le tšusumetso ea masimo a motlakase) e se e batla e felisitsoe ka sGCcy₁(- / -) CC. Ho sGCcy₁(- / -) litoeba, tšusumetso ea boikhathollo ea li-exo native NO (ho tsoa ho sodium nitroprusside le NO gase), 3- (4-amino-5-cyclopropylpyrimidine-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine (BAY 41-2272; NO-e ikemetseng ea sGC e hlohlelletsang), le methyl- (2- (4-aminophenyl) -1,2-dihydro-1-oxo-7- (2-pyridinylmethoxy) -4- (3,4,5-pyridinylmethoxy) -3- (1032-pyridinylmethoxy) -5- (XNUMX-pyridinylmethoxy ) -XNUMX-isoquinoline carboxylic acid, letsoai la sulfate (T-XNUMX; mofuta oa phosphodiesterase XNUMX inhibitor) le tsona li fokotsehile haholo. Ho ile ha fihleloa qeto ea hore sGCcy₁β₁ isoform e kenya letsoho boikhathollong ba mesifa ea CC ho araba li-stimulators tsa NO le NO-e ikemetseng ea sGC.

3- (5'-Hydroxymethyl-2'-furyl) -1-benzylindazole (YC-1) e bontšitsoe ho etsa ts'ebetso e tobileng ea sGC (Feie. 5) ka ho eketsa botsitso bakeng sa GTP le ho eketsa ts'ebetso e matla ea enzyme, e lebisang maemong a eketsehang a cGMP liseleng tsa mesifa e boreleli (Mülsch et al., 1997; Friebe le Koesling, 1998). Ntle le moo, YC-1 e bakile ts'ebetso e kholo boteng ba NO donor sodium nitroprusside, e ileng ea lebisa ho khothatsong ea 2200 e makatsang ea sGC ea motho e kopaneng hape (Lee le al., 2000). YC-1 e bakile likarabo tse itšetlehileng ka boiketlo litokisetsong tsa NA tsa konteraka tsa rat le CC, le likarabo tse ntlafatsang molemong oa tšusumetso ea tšimo ea motlakase. YC-1 e boetse e ntlafalitse karabelo ea boikhathollo e hlahisoang ke carbachol. Ka vivo, YC-1 ha e arabe likarabo tse tsoang ho erectile ka tekanyetso ha e fanoa ka mokhoa o ts'oanelang empa e boetse e eketsa litlamorao khatello ea intracavernosal e hlahisoang ke ts'usumetso ea methapo ea kutlo.Mizusawa et al., 2002a). YC-1 e khonne ho eketsa haholo litlamorao tsa pro-erectile ea lethal dose ea suboptimal ea apomorphine (Hsieh et al., 2003).

   

Sheba tlhahiso e kholoanyane:   

• Leqepheng lena
• Ka fensetere e ncha

Setšoantšo sa 5.   

Soluble guanylyl cyclase e teng e le heterodimer ea α (82 kDa) le β (70 kDa) subunits mme e na le sebaka sa bohanyetsi le libaka tse peli tsa allosteric. Sebaka se le seng sa litlhaloso se hlalositsoe ke SETSI sa tlamo (heme; Fe), 'me sa bobeli se emeloa ke YC-1. Lijana tse kang YC-1 li ka kenya tšebetsong sGC kamora ho tlama sebakeng sa allosteric ho enzyme, ea lebisa ho keketseho ea khatello ea methapo ea cGMP, boikhathollo ba lithane tsa cavernosal, le ho nolofalletsa penile erection ho vivo.

The pyrazolopyridine derivative BAY41-2272 e boetse e fumanoe e tsosa sGC ka tsela e sa ikemelang mme e bakile boikhathollo bo its'etlehileng ba ho hlaseloa ha motho le bo-rabi.Kalsi et al., 2003) empa a hlohlelletsa likarolo tsa 'mele tse fokolang feela tsa' me a humile ka mor'a ho kenella kahare ho tsamaiso ea molomo le molomo moo ho se nang mofani. Leha ho le joalo, ts'ebetso ea BAY 41-2272 e ne e khoneha ke tsamaiso e ts'oanang ea SNP (Bischoff et al., 2003). Ntle le moo, ho kile ha ithutoa le ba bang ba sebetsang ka GCLasker et al., 2010). Ho bontšitsoe hore ho sebetsa ha li-activator tsa sGC bakeng sa ED ha ho e-so tsejoe le hore lithuto tsa lifofane li hlokahala ho lekola ts'ebeliso ea tsona kalafong ea lefu lena. Ts'ebeliso ea li-activators le sGC ka bobeli e ka ba molemo maemong a fetotsoeng a heme hammoho le maemong ao ho seng motsoako o mong o senyehileng (Lasker et al., 2010).

3. cGMP Ho tšoaea.

Mekhoa e kenyelletsang ho saena hoa cGMP e sa tsoa hlahlojoa haholo ke Francis et al. (2010). Ho hlohlelletsa li-GC ka NO le li-peptide tsa natriuretic, le li-ligands tse ling tsa morao-rao (mohlala, CO), e hlahisa cGMP, e nang le tšusumetso ho mefuta e mengata ea sele ea methapo le ho laola molumo oa vasomotor, tumello ea endothelial, kholo ea lisele, le phapang, hammoho le liplatelete. le litšebelisano tsa lisele tsa mali. Ho na le bopaki ba ho khutlisetsa melao-motheo ea litsela tsa NO-cGMP le natriuretic peptide-cGMP le hore tsamaiso e le 'ngoe ea cGMP e hlahisang phello ea khatello ea tse ling (Kemp-Harper le Schmidt, 2009; Francis et al., 2010). matšoao a cGMP ka li-receptor tse tharo tse ka sehloohong liseleng tsa eukaryotic: liteishene tsa ion, phosphodiesterases, le kinases ea protheine (Lucas et al., 2000; Kemp-Harper le Schmidt, 2009; Francis et al., 2010). Morero oa limolek'hule, o kengoa ts'ebetsong ke cGMP 'me qetellong o hlahise ho phomola ha mesifa ea penile boreleli le erection, o ntse o tsejoa ka karolo e itseng.

Li-protein tse tharo tse fapaneng tsa cGMP tse itšetlehileng ka li-cases tsa cGMP (cGKIcy, cGK1β, le cGKII; hape li rehiloe PKGIcy, PKGIβ, le PKGII) li fumanoe ho liphoofolo tse anyesang. Ho se sebetse ha cGKI ho litoeba ho felisitse ho phomola ho itšetlehileng ka mofuta oa NO / cGMP ka ho phutholoha ha mesifa le ka popelong boreleli le ho sitisa ho kopanngoa hoa liplatelete, ho baka khatello ea mali, dysmotility ea mala, le hemostasis e sa tloaelehang (Pfeifer et al., 1998). Limpho tsa CGKI-defrema [cGKI (- / -)] li bonts'a bokhoni bo tlase haholo ba ho ikatisa. Ho li-CC tsa lithane tse tsoang ho litoeba tsena, karabelo e phomotsang methapong ea methapo kapa tsamaiso e tsoang ntle le e fanoeng HONA e ile ea fokotsoa haholo (Hedlund et al., 2000a). Polelo ea cGKI ka lithane tsa penile ho tsoa ho litoeba tsa cGKI (+ / +), joalo ka ha e senotsoe ke immunohistochemistry, e ne e ts'oaretsoe ke mesifa e boreleli ea marako a methapo ea methapo ea methapo ea methapo le mesifa e boreleli ea sepera se potolohileng sebaka se haufi le thipa. Sena se tsamaisana le karolo ea eona e nahannoeng liketsahalong tsa erectile. Kakaretso ea ho boloka thepa (sehlahisoa sa mofuta oa proteni 9.5 immunoreactivity) le ho tsamaisoa ha methapo ea methapo e nang le li-transmitter kapa li-enzymes tse etsang li-transmitter tseo ho lumeloang hore li bohlokoa taolong ea molumo liseleng tsa CC (Andersson le Wagner, 1995li ne li tšoana le litoeba tse tloaelehileng le tsa cGKI-null (Hedlund et al., 2000).

Tlhahlobo ea boikhathollo ba NO / cGMP e kenyellelitsoeng e bonts'itse ka ho hlaka hore cGKI ke 'muelli ea ka sehloohong oa cGMP ea tšoaeang bohlasoa mefuteng ea CC. Ho ba sieo ha eona ho ke ke ha lefshoa bakeng sa papali ea cAMP e tšoaeang bohlasoa, e khutlisang lithane tse tloaelehileng le cGKI-null penile erectile ka tekanyo e ts'oanang. Ha li kopantsoe hammoho, liphumano tsena li fana ka maikutlo a hore ts'ebetso ea cGKI ke mohato oa bohlokoa papaling ea papali ea chelete e lebisang pusong ea penile.

Polelo ea cGKI e ile ea hlahlojoa lipapatsong tsa CC ho tsoa ho bakuli ba nang le ntle le ED (Klotz et al., 2000). Mefuteng eohle ea lithane tsa cavernosal, ts'ireletso e ikhethileng e ne e bonoa likarolong tse fapaneng le meaho, ka polelo e phahameng liseleng tsa mesifa tse boreleli le li stroma tsa fibromuscular. Ha ho ts'ireletso e hlakileng khahlanong le cGKI e fumanoeng ho endothelium. Ho ne ho se na phapang e totobetseng ho li-immunoreactiv le ho ajoa ka seleng pakeng tsa bakuli ba matla le ba se nang matla. Sena ha se qhele ka thoko ho se sebetse ha cGKI e ka ba sesosa sa ED ho batho, le hore cGKI e ka ba sepheo se khahlisang sa ho kenella lipakeng tsa meriana.

Bivalacqua et al. (2007a) e fuputse polelo ea cGKIα (PKGIcy) le cGKIβ (PKGIβ) ho CC mme e lekola phello ea phetisetso ea liphatsa tsa lefutso tsa adenoviral cGKIcy ka komporong ea erectile ho EF ka mokhoa oa mofuta oa lefu la tsoekere. Ba fumane lits'ebetso tsa cGKIcy le cGKI reduced li fokotsoe ka har'a lithane tsa erectile tsa rat la tsoekere. Ho ts'ehetsa karolo ea cGK ts'ebetsong ea erectile, phetisetso ea gene ea cGKIcy ho penis e khutliselitsoeng ketso ea cGK le ts'ebetso ea erectile ho vivo.

4. Phosphodiesterases.

Li-PDE li ts'oara hydrolysis ea man messengersosa a bobeli cAMP le cGMP, tse kenyelletsang litseleng tsa ponts'o tse bohlokoa haholo bakeng sa ho phomola mesifa e boreleli ea CC. Proteine ​​superfamily ea cyclic nucleotide PDE e ka aroloa ho ba bonyane malapa a 11 a li-enzyme tse amanang le sebopeho. Li-isoforms tse fetang 50 li bontšitsoe ho fihlela joale, tsohle li fapana ka meaho ea tsona ea mantlha, ho khetheha ha cAMP le cGMP, litlhoko tsa cofactor, thepa ea kinetic, mekhoa ea taolo, le tsamaiso ea lithane (Francis et al., 2010). Ka lebaka la karolo ea bona ea mantlha taolong ea molumo oa molumo oa mesifa le phapang e fapaneng ea PDE isoenzymes mabapi le mefuta le lisele, PDE e se e le sepheo se khahlehang sa nts'etsopele ea lithethefatsi. Ka lithaelese tsa cavernosal tsa batho, bonyane li-13 isoenzymes li fumanoe, ho kenyelletsa PDE3 (cGMP-inhibited cAMP PDE), PDE4 (cAMP-fulani PDE), le PDE5 (cGMP-PDE)Küthe et al., 1999, 2000, 2001). Ka mokhoa o sebetsang, PDE 3A le 5A li bonahala e le tsa bohlokoahali (Küthe et al., 1999, 2000, 2001; Francis et al., 2010). Malapa a mararo ho PDE (PDEs 5, 6, 9) a na le khetho ea substrate ea makhetlo a 100 bakeng sa cGMP ho feta cAMP joalo ka substrate mme ka hona e nkuoa e le "li-PDE tse ikhethileng tsa cGMP." PDE5 le PDE9 ke tsona feela "cGMP-specific PDEs" tse hlahisoang ke lisele tsa pheriferale; PDE6 e hlahisoa ho retina (Francis et al., 2010).

PDE5, e teng linthong tse phahameng ka har'a mesifa e boreleli ea CC, ke eona ntho ea bohlokoahali ea ho phekola hobane ke eona sepheo sa lithethefatsi tse sebelisoang haholo ho fetisisa tsa ED hona joale, PDE5 inhibitors. PDE5 ke Homodimer e nang le subunits tse peli tse ts'oanang le boima ba molek'hule ba hoo e ka bang 100,000 Da ka subunit. E 'ngoe le e' ngoe ea lihlahisoa tsena tse peli e na le sebaka sa ts'usumetso le taolo. Sebaka sa bohloeki, e leng sepheo sa li-inhibitors tsa PDE5, se na le sebaka se le seng se tlamang bakeng sa cGMP (Francis et al., 2010). Hobane li na le meaho e ts'oanang le ea cGMP, sildenafil kapa li-inhibitors tse ling tsa PDE5 le tsona li ka lula sebakeng sa bohlokoa, ka hona li thibela ho fihlella ha cGMP ka tlholisano. Leha ho le joalo, sildenafil e lula sebakeng seo hoo e batlang e le makhetlo a 1000 ka hloko ho feta cGMP, ka lebaka leo cGMP e ke keng ea tlama ho fihlela mochini o thusang ho bokella lisele tsa mesifa tse boreleli tsa CC. Sena se lebisa phomolong ea CC le penile erection (Francis et al., 2010). Hoa hlokomeleha hore PDE5 e bonahala e laola li-sGC tse nkiloeng empa eseng cGMP e hlahisoang ke pGC, hobane vasodilation ea ANP-mediated ha e ntlafatsoe ka vitro kapa ka vivo ke PDE5 inhibitor sildenafil (Kemp-Harper le Schmidt, 2009).

Lin et al. (2000, 2002, 2005) ho tlalehiloe ho kopantsoe ha li-isoforms tse tharo tsa PDE5 tse tsoang liphoofolong tsa penile ea motho. Li-isoforms tse peli li ne li tšoana hantle le PDE5A1 le PDE5A2, ka ho fapana, eo pele e neng e arotsoe ke lisele tsa nonpenile. Isoform ea boraro e ne e le noha 'me e ne e bitsoa PDE5A3; isoform ena e ne e entsoe feela ka linama tse nang le mesifa e boreleli kapa ea mesifa ea pelo.

Ts'oaetso ea malapa a fapaneng a PDE e tšoantšoa le tšebeliso ea li-inhibitors tse ikhethileng kapa tse ikhethileng. Sildenafil, vardenafil, le tadalafil ke li-inhibitors tse khethiloeng haholo tsa mofuta oa PDE 5, empa metsoako e mecha e ntlafalitsoe, e meng e na le likarolo tse fapaneng haholo (Boolell et al., 1996a,b; Francis le Corbin, 2005; Francis et al., 2010). Kaofela li ntlafatsa boikhathollo ba NO-Mediated ho tsoa ho mefuta e fapaneng ea vitro le vivo ka ho eketsa ho tsepamisa mohopolo ho cGMP ka ho holisa tsela ea tlhaho ea NO-cGMP (Kouvelas et al., 2009; Francis et al., 2010). Lits'ebetso tsa limolek'hule tse amehang li hlahlojoe ka botlalo libakeng tse ling (Francis et al., 2010). Li-inhibitors tsa PDE5 hajoale ke kalafo ea pele ea ED (bona karolo VIII.C), 'me li-inhibitors tse ncha tsa PDE5 tse ncha li maemong a fapaneng a ntlafatso kapa li se li hlahisitsoe ka tliliniki (Hatzimouratidis le Hatzichristou, 2008; Dorsey et al., 2010; Eardley et al., 2010).

Litlhaselo tsa Androgenic li ka ama tšebetso ea PDE5 penis (Morelli et al., 2004; Traish and Kim, 2005; Zhang et al., 2005), empa phello e kanna ea kopanngoa ka tsela e sa tobang ke tšusumetso ea androgens mosebetsing oa NOS. Lintlha tsena li bonts'a hore lintlha tsa taolo ea polelo le ts'ebetso ea PDE5 ho botoneng li khetholla ka botebo karolo ea tlhaho ea enzyme.

5. Barekisi ba Bang ba Gase.

Carbon monoxide (CO) le hydrogen sulfide (H₂S), hammoho le NO, li nkile li-transmitter tsa progectile tse ka sehloohong tse ka lokolloang haholo ke methapo ea cholinergic le sinusoidal endothelium ea ho phomotsa mesifa e boreleli ea CC ka tsela ea cGMP. Joalokaha ho se ho boletsoe, CO e hlahisoa ka ho qhekella ho senyeha ha heme ea cellular mme e khona ho susumetsa sGC, empa ka tekanyo e tlase ho feta NO (Friebe et al., 1996).

Kameho e kholo, e ntle ea sistimi ea HO / CO ho erection ea penile e tlalehiloe lithutong tse 'maloa, mme karolo ea eona e ka bang sepheo sa limolek'hule ho kalafo ea ED e ile ea hlahlojoa ke Shamloul (2009). Ha ho le e 'ngoe ea lithuto e ileng ea hlahloba karolo ea tsamaiso ea HO / CO liphoofolong tse tsofetseng, botsofaling bo nkuoa e le ntho ea bohlokoa ka ho fetisisa ea kotsi ho ED. Ho ile ha phetoa ka hore mokhoa oa HO / CO o ka ba le karolo ho li-penile erection. Leha ho le joalo, lithuto tse ling hape lia hlokahala ho hlakisa bohlokoa ba sistimi ea HO / CO ho physiology le pathophysiology ea tšebetso ea banna le ho se sebetse ka thobalano.

l-Cysteine ​​e sebetsa e le karoloana ea tlhaho bakeng sa motsoako oa H₂S. Exo native H₂S [e laetsoeng e le sodium hydrogen sulfide (NaHS)] kapa l-Cys li hlahisitse phomolo e itšetlehileng ka khatello ea methapo ea CC ea motho. Likhoto, tsamaiso ea intracavernosal ea NaHS kapa l-Cys elicited penile erection (d'Emmanuele di Villa Bianca et al., 2010). Ho hlokometsoe lipatlisiso tsena ho bontša hore hoa sebetsa l-Bys / H₂Tsela e kanna ea ameha ho hokahaneng le ho kenella ho hoholo ha penile ho batho le liphoofolo tse ling.

1. Adrenomedullin, Peptide e amanang le Calcitonin Gene, Nociceptin.

Adrenomedullin, peptide ea lelapa la CGRP, e qalile ho arohanngoa le phaeochromocytoma ea motho mme ho fanoe ka tlhahiso ea hore e sebetse e le hormone e potolohang e laolang khatello ea methapo ea methapo (CGRP; Kitamura et al., 1993). Peptide e bonts'itsoe liseleng tsa "endothelial" tsa lisele tsa thipa tsa setho sa batho (Marinoni et al., 2005). Adrenomedullin e thibela ho ts'oaroa ha mefuta e 'maloa ea lisele tse bonolo tsa mesifa eseng feela ka keketseho ea tlhahiso ea cAMP, empa hape e khothaletsa tokollo ea NO (Miura et al., 1995). Ho kenella ka hare ho likatse, adrenomedullin e bakile khatello ea methapo ea methapo le bolelele ba penile, phello e fumanoang hape le CGRP (Champion et al., 1997a,b,c). Hobane likarabo tsa erectile ho adrenomedullin kapa CGRP li ne li sa angoe ke thibelo ea NOS ka l-NAME kapa ke K_ATP sethala sa inhibition le glibenclamide, ho ile ha fanoa ka maikutlo a hore NO kapa K_ATP liteishene li ne li sa ameha likarabo. CGRP antagonist CGRP (8-37), ka tekanyetso ha e na phello ho karabo ea adrenomedullin, e fokotsitse likarabo ho CGRP, e fana ka maikutlo a hore li-peptide li sebelitse li-receptor tse fapaneng. Ka tekanyetso e phahameng ka ho fetisisa e sebelisitsoeng, adrenomedullin le CGRP li fokotse khatello ea mali (Champion et al., 1997a,b,c). Litlamorao tse tšoanang li fumanoe ha adrenomedullin e kenngoa kahare ho litoeba (Nishimatsu et al., 2001). Lithakaneng tsa 'mutla tse arohaneng tsa' mutla oa CC, adrenomedullin e bakile phello e amanang le khatello ea kelello (Gokce et al., 2004).

Bivalacqua et al. (2001a) o sebelisitse mofuta oa adenoviral phetiso ea prepro-CGRP ho khutlisetsa ts'ebetso ea erectile ka hara rat ea khale mme a fumana ntlafatso mosebetsing oa erectile. CGRP e ne e khothaletsoe pejana hore e ka ba le monyetla oa ho phekola ED (Stief et al., 1990, 1991; Truss et al., 1994), empa ha ho bonahale eka e ka ba adrenomedullin kapa CGRP e tla ba le thuso ea bongaka bakeng sa kalafo ea ED.

Nociceptin ke 17-amino acid peptide e arolelanang thuto ea tlhaho ea lelapa le lelapa la dynorphin la li-peptide. E fapana le li-peptide tse ling tsa opioid ka hore ha e na NH₂Masala a morao-rao, a bohlokoa bakeng sa tšebetso ho μ, δ, le κ opioid receptors (Henderson le McK Night, 1997; Calo 'et al., 2000). Peptide ke ligo ea tlhaho ea kokoana-hloko ea bana ba likhutsana tse fumanoeng mefuteng e 'maloa: clone ea motho e bitsoa ORL1. Ho bonahala e kentse letsoho mesebetsing e fapaneng (Chiou et al., 2007) 'me e bontšitsoe hore e kena-kenana le (inhibit) tlhahiso ea dopamine bokong (Olianas et al., 2008). Hore na ketso ea morao e na le litlamorao ho mekhoa ea erectile kapa boitšoaro ba thobalano ha e tsejoe.

Champion et al. (1997a) bapisa likarabo tsa erectile le tsamaiso ea intracavernosal nociceptin le tse kopantsoeng tse tharo tsa joala, VIP, adrenomedullin, le motho ea sa faneng ka letho likatseng. Nociceptin e lekantsoeng ea 0.3 ho 3 nM e eketsehile ea litekanyetso tse amanang le khatello ea intracavernosal le bolelele ba penile ha bo bapisoa le motsoako oa lithethefatsi tse tharo, empa nako ea karabelo e ne e khuts'oane. Ha ho bonahale eka nociceptin e na le karolo ea bohlokoa mekhoeng ea erectile kapa hore receptor ea ORL1 ke sepheo se nepahetseng bakeng sa lithethefatsi tse ntlafatsang ts'ebetso ea erectile.

2. Endocannabinoids.

Ha ho na leseli le fokolang mabapi le phello ea phello ea li-cannabinoids liseleng tsa CC. Ghasemi et al. (2006) e batlisisitse phello ea endo native cannabinoid anandamide ho likarabo tsa boikhathollo tsa NANC ho ts'usumetso ea tšimo ea motlakase sebakeng se ikemetseng sa rat. Ba bonts'itse hore anandamide e na le tšusumetso e ntle boikhathollong bo kopanetsoeng ke NANC ka li-receptors ka bobeli tsa CB1 le vanilloid. Ntle le moo, ba bonts'itse hore karolo ea NO-mediated ea likarabo tsa boikhathollo tsa NANC mabapi le ho susumetsa ka motlakase e kentse letsoho kholisong ena. Sehlopha sona seo se ithutile phello ea biliary cirrhosis ho phomolo e kopanetsoeng ea NANC le methapo ea methapo ea endocannabinoid le NO litsong tsena.Ghasemi et al., 2007). Boikhathollo ba NANC-Mediated bo ile ba ntlafatsoa ka marang-rang a CC ho tsoa ho liphoofolo tsa cirrhotic. Anandamide o bile le monyetla oa ho phomola lihlopheng ka bobeli. E-na 1- (2,4-dichlorophenyl) -5- (4-iodophenyl) -4-methyl-N- (1-piperidyl) pyrazole-3-carboxamide (AM251; CB1 receptor antagonist) kapa capazepine (treptent receptor mohlomong vanilloid 1 receptor antagonist), empa eseng 6-iodo-2-methl- 1 -LNLXLLLLLLLLLLLLLLLLLLLLLLLLLLX ethyl] -2H-indol-3-yl- (4-methoxyphenyl) methanone (AM630; CB2 receptor antagonist), e thibetse phomolo e ntlafalitsoeng ea methapo ea cirrhotic. Ka bobeli nonselective NOS inhibitor l-NAME le inhibitor ea Nonal e khethiloeng N^ω-propyl-l-arginine o ne a thibetse boikhathollo ka lihlopha tsena ka bobeli, empa lihlopha tsa cirrhotic li ne li loants'oa haholo ke litlamorao tsa litlamorao tsa baemeli bana. Relaxations ka lebaka la sodium nitroprusside (NO mofani) e ne e tšoana ka lithong tse tsoang lihlopheng tsena tse peli. Bangoli ba phethile ka hore cirrhosis e baka boikhathollo ba neurogenic ba "CC", mohlomong ka tsela ea NO mme e kenyelletsa cannabinoid CB1 le receptor ea nakoana e ka amohelang vanilloid 1 receptors.

Ho phatloha ka bophirima ha lisele tsa CC ho bontšitse ho ba teng ha li-receptor tsa CB1 ho li-strips tsa CC tsa rat le monkey ea rhesus (Gratzke et al., 2010b). Ho fapana le lithane tsa "rat" tsa khoebo, likarabo tse khutlisang maikutlo tse khothatsong ea motlakase li ne li sa fetoloe boteng ba anandamide ho 10 nM ho 30 μM metsaneng ea monkey CC. Ho hlokahala lithuto tse ling ho hlakisa karolo ea tsamaiso ea endocannabinoid ho lithane tsa erectile.

3. Tumor Necrosis Factor-α.

Mefuta ea oksijene e sebetsang ke bobuelli ba bohlokoa ba ho lemala le ho senyeha ha lisele, e leng lisosa tse ka sehloohong tsa ts'ebetso ea pathophysiological e lebisang ho lefu la CV. Ntho ea mokhethoa e bakang tlhahiso ea ROS liseleng tsa endothelial ke tumor necrosis factor α (TNF-α). TNF-α e bontšitsoe e bapala karolo ea bohlokoa ho lefu la CV, haholo-holo ka lebaka la litlamorao tsa eona tse tobileng vasculature (Chen le al., 2008; Zhang et al., 2009a), hape e kanna ea ameha ho ED, hobane maemo a phahameng a TNF-α a bontšitsoe ho bakuli ba nang le ED (Carneiro et al., 2010). Ho ile ha fumanoa litoeba tsa TNF-α KO ho bonts'a liphetoho phetohong ea bohlasoa e neng e tla tsamaisa likarabo tsa erectile. Ka hona liphoofolo li bontšitse likarabo tse fokotsehileng mabapi le ts'usumetso ea methapo ea adrenergic le ho eketsa boikhathollo bo itšetlehileng ba NANC- le endothelium bo amanang le maemo a eketsehang a khoebo ea eNOS le liprotheine tsa NNOS (Carneiro et al., 2009). TNF-α e holofatsang endothelium e itšetlehileng ka NO-mediated vasodilation libetheng tse fapaneng tsa methapo (Chen le al., 2008; Zhang et al., 2009a), le karolo ea bohlokoa ea TNF-α ea ho loants'a ho hloka taolo ea endothelial ho ED ho khothalelitsoe (Carneiro et al., 2009). Blockade ea liketso tsa TNF-α (e ka khonehang ka nepo) e kanna ea emela mokhoa o mong oa phekolo bakeng sa ho senyeha ha erectile, haholo-holo maemong a pathological a amanang le maemo a eketsehang a cytokine ena. Hore na TNF-α e ka ba mofuta o mong oa kalafo maemong a joalo a ED e ntse e lokela ho theha.

Leha ho le joalo, kalafo le bahanyetsi ba TNF-α e kanna ea se be le mathata. Liphihlelo tsa kalafo ea mathata a mang ntle le a ED li bontšitse hore karolo ea boraro ea bakuli ha e arabele kalafo ka mabaka a fapaneng (Desroches et al., 2010).

Ho Vivo.

Lithane tsa CC li tsosa maqhubu a motlakase a shebahalang a le bohlokoa ba ho hlahloba bohlasoa ba ED. Le ha ho le joalo, ho bile thata ho fumana ho senyeha ha methapo ea kutlo ea methapo. Electrocavernosography e na le monyetla oa ho sebetsa e le sesebelisoa sa lipatlisiso sa ho khetholla mefuta e fapaneng ea ED (Wagner et al., 1989; Sasso et al., 1996; Shafik et al., 2004a,b). Tsoelo-pele ho electrophysiology ea bongaka joale e lumella ho rekota ho sa lekanyetsoang hoa tšebetso ea motlakase e makatsang. Mokhoa o mong o tšepisang ke ts'ebetso ea matlo a ho sesa, e ka tlalehoang kamora tšusumetso e khutšoane e makatsang (Yang et al., 2008; Yilmaz et al., 2009).

Ho Vitro.

Ho fumanoe liteishene tse fapaneng tsa li-ion liseleng tsa mesifa tse boreleli tsa CC, empa ho bile le lipatlisiso tse fokolang tsa motlakase mabapi le litokisetso tsohle tse bonolo tsa mesifa ea k'homphieutha (Andersson, 2001). Karolong e haufi ea "rat Corpus spongiosum" (penile bulb), Hashitani (2000) e bonts'itse bokhoni ba ho ikatisa molemong oa mesifa e ka hare ea mesifa. Ka lehlakoreng le leng, ha ho na monyetla o ka bonoang ke lipatlisiso tsa motlakase tsa lisele tse boreleli tsa mothapo oa CCKreste et al., 1993). Haeba sena se sebetsa le bakeng sa lisele tse vivo, e hloka hore ho sebelisoe mokhoa o mong oa ts'ebetso bakeng sa ts'usumetso ea ts'usumetso. Likarolo tsa likheo li ka fana ka mochine o joalo.

Joalokaha e thathamisitsoe ke Kreste (2000), phetisetso ea matšoao mesifa e boreleli ea tšebetso ke ketsahalo ea marang-rang ho feta ts'ebetso e bonolo ea ts'ebetso ea "cascade" ea 'mele kapa tsela tseleng e le' ngoe. Likamano tse kopaneng li ka kenya letsoho ho fetoleng molumo oa mesifa o boreleli, ka hona, bokhoni ba erectile, le puisano pakeng tsa likheo tsa likheo li ka fa Corpora "bohlokoa ba polokeho" kapa bokhoni ba likarabo tsa polasetiki / ho fetoha ha maemo.

Ho hokahanya tšebetso har'a lisele tsa mesifa tse boreleli ke ntho ea bohlokoa bakeng sa ts'ebetso e tloaelehileng ea erectile. Tsamaiso ea methapo ea kutlo e bapala karolo ea bohlokoa molemong ona ka ho fana ka phepelo e kholo ea neuralgenible ho botoneng. Mohlala, ts'ebetso ea likarolo tse fapaneng tsa tsamaiso ea methapo ea kutlo e fapana haholo nakong ea kemaro, ho senyeha le ho fifala (Becker et al., 2000). Karolo ea tsamaiso ea methapo e ikemetseng ts'ebetsong e tloaelehileng ea penile e lokela ho hokahanngoa; tekanyo ea ho thunya ea tsamaiso ea methapo ea kutlo, ho hlasimoloha ha myocyte, ts'ebetso ea phetisetso ea maqhubu, le boholo ba puisano ea sele le sele pakeng tsa lisele tsa mesifa tse tsamaeang hantle li tlameha ho hokahanngoa ka hloko ho netefatsa ts'ebetso e tloaelehileng ea erectile.

1. BK_Ca Seteishene.

BK_Ca Channel e tsebahala hantle ka har'a mesifa e boreleli ea batho le ea ratWang et al., 2000; Archer, 2002). BK_Ca liteishene li thehoa ka likamore tse peli: e-subunit ea pore-subunit le transmembrane β-subunit. BK_Ca Channel MRNA le protheine li fumanoe liseleng tse peli tse ikemetseng tsa batho ba sebetsang le liseleng tsa mokokotlo tse boreleli tsa "Kreste et al., 1999). E lumellana le lipono tse joalo, boits'oaro bo 'ngoe bo tsamaisang (≈180 pS), maqhubu a cell cell kantle, le voltage le calcium calcium ea kutlo ea K._Ca seteishene se ts'oana ha se bapisoa le datha tse bokelletsoeng ka mahlale a patch clamp ho li-myocyte tse bonolo tsa mekhatlo ea mesifa e bapileng le liteko tse tšoanang le tsa li-cell tse fumanehang tsa nakoana tsa mokhatloFan et al., 1995; Lee et al., 1999a,b).

BK_Ca mocha o bonahala e le ntlha ea bohlokoa ea ho kopanya ho feto-fetoha ha maemo a khoebo e boreleli ea mesifa. Ts'ebetso ea mocha ona e eketseha kamora ho kenngwa ka seleng ha tsela ea cAMP ka 8-bromo-cAMP kapa PGE₁ (Lee et al., 1999a) kapa tsela ea cGMP ke 8-bromo-cGMP (Wang et al., 2000). Ho bonahala ho hlakile hore litsela tse peli tse sebetsang hantle haholo tsa 'mele oa mora oa bobeli, li sebetsa ho fetolela molumo o bonolo oa tšebetso (ke hore, boikhathollo bo phahameng), bonyane ka karolo, ka ts'ebetso ea BK_Ca seterahlana subtype. Hyperpolarization e hlahisitseng eona, e kopantsoe le ho fokotseha ha transmembrane calcium flux ka L mofuta oa VDCC mme, qetellong, ho phomola mesifa e boreleli.

Karolo e sebetsang ea liteishene tsa BK ho CC e fuputsoe ke Werner et al. (2005), Ho sebelisa toeba ea ho kokota e haellang Se-Slo mofuta (Se-Slo(- / -)) boikarabello ba ho etsa karolo e ka tlase ea pore ea mocha oa BK. CCSM e tloha Se-Slo(- / -) litoeba li bontšitse keketseho e mene-e 'ngoe ea likonteraka tsa phasic, boteng ba phenylephrine. Lithabiso tsa 'mele tse khutliselitsoeng methapo ea methapo li ile tsa fokotsoa ke 50%, ka bobeli ho tloha Se-Slo(- / -) litoeba le ka ho thibela mecha ea BK le iberiotoxin ho Se-Slo+ / + metsero. Tumellanong le liphetho tsa in vitro, khatellong ea vivo intracavernosal e bonts'itsoeng oscillations ho Se-Slo(- / -) litoeba, empa eseng ho Se-Slo+ / + litoeba. Ho feta moo, khatello ea intracavernosal e eketsa ho tsosa ha methapo, ho vivo, e fokotsoe ke 22% ho Se-Slo(- / -) litoeba. Liphetho tsena li bonts'a hore mocha oa BK o na le karolo ea bohlokoa ts'ebetsong ea erectile, mme tahlehelo ea mocha oa BK e lebisa ho senyeha ha erectile. Ho ts'ehetsa pono ena, ente ea cDNA e kenelletseng setsing sa BK sa motho e lebisitse phetohong ea ho se sebetse hantle ha litšoelesa tsa khale kapa tsa lefu la tsoekere le liphoofolong tsa atherosranceotic (Kreste et al., 1998; Kreste et al., 2004, 2009). Lithuto tsena li tšehetsa mohopolo oa hore ho phahamisa BK_CaPolelo ea -channel e ka khutlisa ts'ebetso ea erectile ka mor'a ho fokotseha ha lilemo - kapa ho bakoa ke lefu. Ho buloa ha BK_Ca liteishene e ka ba mokhoa o mong oa ho khutlisa tšebetso e sa lekaneng ea erectile (mohlala, Moshanyana et al., 2004). Kun et al. (2009) o fumane hore NS11021 (1- (3,5-Bis trifluoromethyl- phenyl) -3- [4-bromo-2- (1H-tetrazol-5-yl) -phenyl] -thiourea), sengoli se bulehileng sa BK_Ca liteishene tse bakileng khatholoho ea methapo ea methapo le methapo ea CC haholo ka ho bula BK_Ca dikanale. E ne e boetse e sebetsa hantle ho nolofatseng likarabo tsa erectile ho likhoto tse sa anngoeng. Liphetho tsena li bontša monyetla oa ho sebelisa BK_Ca openers ka kalafo ea Ed. Leha ho le joalo, ho fihlela joale ha ho na liphetho tse atlehileng tsa kliniki tse phatlalalitsoeng.

2. K_ATP Seteishene.

Metsoako ea Bophirimela e metsu e ikhethileng ea lithane, le immunocytochemistry ea lisele tse boreleli tsa mekhatlo e hlophisitsoeng, e sebelisa li-antibodies ho K_ATP seteishene, ba ngotse boteng ba K_ATP protein protein (Kreste et al., 1999). K_ATP Likhoele ho nahanoa hore li entsoe ka liprotheine tse peli: (1) se ka hare-reptures K + Channel subunit (Kir; e sebetsa e le pore ea seterata) le (2) se-sulfonylurea receptor (SUR). 'Meleng oa motho oa boreleli, K_ATP Channel e entsoe ka heteromultimers ea Kir6.1 le Kir6.2 (Insuk et al., 2003). Liteko tsa lisele tsa mesifa tse sa sebetseng hantle tsa tšebetso li hatisitse ka ho ba teng hoa li-KP tse peli tse ikhethileng tsa KP⁺ maqhubu a lisele tsa mesifa tsa mesifa tse bopehileng le tse nchafalitsoeng.Lee et al., 1999a). E lumellana le se bonoang setsing se le seng sa litekanyetso, lithuto tsa cell patch clamp li tlalehile bohlokoa bo boholo, bo bobebe ba glibenclamide, le keketseho ea sele eohle kantle K⁺ maqhubu a boteng ba modithareng oa K Channel module levcromakalim (bona Lee et al., 1999a). Lintlha tsena, ho tloha molek'huleng, ho ea ka liseleng le liseleng kaofela, li hlakisa boteng le botebo ba 'mele oa K_ATP Channel subtype (s) ho feto-fetoha ea molumo oa lentsoe oa mesifa ea batho. Boithuto bo 'maloa bo tlaleha hore li-modulators tsa K, batseteli ba chesehang ba K_ATP mocha, o phahamisa boikhathollo bo itšetlehileng ka khatello ea mohala oa setho se boreleli se ikemetseng (Andersson, 1992, 2001). Leha ts'ebetso ea K_ATP ho fanoe ka mocha oa ho nka karolo ketsong ea yohimbine (Freitas et al., 2009), phentolamine (Silva et al., 2005) le testosterone (Yildiz et al., 2009) ho lisele tsa bohlasoa, bohlokoa ba tlatsetso ena liphellong tse felletseng tsa baemeli ba li-erectile mechanisms ha li so theoe.

3. Litsela tsa calcium.

Kabo ea Ca²⁺ li-ions ho pholletsa le membrane ea sele ea CC ea mesifa e tiisa hore ho buloa ha Ca²⁺ liteishene li tla lebisa ho phatloha hoa Ca²⁺ li-ion ka seleng ea CC e boreleli ea mesifa e theola li-gradient tsa bona tsa motlakase. Ho sisinyeha ha tefiso e ntle seleng ea boreleli ea mesifa ho na le phello e fapaneng le motsamao oa K⁺ ka ntle ho sele, ka hona, e tla lebisa ho depolarization. Boithuto bo 'maloa bo ngotse bohlokoa ba transmembrane Ca e tsoelang pele²⁺ tšusumetso ho pharalla ha li-LVVC tsa mofuta oa L ho fihlela tumellano e tsitsitseng ea mesifa e boreleli ea CC (Andersson, 2001). Ho bonahala ho na le tlaleho e le 'ngoe feela e phatlalalitsoeng ea ka hare Ca²⁺ maqhubu a CC a boreleli mesifa a sebelisa mekhoa e otlolohileng ea patch clamp (Noack le Noack, 1997). Leha ho le joalo, boholo ba datha e qobelloang ka ho fetisisa e mabapi le karolo ea Ca²⁺ Litsela tsa ho feto-fetola molumo oa 'mele oa' mele oa CC e se e thehiloe ka ho sebelisa li-microscopy tsa li-digital imaging tsa Fura-2 e nang le lisele tse boreleli tsa CC ea mesifa e boreleli. Lithuto tsena li fane ka bopaki bo matla bakeng sa boteng le botebo ba 'mele ba transmembrane Ca²⁺ flux ka har'a mofuta oa L-calcium ea calcium e itšetlehileng ka calcium ha e arabela ts'ebetsong ea cellular ka mohlala, ET-1 (ET_{A / B} receptor subtype) le phenylephrine (α₁-drenergic receptor subtype) (Kreste et al., 1992b; Zhao le Kreste, 1995; Staerman et al., 1997). Nifedipine e tsotellang Ca²⁺ maqhubu a tlalehiloe ho tsoa liseleng tsa mesifa tse bonolo tsa mmutla tsa CC (Craven et al., 2004), e fana ka tlhahiso ea hore lisele ka bomong li ka khona ho hlahisa menyetla ea ketso ka ho buloa ha mofuta oa L-Ca²⁺ Mechine.

Taba ea hore li-inhibitors tsa L-mofuta oa calcium tse itšetlehileng ka calcium li thibela mekhahlelo e ikemetseng mekheng ea CC e lumellanang le mohopolo oa hore Ca²⁺ tšusumetso e tseleng ena ho bohlokoa molemong oa molumo oa molumo. Leha ho le joalo, bokhoni ba CC, ba motho, mmutla le rat ho nts'etsapele konteraka ea phasic le tšebetso ea motlakase oa phasic (mohlala, Hashitani et al., 2005), e fana ka maikutlo a hore taba ea bohlokoa ea Ca²⁺ maemo ke oscillatory. Sena se tiisitsoe thutong ke Sergeant et al. (2009) eo ho itlhommeng pele ho eona Ca²⁺ maqhubu a ile a bonts'oa a hlahisoa ka bobeli liseleng tsa mothapo o mong le o mong oa CC le likarolo tsohle tse hlakileng tsa linama tsa CC, moo ho phatlohang hoa Ca²⁺ lipontšo li ka bonoa li tsosa likarolo tsa phasic le tonic tsa contraction. Ts'ebetso ena ea "pacemaker" e kanna ea ba ea bohlokoa ho ts'ebetso e tloaelehileng ea CC, kaha e bonts'itsoe e amana le ho ts'oaroa ha lisele le ho thibeloa ke tsela ea NO / cGMP.

McCloskey et al. (2009) ba ithutile li-VDCC ho 'myocyte ea CC ea' mutla o hasantsoeng ka mokhoa o pharalletseng bakeng sa ho rekota lipampiri le ho etsa sephiri Ca²⁺ monahano. Ba fumane hore li-myocyte tse ikhethileng li hlahisitse li-VDCC tse matla tse neng li ka aroloa likarolo tse peli, e le 'ngoe ea mofuta oa mofuta oa mofuta oa Ca²⁺ea hajoale, ha e 'ngoe e le mofuta oa mofuta oa hona joale oa bongaka L-hajoale e nolofalletsang ho fetola hoa Ca²⁺ Liketsahalo tse etsahalang lefats'e ka bophara Ca²⁺ maqhubu, athe a maiketsetso a T a hona joale a ne a bonahala a sa phetha karolo e kholo ts'ebetsong ena. Liphumano tsena li tiisa tse Zeng et al. (2005) e bonts'a hore lisele tsa CC tsa batho li hlahisa mofuta oa T-mofuta (α2G) Ca²⁺ liketane tse kenyelletsoeng ho boloka [Ca²⁺] homeostasis.

4. Manane a Chloride.

Tlatsetso ea liteishene tsa chloride / maqhubu ho feto-fetohang ha molumo oa lentsoe oa mesifa e boreleli ea batho ha e utloisisehe hantle ho feta ea lits'ebetso tse ling tsa ion. Lithuto tsa Cl tse nang le calcium^- (Cl_Ca) ho sebetsa ka har'a mesifa e boreleli ea CC ho bonts'itse liteishene tsena ho kenya letsoho ho boloka molumo oa tlhaho le karabelo ea contractile ho Noradrenaline le agonists tse ling.Fan et al., 1999; Karkanis et al., 2003; Craven et al., 2004; Williams le Sims., 2007; Chu le Adaikan, 2008; Chung et al., 2009b). Karkanis et al. (2003) e bonts'itse calcium Cl e thabisang_Ca hajoale manoncyte a batho le a rat. Sena sa hajoale se ile sa qaptjoa ke Ca²⁺ lokolloa mabenkeleng hape e etsahala joalo ka maqhubu a ipheta-phetang, a atisang ho bakoa ke Ca²⁺ litlhase. Cl_Ca li-blockers tsa li-channel li ntlafalitse le ho lelefatsa khatello ea khatello kamora ho ts'oaroa ha methapo ea methapo ea methapo, e bontšang hore Cl^- tsa hajoale li kenya letsoho taolong ea khatello ea methapo ea kutlo. Craven et al. (2004) etsa tlhahiso ea hore Ca²⁺ e sebetsang Cl^- maqhubu a molumo o tlase oa molumo ho CC, le ho feto-fetoha ha mochine ona ka tsela ea NO-cGMP ho bohlokoa nakong ea kemaro ea penile. Ho ts'ehetsa lipono tsena, Williams le Sims (2007) e bontšitse hore Ca²⁺ litlhapi ho CC li hlaha Ca²⁺ tokollo ka li-receptors tsa ryanodine mme e hlahisa Cl_Ca hona joale. Ba boetse ba bonts'a taolo ea 'mele ea ho hlaseloa khafetsa ke spolarization ka lebaka la Ca²⁺ ho kena. Liphetho tsena li netefalitsoe ke Sergeant et al. et al. (2009), ho senola hore e 'ngoe ea Ca²⁺ maqhubu a ne a amahanngoa le mokhoa o tloaelehileng oa Ca^{2 + -}e sebetsang Cl^- maqhubu a ntlafalitsoeng ke lisele tsena. Maqhubu a ne a itšetleha ka sarcoplasmic reticulum Ca²⁺ lebenkele, hobane li ne li thibetsoe ke cyclopiazonic acid le li-ejenti tse kenang lipakeng tsa ryanodine receptors le IP₃-mediedi Ca²⁺ lokolloe. Chu le Adaikan (2008) a hlakisa bohlokoa ba Cl^- maqhubu e le mokhoa oa ts'ebetso ea ho boloka molumo oa CC o hlahisoang ke adrenergic le li-constituteors tse fapaneng tsa 'mele ka methapo ea mmutla CC. Ba khothalelitse hore modumo ea Cl^-1 hajoale e ka ba mokhoa o khahlisang le o sebetsang oa ho laola tlholeho ea penile. Likhoto, Chung et al. (2009b) o entse lipatlisiso tsa vivo mabapi le karolo e sebetsang ea likanale tsa chloride ho laola tšebetso ea erectile mme a fihlela qeto ea hore liteishene tsa chloride li ka bapala karolo ea bohlokoa taolong ea molumo oa molumo oa CC.

1. Konteraka.

Ka kakaretso, contraction ea mesifa e boreleli e laoloa ke Ca²⁺ le litsela tsa Rho kinaseBerridge, 2008). Liphetoho ho sarcoplasmic Ca²⁺ mahloriso, 'me ka hona maemong a bokhachane ba sele e boreleli ea mesifa, a ka hlaha ka kapa a sena liphetoho ka bokhoni ba membrane (Somlyo le Somlyo, 1994, 2000; Stief et al., 1997; Berridge, 2008) (Feie. 6). Liphetoho tse ka bakoang ke liphetoho kapa liphetoho tsa nako e telele kamoreng ea phomolo e phomotsang li senya matla a kahare, ka hona, li bula mofuta oa L-mofuta oa mofuta oa C²⁺ menyetla (Kuriyama et al., 1998). Kahoo, Ca²⁺ e kenella ka har'a sarcoplasm e tsamaisoang ke gradient ea mahloriso le e tsitsitseng. Litsela tsa Membrane ntle le Ca²⁺ liteishene li ka boela tsa baka liphetoho mokhoeng oa membrane. Ho buloa ha K⁺ liteishene li ka hlahisa hyperpolarization ea membrane ea sele. Hyperpolarization ena e etsa hore menyetla ea calcium ea mofuta oa L e qale ho fella ka hore Ca e fokotsehe²⁺ tšusumetso le boikhathollo bo latelang ba mesifa.

   

Sheba tlhahiso e kholoanyane:   

• Leqepheng lena
• Ka fensetere e ncha

Setšoantšo sa 6.   

Lits'ebetso tsa ts'ebetso ea mesifa ea penile boreleli. Ho latela Berridge (2008), mohlala, Noradrenaline e na le liketso tse peli tse kholo. E hlahisa IP₃, e sebetsang ka cytosolic Ca²⁺ oscillator. E boetse e kenya tšebetsong tsela ea ho emisa ea Rho / Rho kinase ho eketsa Ca²⁺ kutloisiso ea mochine oa contractile. Ntle le moo, Ca²⁺ li-transients li kenya tšebetsong Ca²⁺-sensitive chloride channide e bakang ho putlama ha membrane ho kenya ts'ebetso liteishene tse tsamaeang ka motlakase. Sena se hlahisa Ca²⁺ ho fetola oscillator hape ho etsa hore ho be le phallo ea hona joale ea ho kenella ts'ebetsong ea lisele tse haufi hore li ikarabelle ka tsela eo lisele tsena tsa k'holeseterole ea k'haravene e sebelisanang ka bonngoe ka bonngoe. A, agonist; R, receptor; PLC, phospholipase C; DAG, diacylglycerol; CPI-17, protein-kinase C-potentiated myosin phosphatase inhibitor; SR, reticulum ea sarcoplasmic; CIC, khalsiamo e hlahisang khalsiamo; RyR, ryanodine e amohelang.

Ho latela Berridge (2008), methapo e metenya ea mesifa e boreleli ea CC e its'etleha ho pacemaker ea endo native e tsamaisoang ke cytosolic Ca²⁺ oscillator e ikarabellang bakeng sa tokollo ea nako le nako ea Ca²⁺ ho tloha sarcoplasmic reticulum (compracellular complication ea Ca²⁺ polokelo). Nako le nako liphetoho tsa Ca²⁺ hangata ho baka membrane depolarization; hona ha se karolo ea ts'ebetso ea mantlha ea ts'ebetso, empa e na le karolo ea bobeli ho hokahanya le ho ntlafatsa mochine oa oscillatory. Li-neurotransmitters le lihormone li sebetsa ka ho feto-fetola molumo oa cytosolic oscillator.

Mekhoa e meholo e kenyellelitsoeng lipakeng tsa mesifa e boreleli, e sa amaneng le liphetoho liphoofolong tsa membrane, ke tokollo ea IP₃ le molao oa tsamaiso ea Ca²⁺ kutloelo-bohloko. Mehato ka bobeli e ka ba ea bohlokoa bakeng sa ts'ebetso ea mosifa o boreleli oa CC. Mabapi le bohlasoa ba bohlokoa ba 'mele ba phosphatidylinositol, li-agonists tse ngata (mohlala, α₁-AR agonists, ACh, angiotensin, vasopressin) e tlama ho li-receptor tse ikhethileng tsa membrane tse kopantsoeng le phospholipase C e khethehileng ea phospholipase C ka liprotheine tse tlamang tsa GTP. Phospholipase C ebe hydrolyzes phosphatidylinositol 4,5-biphosphate ho 1,2-diacylglycerol (sena se kenya tšebetsong PKC) le IP₃. IP e qhibilihang ka metsi₃ e hokahana le sehokahanyo sa eona ka ho khetheha ka membrane ea sarcoplasmic reticulum, ka ho etsa joalo e bula Ca ena²⁺ mocha. Hobane Ca²⁺mahloriso ka har'a sarcoplasmic reticulum e batla e le 1 mM, Ca²⁺ ka hona e khanneloa ka har'a sarcoplasm ke mokokotlo oa mahloriso, o hlohlelletsang botsitso ba mesifa e boreleli. Keketseho ena ea sarcoplasmic Ca²⁺ mahloriso a ka etsa hore ho be le Ca e ikhethang²⁺ mocha oa ho lokolla sarcoplasmic reticulum (ke hore, seterata se sebetsang sa ryanodine), e lebisang keketseho e 'ngoe Ca²⁺mahloriso a sarcoplasm (Somlyo le Somlyo, 1994, 2000; Karaki et al., 1997).

Joalo ka mesifa e tsitsitseng, boholo ba lisebelisoa tsa mahala tsa Ca²⁺ ke senotlolo sa taolo ea molumo o bonolo oa mesifa. Naheng ea ho phomola, boemo ba sarcoplasmic mahala Ca²⁺ e lekana le ≈100 nM, athe mokelikeli oa kantle ho metsi, boemo ba Ca²⁺ e maemong a 1.5 ho 2 mM. The cell-membrane Ca²⁺ pompo le Na⁺/ Ca²⁺ exchanger boloka gradient ena ea 10,000. Ho hlohlelletsoa ha methapo ea kutlo kapa ea hormonal ho ka bula Ca²⁺ liteishene, e hlahisang Ca²⁺ ho kena sarcoplasm tlase ho ts'oaroa ha eona ea mahloreho. Keketseho e nyane haholo maemong a mahala a sarcoplasmic Ca²⁺ ka lebaka la 3 ho 5 ho fihlela 550 ho 700 nM joale e baka phosphorylation ea myosin le tumellano ea morao ea mesifa.

Ka seleng e boreleli ea mesifa, Ca²⁺ tlama le ho boloka khalase, e fapaneng le mesifa e tsitsitseng, moo intracellular Ca e kenang teng²⁺ tlama le troponin e amanang le lifilimi tse nyaneChacko le Longhurst, 1994; Karaki et al., 1997). Ca²⁺-calmodulin complex e kenya tšebetsong myosin light-chain kinase (MLCK) ka ho tloaelana le motsoako o matla oa enzyme. MLCK e sebetsang e kenya letsoho phosphorylation ea li-ketane tsa "light" tsa ketane ea "myosin" (MLC)₂₀). Phosphorylated MLC₂₀ e sebetsa myosin ATPase, ka tsela ena e tsosang lihloho tsa myosin (marokho-a-sefapano) tse tsamaeang le lipina tsa "actin", tse hlahisang mesifa e boreleli. Phokotseho ea maemo a makatsang a Ca²⁺ e etsa karohano ea Ca²-calmodulin MLCK e rarahaneng, e lebisang ho putlosphorylation ea MLC₂₀ ka phofo ea mokokotlo oa "myosin"Somlyo le Somlyo, 1994, 2000; Karaki et al., 1997; Hirano, 2007).

Ka CC mesifa e boreleli, e fapaneng le mesifa e boreleli haholo e qeta nako ea eona e le maemong a konteraka, ho ile ha fumanoa sebopeho sa myosin isoform se neng se le lipakeng tsa mesifa ea aorta le bladder, eo ka kakaretso e bonts'ang litšobotsi tse kang tsa tonic- le phasic. (DiSanto et al., 1998; Berridge, 2008). Myosin e tsamaisang mofuthu oa mokokotlo e entsoe ka liketane tse boima tsa myosin le likara tse peli tsa liketane tsa lebone la myosin (MLC17 le MLC20) tse arohaneng haholo. Ho bontšitsoe hore myosin heavy chain pre-mRNA e sebelisoa ka mokhoa o mong ho hlahisa isoforms e tsejoang e le SM-A le SM-B. Isoform ea SM-B e fumaneha hangata ho li-SM tse bonts'ang mofuta oa tlhaho oa contractile (mohlala, lesapo la mokokotlo), athe SM-A isoform e fumaneha mofuteng oa mofuta oa tonic mofuta oa mohlala (mohlala, aorta). DiSanto et al. (1998) e bontšitse hore CC ea mesifa e boreleli e na le sebopeho sa myosin isoform ka tsela e batlang e le lipakeng pakeng tsa bladder le aortic SM. Zhang et al. (2009b) e batlisisitse litlamorao tsa blebbistatin, molek'hule e nyane e lumellehang ea lisele qalong e tlalehiloe e le inhibitor e khethiloeng ea isosorms ea myosin II. Blebbistatin e khutlisitse bophelo ba CC ba motho hantle ka mokhoa o itšetlehileng ka litekanyetso. Boholo ba ICP le ICP / khatello ea methapo ea kutlo li ne li eketseha ka mokhoa o itšetlehileng ka ente ea entracavernosal blebbistatin. Liphetho tsa Zhang et al., (2009b) o khothalelitse karolo ea bohlokoa bakeng sa lisebelisoa tse bonolo tsa contractile mo mochining oa molek'hule mme o khothalelitse monyetla oa ho tlama blbbistatin ho myosin II e le kalafo ea kalafo bakeng sa ED ka ho hlasela litsela tsa contractile tsa SM.

Ka mesifa e boreleli, matla / Ca²⁺ Karolelano ea lintho ha e tšoane, 'me ho latela likarolo tse itseng tsa ts'ebetso. Mohlala, baetsi ba li-agonists ba α-AR ba susumetsa matla a phahameng / Ca²⁺ karo-karolelano ea litšenyehelo ho feta ha keketseho e tlisoang ke depolarisation (ke hore, KCl) ho intracellular Ca²⁺, ho fana ka maikutlo a "Ca²⁺-sensitizing ”phello ea agonists. Ntle le moo, ho bontšitsoe hore ho sarcoplasmic Ca e sa feleng²⁺ boemo, ho fokotseha ha matla (“Ca²⁺-desensitization ”) e ka bonoa. Ho amoheloa ka kakaretso hore senotlolo sa "calcium sensitization" ke MLC₂₀ mochine o itšetlehileng ka phosphorylation. Kahoo ho leka-lekana lipakeng tsa tsela tse lebisang keketseho ea MLC₂₀ phosphorylation le tse lebisang ho fokotseha ha MLC₂₀ phosphorylation e lekola boholo ba "sensitization ea khalsiamo" (Hirano, 2007).

2. Phomolo.

Joalo ka mesifa e meng e boreleli, boikhathollo ba mesifa ea CC bo loants'oa ka tsamaiso ea methapo ea methapo ea methapo ea methapo ea methapo. Ka li-receptors tse khethehileng, li-agonists li kenya ts'ebetso ea cymbase e kopaneng le membrane, e hlahisang cAMP. cAMP ebe e kenya protheine kinase A (cAK), 'me, ho isa tekanyong e tlase, cGK. ANF ​​e sebetsa ka pGC (Lucas et al., 2000), athe HA HO susumetsa sGC; ka bobeli li hlahisa cGMP, e sebetsang ka cGKI, 'me ka tekanyo e tlase, cAK. CGKI e sebetsang le cAK phosphorylate phospholamban, protheine eo ka tloaelo e thibelang Ca²⁺ pompo ka har'a membrane ea sarcoplasmic reticulum. Ca²⁺ Pompo e kenngoa ts'ebetsong 'me, ka lebaka leo, boemo ba cytoplasmic Ca ea mahala²⁺ ea fokotseha, e fella ka ho phomola mesifa e boreleli. Ka mokhoa o ts'oanang, protheine ea protheine e kenya tšebetsong cell membrane Ca²⁺ pompo, e lebisang ho sarcoplasmic Ca e fokotsehileng²⁺ ho tsepamisa mohopolo le phomolong e tlang (Somlyo le Somlyo, 1994, 2000; Karaki et al., 1997; Berridge, 2008). Hashitani et al. (2002) o khothalelitse hore ho fokotsa kutloisiso ea protheine ea contractile ho Ca²⁺ e ka ba mochine o ka sehloohong oa boikhathollo ba NO-e khothalelitseng ho mesifa e boreleli ea CC. Ka CC mesifa e boreleli e tsoang kolobe ea Guinea, ba fumane hore ho litokisetso tsa NA tse sa bonahaleng, NO mofani SIN-1 a thibetse 80% ea contraction mme ea fokotseha [Ca²⁺]_i ka 20%. Ka lehlakoreng le leng, calcium antagonist nifedipine, e fokotsehile [Ca²⁺]_i ka 80%, athe boemo ba contraction bo ne bo fokotsehile ke 20% feela. Litokisetsong tse phahameng tsa potasiamo e phahameng, SIN-1 e thibile 80% ea contraction mme ea fokotseha [Ca²⁺]_i ka 20%.

1. Endothelial Dysfunction.

Ho hloka taolo ea endothelial e ka ba sesosa se ka sehloohong sa ED se amanang le lintho tse ngata tse kotsing, tse kang khatello ea mali, dyslipidemia, lefu la tsoekere, khatello ea maikutlo, botena, ho tsuba koae le metabolic syndrome. Hobane ts'ebetso ea methapo ea methapo ea kutlo e ka iponahatsa e le hantle qalong ea penile endothelium, monyetla o hlaha oa hore ED e ka ba sesupo sa lefu la CV (Jackson et al., 2010; Shin et al., 2011).

2. Botsofe.

Ho tsofala ke ntho ea bohlokoa ea kotsi ho ED, 'me ho hakanngoa hore 55% ea banna ba na le ED ba le lilemo tsa 75 (Melman le Gingell, 1999; Johannes et al., 2000). Le ha lilemo tse amanang le lilemo tsa ED li hlahisoa ka bongata ke khatello ea maikutlo ea oxidative le ho se sebetse hantle ho phetseng ka nako ea penis, lits'ebetso tsa limolek'hule tse hlahisang phello ena ha li hlalosoe ka botlalo. Ho tsofala ho batho ho boetse ho amahanngoa le liphetoho tse 'maloa ka sebopeho sa arterial le tšebetso, karolo e' ngoe ea tsona e amana le ho theoha ha litekanyetso tsa li-steroid (ke hore, testosterone le estradiol) (Buvat et al., 2010). Liphetoho tse joalo li kanna tsa baka karohano ea ho se sebetse ha kalafo ea ED. Ho na le bopaki ba ho kenya letsoho ha tsamaiso ea NO / cGMP. Kahoo, Garban et al. (1995) e fumane hore ts'ebetso ea NOS e qhibilihang e fokotsehile haholo litoneng tsa penile ho tsoa ho likhaba tsa senescent. Polelo ea tlase ea NOS mRNA e fumanoe ho likhoto tsa khale ho feta ho likhoto tse nyane (Dahiya et al., 1997). Mohlaleng o mong oa ratoa oa botsofali, palo ea methapo ea methapo e amanang le NOS kahare botoneng e fokotsehile haholo, 'me karabelo ea erectile ho bohareng le ho hlohlellehong hoa fokola (Carrier et al., 1997). Ka 'mutla oa botsofaling, ho phomola ho itšetlehileng ka CC ho ile ha amoheloa; leha ho le joalo, eNOS e ne e laoloa ka bobeli ka vasotine endothelium le mesifa e boreleli ea koporasi (Haas et al., 1998). Johnson et al. (2011) ho lekantsoe hore na ho se sebetse ka sepheo sa botona ba eNOS ke mokhoa o kenyang letsoho. Liphumano tsa bona li khothalelitse hore botsofali bo etsa hore eNOS e se ke ea kena-kenana le botoneng, e leng se bakang khatello e matla ea oxidative le ED.

3. Lefu la tsoekere Mellitus.

Lefu la tsoekere ke ntho e bohlokoa e ka etsang hore ho be le lefu la ED (Saenz de Tejada le Goldstein, 1988; Melman le Gingell, 1999; Johannes et al., 2000; Saigal et al., 2006; Chitaley et al., 2009). Ho latela Massachusetts Male Aging Study, banna ba nang le lefu la tsoekere ba na le tšoaetso ea 28% ea ED ha e bapisoa le 9.6% ho bongata ka kakaretso (Feldman et al., 1994). Banna ba nang le lefu la tsoekere ba na le kotsi ea bophelo ba 75% ea ho ba le ED mme ba na le ho qaleha ha pejana ho ED ha ho bapisoa le nondiabetics (Saigal et al., 2006). Lintho tse ngata li ka kenya letsoho ho lefu la lefu la tsoekere la ED. Litlamorao tsa systemic tsa hyperglycemia le hypogonadism li thusa ho nts'etsopele ea matsoao a vasodilatory a senyehileng, mesifa ea mesifa e boreleli, le lefu la veno-occlusive (Hidalgo-Tamola le Chitaley, 2009; Malavige le Levy, 2009). Ho CC e ikhethileng ho tsoa ho bakuli ba nang le lefu la tsoekere le ED, ho phomola ho itšetlehileng ka neurogenic le endothelium ho ne ho senyehile (Saenz de Tejada et al., 1989); sena se ile sa fumanoa le mebutlong eo lefu la tsoekere le neng le qhekelloa ke alloxan (Azadzoi le Saenz de Tejada, 1992). Ketsahalo ea Penile NOS le dikahare li ile tsa fokotsoa mefuteng ea litekanyetso ea lefu la tsoekere la Bobeli la II le II le nang le ED (Vernet et al., 1995). Leha ho le joalo, ho litoeba tse nang le lefu la tsoekere la streptozotocin, NOS binding e eketsehile (Sullivan et al., 1996), mme ts'ebetso ea NOS ho lithane tsa penile e ne e phahame haholo ho feta ho litoeba tsa taolo, leha ho na le tšilafalo e kholo ea boits'oaro ba mato le matšoao a potency erectile (Elabbady et al., 1995). Ho batho, lefu la tsoekere la lefu la tsoekere le ile la khothaletsoa hore le amanang le litlamorao tsa lihlahisoa tsa pheletso ea glycation kamorao ho sebopeho sa NO (Seftel et al., 1997). Bokhoni ba lisele tsa lefu la tsoekere ho fetola l-arginine ho l-citrulline ka NOS e bonts'itsoe e fokotsehile, mme ho ile ha fanoa ka tlhahiso ea hore polelo e eketsehang ea arginase II liseleng tsa lefu la tsoekere e ka kenya letsoho ho ED e amanang le lefu lena (Bivalacqua et al., 2001b). Ho ts'ehetsa pono ena, ho hlakoloa ha arginase II ho ile ha bontšoa ho ntlafatsa boikhathollo ba CC ho litoeba le mofuta oa lefu la tsoekere la mofuta oa I (Toque et al., 2011).

4. Atherosclerosis.

Atherosclerosis ke lintlha tsa bohlokoa tsa kotsi tse amehang ho ntlafatsoeng ha vasculogenic ED. Ho na le bopaki ba khokahano e matla pakeng tsa ED le atherosclerosis (Maas et al., 2002; Grover et al., 2006; Jackson et al., 2006, 2010). ED le atherosclerosis li arolelana mabaka a tšoanang a kotsi, 'me maemo ana ka bobeli a tšoauoa ka ho se sebetse hantle ha endothelial dysfunction le ho senyeha HA bioavailability. Lintlha tsa morao-rao li bonts'a hore ED e ka sebetsa e le leseli la sendinel le etellang pele tlhahlobo ea bongaka ea lefu la methapo ea methapo ea pelo (Montorsi et al., 2003; Gazzaruso et al., 2008). ED ke ponelopele e ikemetseng ea liketsahalo tse bohloko tsa CV tsa nakong e tlang; banna ba bangata ba ba le matšoao a lilemo tsa ED pele ho tlhahlobo ea bona ea lefu la CV ea pele. Ka mohlala oa 'mutla oa atherosulinotic ED (Azadzoi le Goldstein, 1992; Azadzoi et al., 1996), ho ile ha bontšoa hore ischemia e sa foleng ea cavernosal ha e ame feela endothelium empa e boetse e ntlafatsa boikhathollo ba CC le mosebetsi oa NOS (Azadzoi et al., 1998). Ho bile le keketseho e eketsehang ea li-eicosanoids tsa constituteor ho CC. lTsamaiso eaArginine e ile ea hloleha ho ntlafatsa boikhathollo ba CC, bo neng bo khothalelitsoe ka lebaka la ho senyeha ha mosebetsi oa NOS le phokotso ea sebopeho sa NO.

5. Hypercholesterolemia.

Hypercholesterolemia e boetse e fumanoe e sitisa boiketlo ba endothelium-mediated ba mesifa ea borena ea CC (Azadzoi le Saenz de Tejada, 1991; Azadzoi et al., 1998). Hypercholesterolemia ha ea ka ea ama ts'ebetso ea NOS, empa e sitisitse boiketlo ba endothelium empa e seng boikhathollo ba neurogenic ba lithane tsa CC tsa mmutla. Hobane phomolo e itšetlehileng ka endothelium e ntlafalitsoe kamora kalafo le l-arginine, ho ne ho nahanoa hore ho na le sebopeho se sa lekaneng sa NO ka lebaka la khaello ea ho fumaneha ha l-arginine ho liphoofolo tsa hypercholesterolemic (Azadzoi le Saenz de Tejada, 1991; Azadzoi et al., 1998).

6. Ho tsuba.

Ho tsuba ke ntho e ka sehloohong e ka bakang mathata a ho se sebetse hantle ha erectile dysfunction (Mannino et al., 1994; Gades et al., 2005; Shiri et al., 2005; Tostes et al., 2008). Boithuto ba kliniki le ba mahlale a mantlha bo fana ka bopaki bo matla bo sa tobang ba hore ho tsuba ho ka ama ho senyeha ha penile ka lebaka la ho senyeheloa ke boikhathollo ba mesifa ea endothelium kapa ka ho ama tlhahiso ea NO ka phetoho ea ROS. Hore na nikotine kapa lihlahisoa tse ling tsa mosi oa ho tsuba li ka rarolla mathata ohle a amanang le tšenyo ea methapo e ntse e sa tsejoe (Tostes et al., 2008).

7. Radical Prostatectomy.

Leha ho bile le khatelo-pele mokhoeng oa ho buoa, ED kamora ho hlaseloa ka potlako ea prostatectomy, e ntseng e le kalafo e tloaelehileng bakeng sa banna ba nang le mofetše oa mofetše oa lefu la senya, ke bothata bo tloaelehileng. Sena se bakoa haholo ke tšenyo ea nakoana ea methapo ea methapo ea methapo e bakang ho ruruha ha methapo ea methapo, ho fokola ha mesifa, ho ferekana ha mesifa le lefu la pelo (veno-occlusive dysfunction)Magheli le Burnett, 2009).

1. Phosphodiesterase Inhibitors.

Tataiso ea hona joale ea kalafo ea ED e khothaletsa li-inhibitors tsa PDE5 e le kalafo ea mohala oa pele (Hatzimouratidis et al., 2010). Li-inhibitors tsohle tse "ka sehloohong" tsa PDE5, sildenafil, tadalafil, le vardenafil li hlahlobetsoe hore li sebetsa ebile li bolokehile (Hatzimouratidis le Hatzichristou, 2008; Eardley et al., 2010). Tekanyo e sebetsang ea lithethefatsi tsena e batla e le 60 ho 70% empa e tlase haholo bathong ba bang ba bakuli, joalo ka ba nang le ts'enyo e mpe ea methapo, ED kamora lefu la ramatiki, lefu la tsoekere kapa lefu la methapo e matla (Hatzimouratidis le Hatzichristou, 2008). Khetho ea inhibitor ea PDE5 e latela lintlha tse 'maloa, ho kenyeletsoa makhetlo a thobalano le boiphihlelo ba mokuli le moemeli (Mirone et al., 2009).

Li-inhibitors tsa PDE5 li ile tsa hlahisoa e le kalafo e batang; leha ho le joalo, tadalafil e boetse e ngolisitsoe bakeng sa tšebeliso e tsoelang pele, ea letsatsi le letsatsi ho litekanyetso tsa 2.5- le 5-mg. Ketso ea li-inhibitors tsa PDE5 hangata e hlalosoa ho latela selectivity (PDE5 bapisoa le li-PDE tse ling) le potency (mahloriso a hlokahalang bakeng sa ts'ebetso). Khetho ea inhibitor ea PDE5 ke ntlha ea bohlokoa e khethollang boemo ba eona ba phello e mpe mme e ka fapana lipakeng tsa liakhente (Lethathamo 1). Sildenafil le vardenafil ba arabela hanyane ka PDE6. Hobane PDE6 e atile ka har'a retina, sena se ka hlalosa tletlebo ea bakuli ba bang ba hore sildenafil kapa vardenafil e ka baka pherekano ea pono (<2% ea bakuli). Tadalafil e sebetsana ka mokhoa o fapaneng le PDE11 (mohlala, pelo, li-testes le pituitary e ka pele), empa litlamorao tsa phello ena ha li tsejoe.

Thepa e tloaelehileng ea pharmacokinetic ea PDE5 inhibitors [mohlala, bioavailability, mahloriso a plasma a mangata (C_{, max}), nako (T_{, max}) hlokahala bakeng sa ho fihlela C_{, max}, le nako e hlokahalang bakeng sa ho tlosa halofo ea inhibitor ho plasma (t_1/2)] kaofela li susumetsa katleho (Lethathamo 2) (Gupta et al., 2005). Sildenafil, vardenafil, udenafil, le avanafil li tšoana hantle T_{, max}, e bolelang esale pele nako e ts'oanang ea ho qala ketso. The t_1/2 litekanyetso tsa tadalafil le udenafil li telele ho feta tsa li-inhibitors tse ling tsa PDE5, tse ka bakoang ke ho kenngoa butle ka mpeng le / kapa ho theoha butle hoa lithethefatsi tsena ke sebete, kapa ka mabaka a mang. E atolositsoe t_1/2 ea tadalafil e fana ka phello e telele ea kalafo, mme sena e kanna ea ba udenafil le SLx-2101. The C_{, max} ea vardenafil e tlase haholo ho feta sildenafil le tadalafil, mohlomong ho latela boleng bo tlase ba bioavailability (Gupta et al., 2005). Li-inhibitors tsa PDE5 li senyehile ka har'a sebete, 'me ho sebelisana le ketoconazole, ka mohlala (ho thibela CYP3A4) ho ka eketsa nako ea bona ea katleho. Nako ea ts'ebetso ea inhibitor ea PDE5 ha e bonahale kamehla ho tlosoa ha eona ho plasma. Ho builoe ka mekhoa ea limolek'hule e ka kenyang letsoho ho sena (Francis et al., 2008). Ka hona, ho ka ba le ho phehella ha litla-morao tsa biochemical kamora hore inhibitor e hlakoloe ho tsoa lisele (memory memory). Ntle le moo, hobane li-inhibitors li tlama ka thata ho PDE5 ho, mohlala, lisele tsa mesifa, sena se ka hlakola ho tsoa ha tsona liseleng tsena le ho lelefatsa litlamorao (Francis et al., 2008).

Liketsahalo tse tloaelehileng tse mpe tse nang le li-inhibitors tsa PDE li kenyelletsa hlooho ea hlooho (10-16%), leqhubu (5-12%), dyspepsia (4-12%), tšubuhlellano ea nasal (1-10%), le ho tsekela (2-3%)Hatzimouratidis et al., 2010). Tadalafil e ka baka bohloko ba morao / myalgia ho 6% ea bakuli. Liketsahalo tse fapaneng hangata li bobebe ka tlhaho 'me li itšehla thajana ka ts'ebeliso e tsoelang pele, mme sekhahla sa ho theoha ka lebaka la liketsahalo tse bohloko se tšoana le se bonoang ka placebo. Liteko tsa tleleniki le data e hlahisoang ka morao ho li-inhibitors tsohle tsa PDE5 li bontšitse lithethefatsi li sireletsehile ho bakuli ba nang le lefu la CV. Kahoo, ha ho na keketseho ea litekanyetso tsa infaration tsa myocardial tse hlokometsoeng (Vlachopoulos et al., 2009). Ha ho na inhibitor ea PDE e amileng hampe nako ea nako ea ho ikoetlisa kapa nako ea ischemia nakong ea liteko tsa boikoetliso ho banna ba nang le angina e tsitsitseng. Ebile, li ka ntlafatsa liteko tsa boikoetliso. Li-inhibitors tsa PDE5 li kanna tsa ba tsa thusa ho lefu la CV (Takimoto et al., 2005), hape sildenafil e amohetse kalafo ea khatello ea mali ea methapo ea methapo (pulmonary arterial hypertension (Galiè et al., 2005).

Li-nitrate li hanyetsanoa ka botlalo le li-inhibitors tsohle tsa PDE ka lebaka la hypotension e sa lebelloang. Nako ea tšebelisano lipakeng tsa nitrate tsa nitrate le li-inhibitors tsa PDE li fapana ho ea ka PDE inhibitor le nitrate. Haeba mokuli a hlaha angina ha a ntse a sebelisa PDE inhibitor, ho ka sebelisoa li-antiangina tse ling sebakeng sa nitroglycerin kapa ho fihlela nako e loketseng (24 h bakeng sa sildenafil kapa vardenafil le 48 h bakeng sa tadalafil) (Vlachopoulos et al., 2009).

2. Prostaglandin E₁.

Le ha PDE5 inhibitor e lula e le eona phekolo ea pele e atileng haholo ho banna ba nang le bothata ba ho se sebetse hantle ka har'a methapo ea kutlo, intraurethral alprostadil e kanna ea ba ea khetho e nepahetseng bakeng sa kalafo ho lingoli tsa sildenafil (Jaffe et al., 2004), haholoholo ho banna ba neng ba kile ba sebelisa radical retropubic prostatectomy (McCullough, 2001; McCullough et al., 2010). Lisebelisoa tsa Vasoactive li ka tsamaisoa ka holimo ho mucosa ea urethral 'me ho ka etsahala hore li kenelle kahare ho Corpus spongiosum ebe li fetisetsoa CC. Ho khutlisetsa mokhoa o tlatselletsang oa ho hlapela litho tsa 'mele ka har'a mothapo o tebileng oa dorsal le makala a lona a shebahalang e le mokhoa o nepahetseng haholo oa phetisetso ea lithethefatsi kamora ts'ebeliso ea methapo ea methapo ea methapo ea senya ea prostaglandin E₁ (Bschleipfer et al., 2004).

TS'OLO₁ (alprostadil) le PGE₁/ motsoako oa prazosin o bonts'itsoe ho hlahisa li-erections ho bakuli ba bangata ba nang le "organ" e sa foleng (Peterson et al., 1998). Phuputsong e lebelletsoeng, ea mefuta-futa, e foufetseng habeli, e laoloang ke placebo ho bakuli ba 68 ba nang le nako e telele ea ED ea mantlha e tsoang mantlhaHellstrom et al., 1996), alprostadil e tsamaisitsoeng ka nako e fetisisang e hlahisitse katoloso e felletseng ea botona ho 75.4%, mme 63.6% ea bakuli ba tlalehile ho kopanela liphate. Litlamorao tse atileng haholo e ne e le bohloko ba penile, bo fumanoang ke 9.1 ho 18.3% ea bakuli ba fumanang alprostadil. Ho ne ho se na likarolo tsa kemolo. Phuputsong e 'ngoe e sa boneng mahlo, e laoloang ke placebo ho banna ba 1511 ba nang le ED e sa foleng ka mabaka a fapaneng a tlhaho, 64.9% e bile le thobalano ka katleho ha e nka transurethral alprostadil ha e bapisoa le 18.6% ho placebo (Padma-Nathan et al., 1997). Hape, litlamorao tse tloaelehileng ka ho fetisisa e ne e le bohloko bo bobe ba penile (10.8%).

Bakeng sa banna ba fumanang liente tsa intracavernosal li le thata, boiketlo ba tsamaiso ea intraurethral ea alprostadil ke khetho (Nehra et al., 2002). Joalokaha ho se ho boletsoe, intraurethral alprostadil e kanna ea ba khetho bakeng sa banna ba kileng ba feta pele radical retropubic prostatectomy (McCullough, 2001; McCullough et al., 2010). Bohloko ba penile e lula e le bothata ho bakuli ba bangata.

3. Nitrate ea manyolo.

Nitroglycerin le li-nitrate tse ling tsa organic ho lumeloa hore li baka phomolo e boreleli ea mesifa ka ho susumetsa GC e qhibilihang ka tokollo ea enzymatic ea NO (Feelisch, 1992); ka mohopolo, ena e bonahala e le mokhoa o hlakileng oa ho ntlafatsa ntlafalo ho bakuli ba nang le ED. Ka bobeli nitroglycerin le isosorbide nitrate li fumanoe li khatholla maratsoana a ikemetseng a CC (human CC)Heaton, 1989). Phello ea hore tšebeliso ea li-nitroglycerin ka botoneng e ka lebisa ho ekeletsong e lekanang bakeng sa thobalano (Tiking le Crawley, 1985) e khothalelitse lipatlisiso tse 'maloa mabapi le ho sebetsa ha mofuta ona oa kalafo oa ED. Leha a sebetsa hantle ho bakuli ba nang le ED, o bonts'itse lithutong tse 'maloa tse laoloang ke placebo (Andersson, 2001), litlamorao tsa transrermal nitroglycerin li na le moeli, 'me kalafo ena ha e bonahale e le ntho e ka sebelisoang kajeno. Joalokaha ho hatisitsoe pejana, li-nitrate tsa organic li hanyetsoa ho banna ba nkang li-inhibitors tsa PDE5.

4. K⁺-Mino oa Lits'oaetso.

Tse 'maloa K⁺-vannel openers (pinacidil, cromakalim, lemakalim, le nicorandil) li bontšitsoe li sebetsa hantle ho bakeng phomolo ea lithane tse tsoang ka thoko ho liphoofolo le motho le ho hlahisa tsoalo ha e kenelletse ka hare ho litšoene le batho (Andersson, 2001). Leha ho le joalo, ke minoxidil feela, vasodilator ea arteriolar e sebelisoang e le moemeli oa antihypertgency ho bakuli ba nang le khatello e matla ea mali, ho bonahala eka e lekoe e le kalafo ea molomo ho monna. Liphihlelo tsa tleliniki le moriana li lekane (Andersson, 2001), le K⁺Ho qala ka sethethefatsi, le haeba ho ka sebetsa ho bakuli ba bang, ha ho so ka ha netefatsoa hore liteko tse fumanehang tsa kliniki ke khetho e sebetsang ho banna ba nang le ED. Ha ho liketsahalo tse ncha tse tlalehiloeng lilemong tse leshome tse fetileng.

5. α-Adrenoceptor Antagonists.

6. Liphephetso tsa Opioid Receptor.

Ho ngotsoe hantle hore ente ea nako e telele ea li-opioids e ka lebisa ho fokotseha ha libido le ED (Parr, 1976; Crowley le Simpson, 1978; Mirin et al., 1980; Abs et al., 2000; Hallinan et al., 2008), mohlomong ka lebaka la hypogonadotropic hypogonadism (Mirin et al., 1980; Abs et al., 2000; Hallinan et al., 2008; Vuong et al., 2010). Ho nahanoa hore li-opioid tsa mehleng ea khale li ka kenella ts'ebetsong ea thobalano, bahanyetsi ba opioid receptor ba khothalelitsoe hore ba ka sebetsa hantle joalo ka kalafo (Fabri et al., 1989; Billington et al., 1990). Ho na le liphihlelo tse ntle tsa kliniki ka naltrexone, eo hammoho le metabolism ea eona e sebetsang ea 6-β-naltrexol ke bahanyetsi ba tlholisano ho li-receptors tsa μ- (le κ-opioid). Sena se ka supa bopaki ba molao-motheo (Andersson, 2001), 'me e ke ke ea qheleloa ka thoko hore inhibition e eketsehang ka li-peptide tsa opioid e kanna ea ba tlatsetsa ho se atleheng hoa erectile ho bakuli ba bang. Ho bakuli ba joalo, kalafo ea naltrexone e ka ba moemeli ea sebetsang oa kalafo. Leha ho le joalo, lithuto tse laoloang hantle tse netefatsang sena lia haella, 'me ho bonahala ho se na liphetoho tse ncha lilemong tse leshome tse fetileng.

7. Apomorphine.

Apomorphine, dopamine receptor agonist e hlohlelletsang dopamine D ka bobeli₁- le D₂- joalo ka li-receptors, ho bonts'itsoe hore ho etsa hore penile erection e be likhoto (Mogilnicka le Klimek, 1977; Benassi-Benelli et al., 1979) le banna ba phetseng hantle (Lal et al., 1984) le ho banna ba nang le ED (Lal et al., 1987, 1989). l-DOPA e kanna ea susumetsa leqeba ho bakuli ba nang le lefu la Parkinson (bona, mohlala, Vogel le Schiffter, 1983). Ho khothalelitsoe hore dopamine D₂ ho hlohlelletsoa ha li-receptor ho ka baka ho kenella ho hoholo litlamong, athe ts'ebetso ea D₁ li-receptors li na le litlamorao tse fapaneng (Zarrindast et al., 1992). Ho litšoene tsa rhesus, quinelorane, dopamine D₂ receptor agonist hlahisa penile erection (Pomerantz, 1991), e khahlisa pono eo D₂ ho hlohlelletsa li-receptor ho bohlokoa bakeng sa karabo ena. Apomorphine e na le tšebelisano e phahameng ho D₂- ho feta D₁- Lisebelisoa tse fumanehang (Rampin et al., 2003). D₂ li-receptors ho PVN ho lumeloa hore ke sebaka sa mantlha sa ho kenyelletsa li-erections ho rat (Chen le al., 1999). Ho ka ba joalo le ka monna (Brien et al., 2002).

Heaton et al. (1995) e tlaleha hore apomorphine, e kenngoeng ka mucosa ea molomo, e tla sebetsa joaloka erectogenic agent. Sena se netefalitsoe haholo ho li-RCT, mme ho na le bopaki ba hore apomorphine e sebetsa hantle kalafong ea ho senyeha ha erectile ho palo e pharalletseng ea li-ED ka tekanyetso ea 2 le 3 mg e nkuoe hanyane ka mokhoa o batlang.Dula et al., 2000, 2001; Heaton et al., 2002; Von Keitz et al., 2002). Ho mamella ha apomorphine ka tekanyetso ea 2 le 3 mg ho fumanoe hantle (Fagan et al., 2001; Adams et al., 2002; Ralph et al., 2002). Litlamorao tse atileng haholo ke ho nyekeloa ke pelo, ho opeloa ke hlooho le ho tsekela, ka palo e fokolang ea bakuli ba ntseng ba eketseha ka syncope. Litlamorao tsena tsa morao-rao li ile tsa bonoa haholo ho litekanyetso tse phahameng ho feta tsa lengolo la tumello ea ho sebelisoa Europe. Ka kakaretso, ho fana ka hore moriana o sebelisoa tumellanong le ho ngola, ho bonahala ho se na bopaki ba mamello ea bohlokoa litabeng tsa polokeho (Eardley et al., 2010).

Leha lithethefatsi li bontsitse molemo o moholo oa lipalo mabapi le placebo mohatong oa bongaka oa II / III, tlhahlobo ea tlhaiso-leseling e senotse kakaretso ea melemo e tlase (ke hore, ts'ebetso e sebetsang ea minus placebo) ka lipalo lipakeng tsa 11 le 13% feela (Stief et al., 2002). Ts'ebetso ena e fokolang, haholo ho bakuli ba nang le organic ED, e netefalitsoeng lithutong tse 'maloa (Perimenis et al., 2004a,b; Strebel et al., 2004; Gontero et al., 2005), e lebisa tlhahiso ea hore moriana o ka tšoaneleha hantle ho banna ba nang le ED e bonolo. Papiso e latelang lithuto tse tlang ho ba teng lipakeng tsa apomorphine SL le sildenafil li fane ka bopaki bo hlakileng ba hore sildenafil e sebetsa hantle ho feta apomorphine, mme litheko tse phahameng li ne li emela sildenafil (Pele et al., 2007; Afif-Abdo et al., 2008; Giammusso et al., 2008; Pavone et al., 2008). Ka lebaka la bosholu ba sildenafil, apomorphine SL ha e so ka ea amoheloa.

8. Trazodone.

Trazodone ke moemeli oa lithibela-mafu "atypical", ea lik'hemik'hale le ea lithethefatsi ka mokhoa o fapaneng le li-antidepressants tse ling tse fumanehang hona joale (Haria et al., 1994). Mokhoa ona oa lithethefatsi o thibela ho kenella bohareng ba 5-HT mme o eketsa phetoho ea dopamine ea boko empa ha e thibele ho khutlisetsoa morao ha NA (Georgotas et al., 1982). Trazodone e boetse e bontšitsoe ho thibela li-receptor tsa 5-HT le dopamine, athe metabolite ea eona e kholo, m-CCP, e na le ts'ebetso ea agonist ho 5-HT_2C receptors (Monsma et al., 1993). Metabolite ena e etsa hore ho be le litla-morao 'me ka mokhoa o ikhethileng e eketsa sekhahla sa ho thunya ha methapo ea kutlo (Steers le de Groat, 1989). Mokhoa oa ts'ebetso oa trazodone ka khatello ea maikutlo ha o utloisisehe ka botlalo; e na le ketso e tsebahatsang ya ho susumetsa. Trazodone e na le serum halofo ea bophelo ba hoo e ka bang 6 h mme e na le metabolism e ngata (Haria et al., 1994). Trazodone le metabolite ea eona e kholo li bonts'itsoe li e-na le phello ea thibelo ea α-AR liseleng tse ka thoko tsa batho ba khubung (Blanco le Azadzoi, 1987; Saenz de Tejada et al., 1991). Krege et al. (2000) e bontsitse trazodone ho ba le tšebeliso e phahameng le e leka-lekaneng ea setho sa motho₁- le α₂-ARaro, ka ho latellana, le hore setlhare ha se khetholle pakeng tsa subtypes ea α₁- le α₂-MAROLO. Metabolite e sebetsang, m-CCP, e ne e bonahala e sena litlamorao tse kholo.

Trazodone e laetsoeng ka molomo e amahanngoa le priapism ho banna ba nang le matla (Azadzoi et al., 1990) le ho eketseha ha mantsiboea mosebetsing oa boithaopo ho baithaopi ba phetseng hantle (Saenz de Tejada et al., 1991). Phihlelo e ntle ea kliniki ka moriana o tlalehiloe (Lance et al., 1995). Leha ho le joalo, litekong tse laoloang habeli, tse laoloang ke placebo ho bakuli ba nang le etiology e fapaneng ea bona ea ED, ha ho na tšusumetso ea trazodone (150-200 mg / letsatsi) e ka bontšitsoeng (Meinhardt et al., 1997; Enzlin et al., 2000).

Leha tlhahisoleseling e tsoang ho liteko tsa bongaka tse sa laoloang, e sa tšehetse pono ea hore trazodone ke kalafo e sebetsang bakeng sa banna ba bangata ba nang le ED, e ke ke ea qheleloa ka thoko hore lithethefatsi e ka ba mokhoa o mong ho banna ba bang ba nang le matšoenyeho kapa ba tepeletseng maikutlo. Phuputsong e entsoeng ka sefofane, ho hlokometsoe hore trazodone e ka ba molemo ho taolo ea khethollo ea takatso ea thobalano ea serotonin-reuptake inhibitor.Stryjer et al., 2009). Bakeng sa banna ba nang le ED le tekanyo ea karolo ea psychogenic e lekaneng ho fokotsa ts'ebetso ea taolo ea bongaka, motsoako oa trazodone e nang le sildenafil e fane ka liphetho tse khothatsang thutong ea sefofane (Taneja, 2007).

9. Melanocortin Receptor Agonists.

MT-II ke synthet ea cyclic heptapeptide eo qalong e neng e entsoe e le moemeli oa litheipi tsa maiketsetso (King et al., 2007). Ke cyclic nonselective melanocortin receptor agonist eo, ha e ente ka mokhoa o sa ts'oaneng, e fumanoeng e le moqapi oa matla oa ts'ebetso ea penile erection ho banna ba nang le nonorganic ED (Wessell et al., 1998, 2000). Leha ho le joalo, ho hlohlona / ho otlolla 'me ka linako tse ling ho nyekeloa hoa pelo le ho hlatsa ho fokotsa ts'ebeliso.

PT-141 (bremelanotide) ke heptapeptide ea maiketsetso; ke derivative e tsoang 'me mohlomong metabolite ea MT-II. K'homphieutha ena e na le tlamo e matla ho li-receptor tsa 'mele tsa 1, 3, le 4, e nang le tumellano e phahameng ea "MC4 receptor" e fetang MC3, moo e sebetsang joaloka agonist (Giuliano, 2004; King et al., 2007).

Lithuto tse 'maloa tsa kliniki li hlahlobe phello ea PT-141 (Molinoff et al., 2003; Diamond et al., 2004, 2005; Rosen et al., 2004). PT-141 e ne e fanoa ka mokhoa o sa khaotseng ho doses ho tloha 4 ho isa 20 mg ho ea ho lithuto tsa 32 tse phetseng hantle thutong e sa sebetseng, e foufetseng hape e laoloang ke placeboDiamond et al., 2004). Boithuto bona bo entsoe ntle le ts'usumetso ea thobalano e bonts'ang. Ha e bapisoa le lithuto tse tšoaroang ke placebo, PT-141 e eketsehile haholo ts'ebetsong ea erectile. Nako ea li-erections tse nang le rigidity (tlhokomeliso ea Rigi-Scan) e kholo ho feta 60% base e ne e batla e le 140 min lithutong tse tšoaroang le 20 mg ea PT-141 ha e bapisoa le 21 min sehlopheng sa phekolo ea placebo.

Tekong ea crossover e laoloang ke placebo ea banna ba 24 ba nang le bonolo le ho leka-lekana ED (Diamond et al., 2004), phello ea PT-141 (20 mg) e fanoe hammoho le maikutlo a susumetsang a thobalano (lifilimi tse tsosang takatso). Keketseho ea 3-fold ea tšebetso ea erectile e ile ea bonoa lithutong tse fuoeng PT-141 ha e bapisoa le placebo. Nako ea ho kopitsa le ho ruruha ha penile le eona e ile ea eketseha haholo ka mor'a tsamaiso ea PT-141.

Phuputso e entsoeng ka tsela e hlophisehileng ea crossover e laoloang ka mokhoa o hlophisitsoeng, e bapisoang le kalafo ea bakuli ba 19 ba nang le ED ka sildenafil (25 mg) e le 'ngoe khahlanong le sildenafil (25) e nang le 7.5 mg ea intranasal PT-141 (Diamond et al., 2005). Tsamaiso ea taolo ea mahlahana a mabeli e hlahisitse nako e telele haholo ea ho thatafala hoa motheo (> 60%) ha ho bapisoa le sildenafil feela nakong ea thupelo ea 2.5-h. Motsoako oa lithethefatsi o ne o mamelloa hantle ntle le litla-morao tse eketsehang haholo ho feta sildenafil kapa PT-141 feela. Ha ho litla-morao tse mpe tse tlalehiloeng kamora tsamaiso ea PT-141 lithutong tse tloaelehileng kapa ho bakuli ba nang le ED.

Ho totobetse hore li-agonists tsa MC li ka ba le litlamorao ho bakuli ba nang le ED tse ka thusang lipetlele. Leha ho le joalo, kamano pakeng tsa ho sebetsa hantle le litlamorao tse mpe e tlameha ho khethoa ho li-RCT tse kholo pele ho tumello ea taolo le tlhahiso e ka khonehang ea kliniki.

1. Papaverine.

Intracavernosal papaverine ente e ne e le eona kalafo ea pele e sebetsang ea bongaka ea merianaVirag, 1982). Hangata moriana o khetholloa e le phosphodiesterase inhibitor, empa o na le mokhoa o rarahaneng oa ts'ebetso mme o ka nkuoa e le "lithethefatsi tse sebetsang tsa multilevel" (Andersson, 1994). Ho thata ho tseba hore na ke mekhoa efe ea ts'ebetso e mengata e ka lebelloang ho litekanyetso tse phahameng tse ka lebelloang ha moriana o entoa ka intracavernosally. In vitro, ho bontšitsoe hore papaverine e hlasimolla methapo ea methapo, li-sinvernids tsa cavernosal, le methapo ea penile (Kirkeby et al., 1990). Lintong, Juenemann et al. (1986) e bonts'itse hore papaverine e ne e na le phello e kopantsoeng ea hemodynamic, e fokotsang ho hanyetsa ho kenella ka hare ho arterial le ho eketsa ho hanyetsa ho tsoa ha venous. Phello ea morao, e bontšitsoeng hape ho motho (Delcour et al., 1987), e kanna ea amana le ts'ebetso ke papaverine ea mochini oa veno-occlusive. Papaverine ea sebetsa empa ha e sa sebelisoa e le monotherapy ka lebaka la litheko tsa eona tse phahameng tsa fibrosis le priapism.

2. α-Adrenoceptor Antagonists.

Hobane NA e nkuoa e le e 'ngoe ea lintho tsa bohlokoa tse bolokang molumo oa' mele o boreleli oa CC ka ho hlohlelletsa li-α-AR, ho ka lebelloa hore ho thibela li-receptors tsena ho ka baka karabelo erectile. Leha ho le joalo, liphihlelo tsa kalafo ea ho hanyetsa li-í-adrenoceptor e le li-monotherapy ha lia atleha haholo.

3. Prostaglandin E₁ (Alprostadil).

TS'OLO₁, ente e kenelletseng ka hare ho eona, e le mong kapa e kopane, kajeno ke kalafo ea mokokotlo oa bobeli bakeng sa ED (Alexandre et al., 2007; Albersen et al., 2011). Lintlha tse 'maloa tsa litlamorao tsa eona le tšebeliso ea bongaka li hlahlobiloe pele (Linet le Ogrinc, 1996; Porst, 1996; Andersson, 2001; Alexandre et al., 2007). Litekong tsa bongaka, 40 ho 70% ea bakuli ba nang le ED ba arabela jekeng ea intracavernosal ea PGE₁. Lebaka leo bakuli ba bangata ba sa arabeng ha le tsejoe. Angulo et al. (2000) e bonts'itse hore motsoako oa PGE₁ le S-nitrosoglutathione e ne e khutsufatsa penile e boreleli mesifa hore na e ile ea phomola hantle kapa che₁. Ba khothalelitse karabo ea bongaka ho PGE₁ e kanna ea fokola ho bakuli ba bang ka lebaka la ho haelloa ke karabelo ea mesifa e bonolo ea Pile₁ ha a ntse a boloka bokhoni ba ho phomola ka lebaka la basebeletsi ba sebelisang mekhoa e meng ea boikhathollo. Motsoako oa PGE₁ 'me S-nitrosoglutathione o ne a e-na le tšebelisano ea synergistic ho hlasimolla mesifa ea penile trabecular boreleli, mme ho ne ho nahanoa hore motsoako o joalo o ka ba le melemo e meholo ea kalafo kalafong ea banna ba batona. Leha ho le joalo, ho bonahala eka ha ho na tsoelo-pele e ncha ea motsoako ona.

TS'OLO₁ e kenngoa ka har'a lisele tsa penile ho PHE₀ (Hatzinger et al., 1995), e sebetsang ka bioloji mme e ka kenya letsoho phello ea PGE₁. TS'OLO₁ e ka nka karolo e itseng ka ho thibela tokollo ea NA (Molderings et al., 1992), empa ketso ea mantlha ea PGE₁ le PGE₀ mohlomong e le ho eketsa ho tsepamisa mohopolo ho cAMP liseleng tsa CC tsa mesifa e bonolo ka ho hlohlelletsoa ha EP receptor (Palmer et al., 1994; Lin et al., 1995).

TS'OLO₁ e tsejoa hore e na le litlamorao tse fapaneng tsa meriana. Mohlala, e hlahisa vasodilation e hlophisehileng, e thibela ho kopana ha liplatelete, 'me e matlafatsa tšebetso ea mala. E sebelisitsoe ka mokhoa o hlophisitsoeng, lithethefatsi li sebelisitsoe tliliniki ho isa tekanyong e lekanyelitsoeng. Hanyane hanyane ho tsejoa ka pharmacokinetics ea eona, empa e na le nako e khuts'oane ea ts'ebetso mme e sebetsa haholo. Hoo e ka bang 70% e kanna ea ts'oaetsoa ka har'a 'mala o le mong.Golub et al., 1975), e ka 'nang ea hlalosa hore na ke hobaneng ha e baka litla-morao tsa ho potoloha ha e ente intracavernosally.

4. Vasoactive Intestinal Polypeptide.

Joalokaha ho hlalositsoe pejana, karolo ea VIP e le neurotransmitter le / kapa neuromodulator ka botoneng e tšehelitsoe ke bafuputsi ba bangata, empa bohlokoa ba eona ba 'mele bakeng sa penile erection ha bo so theoe (Andersson, 2001). Leha ho le joalo, ho se khonehe ha VIP ho hlahisa letsopa ha le kenella kahare ho banna ba nang le matla (Wagner le Gerstenberg, 1988) kapa banna ba nang le ED (Adaikan et al., 1986; Kiely et al., 1989; Roy et al., 1990) e bonts'itse hore e ke ke ea ba mokena-lipakeng oa NANC oa boikhathollo ba lithane tsa penile erectile.

VIP e bontšitsoe ho hlahisa mefuta e mengata ea litlamorao. Ke vasodilator e nang le matla, e thibelang ts'ebetso ea bokhachane ka mefuta e mengata ea mesifa e boreleli, e tsosa boikemisetso ba pelo le makunutu a mangata a emelang. E hlohlelletsa cymbase ea adenylyl le sebopeho sa cAMP (Palmer et al., 1994; Fahrenkrug, 2001). VIP e fuoeng kahare e ka hlahisa hypotension, tachycardia, le ho thunya (Frase et al., 1987; Krejs, 1988). Leha ho le joalo, bophelo ba plasma halofo ea peptide e khuts'oane, e ka kenyelletsang taba ea hore litla-morao tsa li-systemic li na le seoelo ha li tsamaisoa ka mokhoa o hlakileng (McMahon, 1996; Dinsmore et al., 1999; Sandhu et al., 1999).

Joalokaha ho boletsoe, Wagner le Gerstenberg (1988) e bontšitse hore VIP, leha e le ka tekanyetso e phahameng (60 μg), e ne e sa khone ho kenya letsoho ho kenella ka ente ea intracavernosal ho banna ba nang le matla. Ka lehlakoreng le leng, ha e sebelisoa hammoho le tšusumetso ea bono kapa e susumetsang, VIP ea Intracavernosal e nolofalitse erection e tloaelehileng. Kiely et al. (1989) ente VIP, papaverine, le motsoako oa lithethefatsi tsena tse nang le phentolamine intracorporally ho banna ba 12 ba nang le lisosa tse fapaneng. Ba netefalitse hore VIP feela e haelloa ke ts'usumetso ea maiketsetso a batho. Leha ho le joalo, hammoho le papaverine, VIP e ile ea hlahisa botsitso ba penile e ts'oanang le e fumanoeng ka papaverine le phentolamine. Gerstenberg et al. (1992) e tsamaisoa VIP hammoho le phentolamine intracavernosally ho bakuli ba 52 ba nang le ho se sebetse hantle ha erectile. Liperesente tse 40 tsa bakuli ba ne ba kile ba fumana kalafo ka papaverine ba le bang kapa ka papaverine hammoho le phentolamine. Kamora ho hlohlelletsa ka thobalano, bakuli bohle ba ile ba fumana erection e lekane bakeng sa ho kenella kahare. Bakuli bao ba kileng ba phekoloa ka papaverine kapa papaverine / phentolamine ba boletse hore ketso ea motsoako oa VIP e batla e tšoana le potoloho e tloaelehileng ea likamano. Ha ho na mokuli ea neng a e-na le bokuli ba 'mele, kapa li-fibrosis tsa khoebo, kapa bothata bofe kapa bofe bo bong bo tebileng (Gerstenberg et al., 1992). Liphetho tsena tse ntle li netefalitsoe ke bafuputsi ba bang (McMahon, 1996; Dinsmore le Alderdice, 1998; Dinsmore et al., 1999; Sandhu et al., 1999; Dinsmore le Wyllie, 2008). Kahoo, Sandhu et al. (1999) e fumanoeng tlhahlobong e lebelletsoeng, e sa boneng habeli, e laoloang ke placebo ho bakuli ba 304 ba nang le psychogenic ED, ba sebelisa jekete ea auto-auto, eo ho feta 81% ea bakuli le 76% ea balekane ba tlalehileng bophelo bo ntlafalitsoeng. Liphetho tse tšoanang li fumanoe ke Dinsmore et al. (1999). Motheong oa liteko tsena tsa tleliniking, ho netefalitsoe ho sebetsa hantle le polokeho, 'me motsoako o amohetse kalafo ea banna ba nang le ED United Kingdom, Denmark le New Zealand. Litlamorao tse neng li sa bonoe haholo e ne e le ho tjhaba sefahleho le hlooho.

5. Apomorphine.

Phuputsong e laoloang ke sebaka, e sa boneng mahlo ho baithaopi ba phetseng hantle, ho ile ha bontšoa hore apomorphine, e kentse ente ka tšohanyetso (0.25-0.75 mg), e khonne ho qhekella (Lal et al., 1984). Sena se tiisitsoe ke Danjou et al. (1988), e bonts'ang hore apomorphine e khelositse mohopolo ebile e matlafalitse mohopolo o susumetsoang ke tšusumetso e mpe ea pono. Ha ho na keketseho ea libido, e neng e lumellana le se hlokometsoeng nakong e fetileng (Julien le Over, 1984). Ho bakuli ba 28 ba nang le ED, Lal et al. (1989) fumane hore 17 e arabile ka erection kamora apomorphine e subcutaneous (0.25-1.0 g); ha ho mohopolo o qalileng ka mor'a placebo. Segraves et al. (1991) hape e fana ka apomorphine subcutaneously (0.25-1.0 g) ho banna ba 12 ba nang le psychogenic ED thutong e laoloang habeli le sefofu. Ba fumane keketseho e amanang le tekanyetso ea boholo ba penile. Ho hahiloe ka keketseho ea 1-cm ea bolelele bo boholo ba penile ho fumanoe ho bakuli ba 11 ho ba 12.

Ha ho na ho qheleloa ka thoko hore sehlotšoana sa bakuli ba se nang matla se ka ba le tšenyo ea mesebetsi e bohareng ea dopaminergic le hore molao-motheo oa dopamine receptor stimulation o ka sebelisoa eseng feela ka ho hlahloba empa hape le kalafo. Monyetla oa kalafo oa "subcutaneous apomorphine", leha ho le joalo, o bonahala o fokola haholo ka lebaka la litla-morao tse bang teng khafetsa. Litekanyetso tse phahameng (ke hore, ho fihlela ho 5-6 mg ho bakuli ba baholo) li ka baka khatello ea maikutlo, le lethathamong la litekanyetso tse tlase (0.25-0.75 mg) moo litla-morao tsa penile li ka bonts'ang, emesis, yawning, ho otsela, ho tsitsinyeha hoa pelo, lacrimation, Flush, le ho tsekela li ka hlaha (Lal et al., 1984; Segraves et al., 1991). Lal et al. (1987) o hlokometse hore lingoli, empa eseng babuelli, li bile le litlamorao tse mpe. Le ha ho le joalo, apomorphine e tsamaisoang ka mokhoa o sa bonahaleng e bonahala e sena sephetho se amohelehang, 'me ha e sa sebelisoa kalafo.

6. Linsidomine Chlorhydrate le Li-Donors tse ling tse NO.

Linsidomine, metabolite e sebetsang ea lithethefatsi tsa antianginal molsidomine, ho lumeloa hore e sebetsa ka tokollo ea nonenzymatic ea NO (Feelisch, 1992). The pharmacology ea linsidomine e entse hore e be mokhoa o khahlisang bakeng sa kalafo e kenelletseng ea lithuto tsa ED le lithuto tsa pele li ne li bonahala li tšepisa. Leha ho le joalo, liphetho tsa pele tse ntle ha lia ka tsa tiisoa (Andersson, 2001), mme sethethefatsi ha se sa sebelisoa kalafo.

Intracavernosal NO bafani ba joalo ka SNP ba bonahala ba sebetsa hantle ho phekola ED empa ba bile le likhang ka lebaka la litla-morao tsa hypotensive (Martinez-Piñeiro et al., 1995; Martínez-Piñeiro et al., 1998; Shamloul et al., 2005). Lasker et al. (2010) e bonts'itse ho Rage eo sodium nitrite (NaNO₂), e tsamaisoa kahare, e eketse ICP, e fokotse khatello ea methapo, 'me 1000-fold e ne e se matla ho feta SNP ea fanang ka eona. Ba khothalelitse hore ka hara rat, NaNO₂ e fetoloa hore e be Vasoactive NO ka har'a coora cavernosum le bethe ea methapo ea methapo ka mehato e fapaneng. Kahoo, liteko tsa NOS inhibitor l-NAME le xanthine oxidoreductase inhibitor allopurinol li khothalelitse hore nitrite bioactivation ho Corpora e kopantsoe ka har'a INOS, athe nitrite bioactivation ka litsing tsa methapo ea methapo e ne e bakoa haholo ke ts'ebetso ea xanthine oxidoreductase. Ho boetse ho fanoe ka maikutlo a hore bokhoni ba nitrite ba ho ntlafatsa ts'ebetso ea erectile bo susumetsa lipatlisiso tse eketsehileng ts'ebelisong ea nitrite e le moemeli oa kalafo bakeng sa ED.

7. Pheko ea Motsoako.

Phentolamine, papaverine, PGE₁, 'me VIP ke li-vasoactive tse sebelisoang haholo kalafong ea ho kopanya ho phekola ED. Ka khopolo, phekolo e kopaneng e ka fana ka katleho e betere, hobane lithethefatsi tse ngata li ka nahanoa hore li sebetsa ka mokhoa o kopanetsoeng empa phokotso ea litlamorao tsa litla-morao le theko ea pilisi le eona e ka lebelloa. Motsoako o sebelisoang khafetsa ke trimix, motsoako oa papaverine, phentolamine le PGE₁. Bechara et al. (1996) e tlalehiloe litholoana tse ntle ka ho kopanya ho fapana le PGE₁ a le mong. Empa, Seyam et al. (2005) bapisa trimix ba sebelisa tekanyetso ea 1-mg ea phentolamine le litekanyetso tse fapaneng tsa papaverine le PGE₁ ka lethal la 20-μg la PGE1, ha a fumana phapang e kholo litlamorao tsa hemodynamic, rigidity, bohloko le boitšepo lipakeng tsa lithethefatsi tsena tse peli. Leha ho le joalo, trimix e hlahisitse nako e telele ea ho qaptjoa le ho tsepamisa maikutlo ho feta PGE₁. Mekhoa ena ea kalafo le e meng e mengata e ntse e sa ngolisoe. Leha ho le joalo, ho ikopanya ha VIP le phentolamine ho amohelitsoe linaheng tse 'maloa.