Kusinthasintha kwa njira ya Dopaminergic Njira yochitira Erectile Dysfunction (2016)

2016 Oct; 119 Suppl 3: 63-74. onetsani: 10.1111 / bcpt.12653.
Simonsen U1, Comerma-Steffensen S2,3, Andersson KE2.

Kudalirika

Njira zamakono zothandizira odwala matenda a erectile (ED), phosphodiesterase mtundu wa 5 inhibitors (PDE5i), mwachitsanzo chitsanzo cha sildenafil, ndi othandiza kwa odwala ambiri omwe ali ndi ED, koma mankhwalawa sali okwanira pafupifupi 30-40% ya amuna ndi ED pomwe palinso chikondi cha neuronal. Pali zofunikira za njira zachidule zothetsera vutoli. Timayang'ana momwe tingathe kuyendetsa njira za dopaminergic kuti tipange ntchito erectile. Dopamine D1 (D1 , D5 ) - ndi D2 (D2 -D4 ) -momwe amalandirira m'chigawo chowoneka bwino, m'dera lamankhwala am'magazi, msana, komanso minofu ya erectile imakhudzidwa, ndipo ma agonists angapo omwe adapangidwa kuti azitha kuchiza matenda a Parkinson amalumikizidwa ndi kuchuluka kwa libido. Windo lakuchiritsira la ED lidapezedwa ndikuwongolera kwa anthu wamba dopamine receptor agonist apomorphine, koma inalephera makamaka chifukwa cha kuchepa kwa erectile ntchito poyerekeza ndi PDE5i. Kupewa zotsatira zoletsedwa za mlingo woyendetsedwa ndi D2 obwebweta, nseru ndi emesis, dopamine D4 odwala agonist analandira, ndipo amachititsa kuti makoswe amveke, koma mankhwalawa sanadziwikirepo kuchipatala. The β-lactamase inhibitor clavulanic acid imakula dopamine ndi serotonin ndipo anapezeka akuwonjezeka kugonana chilakolako chogonana ndi mazira, koma mlingo woyankha mlingo ndi mawonekedwe a belu. Bupropiony ili ndi chisankho choletsera dopamine kubwezeretsanso nthumwi ndipo ingagwiritsidwe ntchito kuchepetsa kugonana zizindikiro za mankhwala ena opatsirana pogonana, motero amapereka njira yosangalatsa yothandizira ED. Mwachidule, kusintha kwa dopaminergic njira kumapereka chithandizo cha ED.

PMID: 27541930
DOI: 10.1111 / bcpt.12653

Kukwera kwa magazi ndi chochitika cha hemodynamic pomwe kufalikira kwa mitsempha yamagazi yamkati mwa cavernous ndi helicine kumatsatiridwa ndi kuchuluka kwa magazi m'mitsempha kupita ku corpora cavernosa. Kukwera kwa magazi kumakhudza njira zosiyanasiyana zapakati ndi zamkati za mitsempha ndi/kapena za humoral 1. Ma neurotransmitters apakati ndi ma neuropeptide amatha kuthandizira, mwachitsanzo dopamine (DA), kapena kuletsa (monga opioid peptides) kukwera kwa mbolo mwa kuchita zinthu m'malo angapo a ubongo. Serotonin imatha kukhala ndi zotsatira zothandiza komanso zoletsa, kutengera mtundu wa receptor womwe umakhudzidwa 2.

Ma neurotransmitters opangidwa kuchokera ku mitsempha ya sympathetic (noradrenaline, ATP) ndi parasympathetic (acetylcholine, nitric oxide, vasoactive intestinal peptide) yomwe imalowa mu corpora cavernosa, corpus spongiosum ndi glans mbolo imayang'anira kuyenda kwa magazi panthawi yomanga ndi kutsika kwa chiberekero 1 , 3 , 4. Mu matenda a metabolic syndrome ndi matenda a shuga, neuropathy komanso kusalingana pakati pa zinthu zotsekeka m'mimba ndi zopumula m'thupi la chiberekero zingathandize kusokoneza chiberekero (ED) 5.

Malangizo apano amalimbikitsa kuti phosphodiesterase type 5 inhibitors (PDE5i), sildenafil, vardenafil, tadalafil ndi avanafil, ndi mankhwala oyamba a ED; komabe, pafupifupi 30-40% ya amuna omwe ali ndi ED sayankha chithandizo cha PDE5 inhibitors 6 , 7. Odwala omwe ali ndi vuto la mitsempha, matenda a shuga kapena matenda oopsa a mitsempha akhoza kukana PDE5 inhibitors 8. Kuwonjezera pa matendawa, mankhwala a matenda a central nervous system (CNS), monga antidepressants, antipsychotics ndi anxiolytics, nawonso amakhudza ntchito ya erectile 5. Mankhwala oletsa kuvutika maganizo, monga selective serotonin reuptake inhibitors (SSRIs) ndi venlafaxine, amatha kusokoneza ntchito ya kugonana kwa amuna (chilakolako/kukwiya–chisangalalo–orgasm). Mankhwala ena oletsa kuvutika maganizo, monga bupropion, nefazodone ndi mirtazapine, amakhudzanso ntchito ya kugonana, ngakhale kuti kuchuluka kwa kusokonezeka kwa kugonana n’kochepa, poyerekeza ndi SSRI 9 . Kuwonjezera pa matenda a maganizo, mankhwala oletsa kuvutika maganizo amagwiritsidwanso ntchito pochiza ululu wa mitsempha; chifukwa chake, kusokonezeka kwa kugonana komwe kumachitika chifukwa cha mankhwala oletsa kuvutika maganizo kumakhudza anthu ambiri. M'mayesero ena azachipatala, sildenafil yokonzedwa ED yoyambitsidwa ndi mankhwala oletsa kuvutika maganizo; komabe, chifukwa cha kuchuluka kwa anthu osayankha ku zoletsa za PDE5, pali kufunika kwa njira zatsopano zochizira ED. Njira ina ingakhale yolunjika osati njira za m'mphepete zokha komanso njira zofunika kwambiri pa ntchito ya erectile. Monga tanenera, ma neurotransmitters angapo amagwira ntchito ya erectile pamlingo wapakati komanso wa m'mphepete ndipo ndemanga zingapo zaposachedwa zafotokoza mwatsatanetsatane lamuloli 1 , 2 ndi maphunziro azachipatala okhudzana ndi kusokonezeka kwa kugonana ndi monoamines 10. Ndemanga yonse yomwe ikukhudza mankhwala ena aposachedwa omwe akupangidwa a ED ingalimbikitsidwenso 11. Pochiza matenda a Parkinson, mankhwala angapo omwe ali ndi dopaminergic effect adapangidwa, ndipo imodzi mwa mankhwala awa , general dopamine receptor agonist, apomorphine, idapezeka kuti imayambitsa erectile 12-15 . Chifukwa chake, cholinga chachikulu cha MiniReview pano ndikuganizira kuthekera kosintha njira za dopaminergic kuti ziwongolere ntchito ya erectile.

Njira za Dopaminergic Zomwe Zimagwira Ntchito Erectile

Central pathways

Njira zazikulu zomwe zimakhudzidwa ndi kuwongolera ntchito ya erectile zimaphatikizapo madera angapo a ubongo monga medial pre‐optic area (MPOA), paraventricular nucleus (PVN) ya hypothalamus, ventral tegmental area, hippocampus, amygdala, bed nucleus ya stria terminalis, nucleus accumbens, medulla oblongata ndi spinal cord 2 , komwe PVN ya hypothalamus ndi ventral tegmental area ndizofunikira kwambiri 2 , 15. Ma neurotransmitters angapo amagwira ntchito yolamulira pakati pa erection ndipo amathandizira erectile ntchito (dopamine, nitric oxide, glutamate, acetylcholine, oxytocin, hexarelin peptide, ACTH, MSH ndi pro‐VGF), amaletsa erectile ntchito (monga noradrenaline, enkephalins, GABA ndi endocannabinoids) kapena ngati serotonin ikugwiritsidwa ntchito zonse zimathandiza ndikuletsa erectile ntchito 2. Dopamine ndiye neurotransmitter yayikulu mu CNS ndipo imathandizira chilakolako chogonana, kugonana ndi genital reflexes 1 , 16 . Dopamine, yomwe imaganiziridwa kuti ndi yofunika kwambiri pa ntchito ya erectile, imapezeka mu MPOA ndi PVN ya hypothalamus ndi nucleus accumbens. Madera atatuwa amalandira dopaminergic innervation kuchokera ku incertohypothalamic system 17. Mu PVN, dopamine imayambitsa kuyambitsa ma neuron a oxytocinergic mwina mwa kuwonjezera calcium yamkati mwa maselo kutsatiridwa ndi kuyambitsa kwa neuronal nitric oxide synthase (nNOS). Nitric oxide kudzera munjira yosadalira GMP mwina nitrosylation ikuganiza kuti imayambitsa kuyambitsa ma neuron a oxytocinergic (chithunzi 1 ). Nitric oxide imapangidwa ndi nNOS ndi castration komanso testosterone yakunja, motsatana, kutsika ndi kukwera-kulamulira kuwonetsedwa kwa nNOS mu PVN 2.

chithunzi

Chithunzi 1

Tsegulani muwona wojambulaPower Point
Njira za Dopaminergic zomwe zimaphatikizapo penile erection (yokopa wakuda). Maganizo, kukumbukira kukumbukira, zochititsa chidwi, zooneka ndi zovuta zowonongeka zimagwiritsidwa ntchito mu cortex ndipo zimapangitsa kuchuluka kwa dopamine m'magulu a pooparine a hypothalamus pambuyo poyambitsa dopamine D2, D3, D4 mapuloteni ndi kuwonjezeka kwa ntchito ya neuronal nitric oxide synthase (nNOS) mu oxytocinergic neurons, yomwe imayambitsa malo ena owonjezera omwe ali ndi lumbosacral pamtunda, komwe kumatulutsa mitsempha ya mitsempha, ndipo kupyolera mu mitsempha yowonjezera imachititsa kuti mitsempha yambiri isinthe. Kugwiritsa ntchito mapuloteni a dopamine m'chigawo cha lumbosacral mumtsempha wamtsempha komanso minofu ya erectile ikuphatikizidwanso.

Kuphatikiza apo, ma neuron a dopaminergic apezeka omwe amayenda kuchokera ku caudal hypothalamus kupita ku innervate autonomic ndi somatic nuclei mu lumbosacral spinal cord 18 , 19. Chifukwa chake, dopamine ingayembekezeredwe kutenga nawo mbali pakulamulira zigawo zonse ziwiri za autonomic ndi somatic za penile reflexes.

PVN oxytocinergic neurons polojekiti ya neurohyphysics ndi madera ena a ubongo, komanso medulla oblongata ndi msana wa msana, kumene kumayambitsa kukhazikitsidwa kwa mavitamini osatetezeka a pro-erectile lumbo-sacral.

Mphepete njira

Zikuoneka kuti njira ya dopaminergic ya msana ndi yofunika kwambiri pa ntchito ya erectile. Ulusi woteteza thupi ku dopamine umapezeka mu thoracolumbar sympathetic chain komanso mu lumbosacral parasympathetic nucleus 20 , 21. Kuphatikiza apo, dopamine D2 receptor expression yamphamvu idapezeka mu lumbosacral parasympathetic neurons 22. Thandizo lina la njira ya dopaminergic pamlingo wa msana limachokera ku zomwe zapezeka kuti m'makoswe omwe ali ndi zilonda za msana pa thoracic T8 segment, dopaminergic agonist apomorphine yomwe imalowetsedwa m'thupi imatha kuyambitsa kukhazikika kwa makoswe ndi njira yomwe imatsutsidwa ndi dopamine D2 receptor antagonist (haloperidol, sulpiride) ndikuthandizidwa ndi dopamine D1 receptor antagonist (SCH23390) 23. Zomwe zapezekazi zidathandizidwanso ndi zomwe zapezeka kuti kuperekedwa kwa apomorphine mkati mwa thecal kumayambitsa mayankho okhazikika a erectile 24.

Peripheral pathways

Kukhazikika kwa mbolo kumayamba chifukwa cha kuletsa mitsempha ya sympathetic ndi kuyambitsa mitsempha ya m'chiuno ya parasympathetic zomwe zimapangitsa kuti mbolo ikule komanso kumasula maselo osalala a minofu ya erectile ya corpora cavernosa. Izi zimathandiza kuti magazi azidzaza ndi sinusoids komanso kuchepetsa kutuluka kwa magazi m'mitsempha, zomwe zimapangitsa kuti magazi opanikizika atseke mu corpora cavernosa. Kutulutsidwa kwa nitric oxide kuchokera ku mitsempha ya parasympathetic kumachita gawo lofunikira pakupumula, ndipo kuwonjezeka kwa magazi kulowa mu mbolo panthawi yokhazikika kumalimbikitsanso gawo la maselo a endothelial kuti atulutse nitric oxide ndi ma vasodilator ena omwe amadalira endothelium omwe amathandizira kuti mbolo ikhazikike 25-27.

Mosiyana ndi ntchito ya dopamine mu CNS, ntchito ya dopamine mu minofu ya erectile siidziwika bwino. Kulowetsedwa kwa dopamine kumayambitsa kukhazikika kwa amphaka 28 , ndipo wotsutsana ndi dopamine D1 receptors , SCH23390, amaletsa kwambiri kuwonjezeka kwa kuthamanga kwa intracavernosal komwe kumachitika chifukwa cholimbikitsa mitsempha ya cavernous mu makoswe 29. Ma receptors a Dopamine D1 ndi D2 amawonetsedwa mu minofu ya erectile kuchokera ku makoswe ndi amuna 30 , 31 , ndipo patch clamp ya maselo osalala a minofu yosalala kuchokera ku corpus cavernosum ikuwonetsa kuti dopamine ndi dopaminergic agonists zimayambitsa kupumula potsegula njira zazikulu za calcium-activated potassium 32. Pali umboni wosonyeza kuti dopamine transporter imaonekera mu maselo a endothelial a mitsempha ya systemic 33 , 34 , koma izi sizinafufuzidwebe mu maselo a endothelial a minofu ya erectile. Ngakhale kuti dopamine imatha kupangidwa m'malo olumikizirana mitsempha, komwe dopamine imachokera mu minofu ya erectile sikunadziwikebe, komanso ngati dopamine yomwe imagwira ntchito mu endometrium imachokera ku endothelium kapena ziwalo zina mu minofu ya erectile.

Mwachidule, njira za dopaminergic mu CNS ndi mbali ya lumbosacral ya msana zimagwira ntchito mu erectile ntchito, ndipo mu minofu erectile mwina mwina dopaminergic njira. Izi zikusonyeza kuti njira ya dopaminergic ingayende pa magulu atatu kapena hydrophilic mankhwala omwe akungoyang'ana kokha padera dopaminergic njira akhoza kuyesedwa.

Kusintha kwapadera kwa njira ya Dopaminergic Njira Yothandizira Erectile Ntchito

Dopamine receptor agonists

Mankhwala oyamba omwe ali ndi dopaminergic effect omwe adapezeka kuti amayambitsa erection anali general dopaminergic receptor agonist, apomorphine 12 , ndipo umboni wambiri wokhudzana ndi zotsatira za pro-erectile wapezeka kwa ma dopaminergic receptor agonists. Pali mitundu isanu ikuluikulu ya ma dopamine receptors D 1 -D 5 omwe ali m'gulu la ma D 1- like (D 1 , D 5 ), ndi D 2 -like (D 2 , D 3 ndi D 4 ). Ma binding affinities afotokozedwa kwa ma dopamine receptor agonists mu tebulo 1 , ngakhale kuti sizikugwirizana ndi zotsatira za mankhwala pa ma receptors omwewo. Mankhwala ena ndi a agonists ochepa okha pa ma receptors kutanthauza kuti kuchuluka kwakukulu kumatha kutsutsa endogenous ligand dopamine. Kuphatikiza apo, ma homo- ndi heterodimers a dopamine receptors afotokozedwa, ndipo izi zitha kusinthanso affinity ndi effect ya ma agonists omwewo 35.

Gulu 1. Kugwirizana (-log Ki) a dopamine receptor agonists a dopamine D1-5 Zovomerezeka
D1 GαS cAMP ↑, Ca2+↑ D2 Gi/Go cAMP ↓, K+↑ D3 Gi/Go cAMP ↓, K+↑ D4 Gi/Go cAMP ↓, K+↑ D5 GαS cAMP ↑
Dopamine 4.3-5.2 4.7-7.2 6.4-7.3 7.6 6.6
Apomorphine 5.3-6.2 7.6 (PA) 6.1-7.6 8.4 (PA) 6.4-7.8 (PA)
Bromocriptine 6.2 (PA) 7.3 7.1 (PA) - 6.3 (PA)
Fenoldopam 6.5-7.9 - - 6.5 -
Cabergoline 6.7 9.0-9.2 (PA) 9.1 7.3 (PA) 7.7
Per gold 5.9-6.5 7.5-7.6 8.3 7.2 6.0-7.5
Ropinirole - 8.1 7.7 - -
Rotigotine 5.6 10.2 8.4 7.3 6.0
Lisuride 7.2 9.2-9.5 9.3 (PA) 8.3 -
Quinpirole - 4.9-7.7 6.4-8.0 7.5 -
Quinelorane - 5.5-5.7 7.2-7.4 - -
PD168,077 - - - 8.8 (PA) -
ABT 724 - <5 - 7.2 (PA) -
ABT 670 - <5 - 5.8 (PA) -
  • Tebulo yakhazikitsidwa molingana ndi chidziwitso chokakamiza anthu omwe ali ndi dopamine receptors omwe ali m'ndandanda: www.guidetopharmacology.org yomwe ili ndi bungwe la International Union of Pharmacology (IUPHAR) ndi British Pharmacological Society, kumene malemba omwe amapereka zowonongeka angapezenso. Pamene mtundu waperekedwa, umasonyeza kuti ndizovomerezeka kuzinthu zochepa za receptor subtype. Ponena za ABT 724, a Ki Makhalidwe akuchokera ku ntchito yapachiyambi 57. Ena mwa agonists akhala akudziwika kuti ali agonists (PA) pa mapulogalamu. Mapuloteni a G ndi mawonekedwe opatsirana njira amangotenga njira zamakono. Kuti mudziwe zambiri, chonde onani malemba 35.

Dopamine receptors amalingaliridwa kuti amawonetsa njira za G zotetezera mapuloteni, kumene D1-Mitundu yamtundu (D1 ndi D5) banja ku GαS mapuloteni ndi mavitamini amachititsa adenylate cyclase ndikuwonjezera AMP, pamene D2-Mitundu yamtundu (D2, D3 ndi D4) banja ku Gαi/ Gα0 mapuloteni ndi kulepheretsa adenylate cyclase kuti apite ku mapiri a AMP ochepa 35, 36. Komabe, posachedwa, dopamine D1-Popopotopang'ono zowonjezereka zimapezedwanso kuti zikhale zowonjezereka mu kashiamu yamatenda mwinamwake kupyolera mwa Gayq pambuyo poyambitsa phospholipase C ndi kutulutsidwa kwa intracellular calcium ndi inositol triphosphate (IP3) 35, ndipo izi zikhoza kufotokoza dopamine D1 Kuwonjezeka kwa kolera kwa calcium ndi mapangidwe a nitric okusakaniza (mkuyu. 1). Komanso D2-Madzi a receptors ndi / kapena heterodimers a dopamine receptors akhala akufotokozedwa kuti angapitenso ku njira zina zoperekera zizindikiro kudzera mwa Gβγ ndi kumangidwa 35. Choncho, chifukwa cha kugonosana kwa ena mwa agonists, zotsatira za ntchito za agonists zomwe zikuoneka kuti zimagwirizanitsa zimasiyana kwambiri.

Apomorphine

Pali mabuku ochulukirapo pa apomorphine ndi ntchito yogonana 1, 37. Mwachidule, apomorphine ndi wamba wa dopamine receptor agonist ndi mbiri yovomerezeka yolumikiza chiyanjano (Ki) kwa dopamine receptors motere: D1-Kufanana ndi [D1 (101 nM), D5 (10 nM)] ndi D2-Kufanana ndi [D2 (32 nM), D3 (26 nM), ndi D4 (2.6 nM)] 38 (tebulo 1). M'mutu wa supraoptic (SON), MPOA, ndi PVN wa hypothalamus, oxytocinergic neurons akufotokoza D2, D3 ndi D4 mapuloteni, ndi apomorphine adalangizidwa kuti athandize kukonzekera D2-Mitundu yamtundu wa PVN 39. Kugwiritsa ntchito msana wa dpamine D2 mapuloteni amathandizanso kuti apomorphine asatuluke monga momwe tafotokozera pamwambapa 23. Matsumoto et al. 40 anapeza kuti kumatulutsa mpweya wotchedwa apomorphine, womwe umachititsa kuti pakhale mpweya wochuluka, umaoneka kuti ukuphatikizapo dopamine D1 ndi D2 olemba mapulogalamu, koma olembawo adanena kuti 'pa mapulogalamu oyenera a apomorphine, zotsatira za pulogalamu za pakompyuta sizikuwoneka kuti zimapangitsa kuti ziphuphu zikhale ndi zotsatira za erectile'. Choncho, mbiri yokhudzana ndi maphunziro a erectile ntchito imathandizira makamaka kugwirizanitsa pakatikati D2-Mitundu yamtundu wa mapuloteni m'thupi la aproorphine.

Apomorphine idapangidwa kuti ithandize kuchiza matenda a Parkinson, koma vuto lalikulu ndi kuyambitsa nseru ndi kusanza. Komabe, popereka apomorphine m'zilankhulo zingapo, njira yochiritsira yovomerezeka idapezeka kuti imalola kuyambitsa kukhazikika kwa chiberekero ndikuchepetsa kuchuluka kwa zotsatirapo zoyipa (kuyasamula, nseru, kusanza, chizungulire, kusawona bwino, kutulutsa magazi m'thupi, khungu lofiira, kuchepa kwa magazi m'thupi, komanso bradycardia) zomwe zimawonedwa ndi kupereka apomorphine m'mphuno 41. Mu kafukufuku wa gawo lachitatu wa momwe apomorphine imakhudzira ED yokhala ndi vuto lapakati mpaka lalikulu mwa amuna 74%, kukhazikika kwa apomorphine komwe kumabwera chifukwa cha kukhazikika kwa chiberekero kunachitika mphindi 10-25 pambuyo pa kuperekedwa. Kuphatikiza apomorphine mu kafukufukuyu idapangitsa kuti kukhazikika kwa chiberekero kukhale koyenera kugonana mu 54.4% poyerekeza ndi 33.8% mu gulu la placebo 42 . Komabe, mu kafukufuku wofufuza za gulu la anthu omwe adawonetsa pambuyo pa malonda mwa amuna 11,185 omwe anali ndi ED nthawi zambiri, chifukwa chachikulu chosiya kulandira chithandizo ndi apomorphine chinali chakuti mankhwalawa sanagwire ntchito mwa odwala 64.7% 43.

Monga tanenera, apomorphine ili ndi zotsatirapo zingapo zoyipa. Zotsatira zoyipa zomwe zimachitika kawirikawiri pakupanga apomorphine m'njira ya sublingual mu kafukufuku wotsatira malonda zinali mutu 43 , ndipo mofanana ndi hypotension ndi kuyabwa, zotsatira izi mwina zimadziwikiratu ndi zotsatira za dopamine receptors. Komabe, apomorphine yawonetsedwanso kuti imakhala ndi kuchuluka kochepa kuti iyambe njira za transient receptor potential ankyrin 1 (TRPA1) zomwe zimakhudzidwa ndi ululu, kutupa ndi nseru 44 , zomwe zikusonyeza kuti kumangirira kwapadera kumathandizira ku zotsatira zoyipa za apomorphine.

Dopamine D1 ovomerezeka ndi orectile ntchito

Mu maphunziro oyamba okhudza mphamvu ya apomorphine microinjected mu PVN, mphamvu ya pro-erectile inaletsedwa ndi dopamine D1 receptor antagonist, SCH 23390, ndi dopamine D2 receptor antagonists, haloperidol ndi (−)-sulpiride 12. Fenoldopam ndi benzazepine derivative komanso agonist wosankha partial makamaka pa dopamine D1 receptors (tebulo 1 ) ndipo alibe mphamvu yaikulu pa dopamine D2 receptors , koma imagwirizana ndi mphamvu yapakati pa α2 - adrenoceptors. Imalembedwa ngati mankhwala ochepetsa kuthamanga kwa magazi makamaka pochiza matenda oopsa komanso/kapena matenda a mitsempha ya m'mitsempha. Kulowetsedwa kwa fenoldopam motsatira dongosolo kunapangitsa kuti kuwonjezeka kwa kuthamanga kwa magazi m'mitsempha ya m'mimba (muyeso wa ntchito ya erectile) komwe kumachitika chifukwa cha mphamvu yamagetsi yochepa ya gawo lakutali la mitsempha ya m'mimba mwa makoswe ogonekedwa ndi mankhwala oletsa ululu 45 . Ngakhale kuti kafukufuku wa mu vitro adawonetsa kuti nitric oxide imagwira ntchito pochepetsa mphamvu ya corpus cavernosum yomwe imayamba chifukwa cha fenoldopam ndi dopamine D1 receptor selective agonist ina , A-68930 31 , 45 , mu vivo mphamvu ya pro-erectile ya fenoldopam idapitilirabe ngati pali choletsa cha NOS chomwe chikusonyeza kuti pali mphamvu ya pro-erectile ya fenoldopam mwachindunji. Komabe, zomwe zapezekazi ziyenera kutsimikiziridwa ndi maphunziro ena, ndipo zingakhalenso zosangalatsa kufotokoza ngati kuperekedwa kwa fenoldopam m'deralo kapena kuperekedwa kwa fenoldopam mwa nyama zomwe zili ndi thanzi labwino komanso/kapena munthu kumabweretsa kukhazikika.

Dopamine D2 ndi D3 ovomerezeka ndi orectile ntchito

Mofanana ndi apomorphine, dopamine D2/D3 agonists, bromocriptine ndi quinelorane, kukopetsani zozizwitsa zokha ndi kuonjezera chiwerengero cha zochitika za erectile m'makoswe 46-48, mwinamwake mwa kuyambitsa oxytocinergic neurons mu PVN ya makoswe 47. Dopamine D2 ndi D3 mapuloteni ali ndi 50% ovomerezeka mu chikhalidwe, ndipo zatsimikizira kuti n'zovuta kupeza mankhwala omwe amasankha dopamine D3, mosiyana ndi D2, receptors 49. Dopamine D2 zolandilira ndizomwe zithandizira kuchiza zovuta zokhudzana ndi matenda a Parkinson ndi dopamine D.2 agonists, pamene kusintha kwa dopamine D3 zolandilira ndizosangalatsa pochiza matenda a Parkinson, kugwiritsa ntchito mankhwala osokoneza bongo komanso schizophrenia 49, 50. Ambiri mwa a dopamine agonists, mwachitsanzo bromocriptine, cabergoline, per gold, ropinirole ndi rotigotine, omwe amagwiritsidwa ntchito pochiza matendawa ndi dopamine D2 receptor agonist zotsatira (tebulo 1), ndipo amathanso kuphatikizidwa ndi kuchuluka kwa libido (chiwerewere). Kukhalitsa kwakanthawi (> 4 hr) kotanthauzidwa kuti kukhudzika mwa munthu kumafotokozedwa ngati zingachitike za cabergoline ndi rotigotine 51, 52 ndipo ndi yopweteka kwambiri chifukwa cha erectile ntchito. Kuwonjezera pa kuwonetsa dopamine D2 receptors, cabergoline ndi rotigotine onse amamanga ndi kutsutsa α1-Madalitso, ndi kutsutsana kwa α1-Adrenoceptors ndilo chifukwa chachikulu chomwe chimapangidwira 53.

Chiwerengero cha maphunziro ofufuza momwe dopamine D2 ndi D3 agonists zimakhudzira vuto la kugonana ndi chochepa. Mu kafukufuku wina wotseguka pomwe odwala 13 adanena kuti ali ndi vuto la kugonana atayamba kulandira chithandizo cha antidepressant, ntchito yogonana, yoyesedwa pogwiritsa ntchito Arizona Sexual Experience Scale ndi Clinical Global Impression of Improvement scale, idawonetsa zotsatira zazikulu pa sikelo zonse ziwiri milungu itatu atayamba kulandira chithandizo ndi ropinirole 54. Mlingo wa ropinirole (3-4 mg/tsiku) mu kafukufuku womaliza unali wochepa kwambiri kuposa mlingo (20-25 mg/tsiku) womwe umafotokozedwa kuti umayambitsa hypersexual ndi chilakolako chogonana mwa odwala omwe ali ndi matenda a Parkinson 10 , 54. Chifukwa chake, kuthekera kochiza ED yosakanikirana ndi agonists osankhidwa a dopamine D2 kapena D3 receptors kukadali kofunikira, ngakhale zotsatira zake pa zotsatira zoyipa monga khalidwe ndi kuthamanga kwa magazi ziyenera kuganiziridwa. Kuphatikiza apo, kungakhale kofunikira kuchita maphunziro osasinthika, osawona kawiri pogwiritsa ntchito mlingo wochepa wa agonists awa pochiza vuto la kugonana lomwe limayambitsa antidepressant.

Dopamine D4 ovomerezeka ndi orectile ntchito

Mankhwala osankha dopamine D4 receptor agonist, PD168077, adapezeka kuti amayambitsa kukhwima mwa makoswe akalowetsedwa mu PVN 47 , 55 , 56. Komabe, popaka utoto wa Fos mu oxytocinergic neurons mu PVN, PD168077, mosiyana ndi quinelorane, sanapezeke kuti amayambitsa ma neuron awa. Komanso, zotsatira za PD168077 zinali kutengera momwe zinthu zilili; mwachitsanzo, zotsatira zake zidawonedwa pamaso pa makoswe achikazi omwe amalandira ndipo zitha kuphatikizapo dopamine D4 receptor activation ya magnocellular oxytocin system 47.

Apomorphine ili ndi mgwirizano wapamwamba wa dopamine D4 amalandira, koma amamanganso dopamine D2 olandila okhala ndi mgwirizano wapatali (tebulo 1). Kupewa zotsatira zoletsedwa za mlingo woyendetsedwa ndi D2 obwereza, mwachitsanzo, nseru ndi emesis, Dopamine D4 abon agonists, ABT 724 ndi ABT 670, adapangidwa kuti athetse ED. Poyendetsa makoswe, kuwonjezeka kwa mphamvu ya intracavernosal kunayesedwa ndipo kunasonyeza kuti ABT 724 imayendetsedwa mosagwirana-dose-kudalira kwambiri kuwonjezeka chiwerengero ndi kukula kwa zozizwitsa zokha, ndipo mayankhowa anali aakulu ndipo anakhalapo nthawi yaitali pamaso pa PDE5i, sildenafil 57. Kupweteka mu ferrets, monga chitsanzo choyambirira cha mankhwala ozunguza bongo ndi emesis, kunavumbula kuti mosiyana ndi dopamine D2 receptor agonist, PNU-95666E, ABT 724 mu mlingo waukulu kwambiri alibe zotsatira 57. Dopamine winanso D4 receptor agonist, ABT 670, ndi bwino kumwa mowa bioavailability anapangidwa, koma ali ndi zochepa kwambiri kugwirizana Dopamine D4 zovomerezeka poyerekeza ndi ABT 724 (tebulo 1, 58). Kutsogoleredwa mochepa, zochitika za ABT 670-zopangidwa ndi penile zoyezera zosawerengeka zinali zochepa kusiyana ndi zomwe zinawonedwa ndi mlingo womwewo wa apomorphine 58. Deta imeneyi ikugwirizana ndi zochitika zomwe ABT 724 ndi ABT 670 zili zochepa kwambiri ndipo zimakhala zochepa poyerekeza ndi apomorphine, mwinamwake amafotokozedwanso ndi zomwe akuwona kuti ndi agonists ochepa pa dopamine D4 Zovomerezeka 57, 58. Kukula kwa dopamine D4 agonists, ABT 724 ndi ABT 670, anafika, mwachindunji, gawo I ndi mayesero a II. Choncho, ngakhale kuti zotsatira zake zinali zochepa kwambiri ndi ABT 724 ndi ABT 670 poyerekeza ndi apomorphine, potency ndi efficacy anali otsika. Apa, komanso kupeza kuti zotsatira za erectile ntchito ya dopamine D4 olandila ndi ovomerezeka pazomwe angagwirizane nawo akhoza kuthandizira zotsatira.

Dopamine D5 ovomerezeka ndi orectile ntchito

Chidziwitso chokhudza momwe dopamine D 5 receptor agonists imakhudzira ntchito yogonana ndi chochepa. Kafukufuku wambiri wachitika kuti adziwe madera omwe dopamine D 5 receptors imakhudzira. Dopamine D 5 receptor imakhudzira mu hypothalamus ndi parafascicular nucleus ya thalamus muubongo wa makoswe ndi munthu. Madera osiyanasiyana okhudzira dopamine D 5 receptors poyerekeza ndi ma dopamine receptors ena akusonyeza kuti dopamine D 5 receptors imagwira ntchito ngati wowongolera komanso wophatikiza ntchito ya dopaminergic 59. Ma dopamine D 5 receptors amakhudziranso madera ena a ubongo, mwachitsanzo substantia nigra-pars compacta, striatum, cerebral cortex, nucleus accumbens ndi olfactory tubercle 60. Lipoti laposachedwa lawonetsa kuti kuchotsedwa kwa dopamine D 5 receptors kumachepetsa kulandirira kugonana mwa mbewa zachikazi komanso mwa amuna kumakhudza zotsatira zabwino za kulowa kwa mbolo isanakwane 61. Kuchepa kwa chidwi chogonana, ED ndi mavuto otulutsa umuna amapezeka mwa odwala omwe ali ndi antipsychotics 62 . Chifukwa chake, dopamine D5 receptor agonist ikhoza kukhala yowonjezerapo kuti iwonjezere chilakolako chogonana komanso mwina chilakolako cha kugonana mwa odwala awa.

Mwachidule, kusonkhezera kwa agonist kwa ma dopamine receptors ndi njira yopitira patsogolo yopezera zotsatira za pro-erectile, ndipo ma dopamine receptors onse apakati ndi a m'mphepete ndi omwe angakhalepo pochiza ED. Zikuwoneka kuti zotsatira za erectile zimadalira kuyambika kwa ma dopamine D2 , D3 , D4 receptors mu CNS komanso m'mphepete mwa thupi makamaka zimadalira kuyambika kwa dopamine D1 receptor receptor mu corpus cavernosum (chithunzi 1 ). Ngakhale apomorphine idawoneka ngati mankhwala odalirika pochiza ED, imayimira m'badwo woyamba. Chofunikira cha m'badwo wotsatira chidzakhala kuti omwe akufuna mankhwalawo akhale ndi mphamvu yofanana, mwachitsanzo, ma D3 / D4 receptors ndipo nthawi yomweyo kupewa zotsatira zoyipa za apomorphine.

Otsutsa Dopamine receptor ndi erectile ntchito

Antipsychotics ndi erectile ntchito

Mankhwala ambiri oletsa kusokonezeka maganizo amamangirira ndi kutsutsa mphamvu ya dopamine pa dopamine D2 receptors , mwachitsanzo haloperidol. Chifukwa chake, mankhwala akale oletsa kusokonezeka maganizo nthawi zambiri amagwirizanitsidwa ndi kuchepa kwa erection ndi anorgasmia mwa odwala 30-60%, pomwe mankhwala atsopano oletsa kusokonezeka maganizo akuwoneka kuti ali ndi vuto lochepa la kusokonezeka maganizo 5 , 62. Pakati pa mankhwala atsopano oletsa kusokonezeka maganizo, risperidone ikuwoneka kuti ili ndi chiŵerengero chachikulu cha kusokonezeka maganizo, pomwe palibe deta yokwanira pa aripiprazole ndi ziprasidone. Kafukufuku woyeserera kusintha chithandizo kuchokera ku mankhwala a antipsychotic atypical, risperidone, amisulpride ndi olanzapine kupita ku aripiprazole mwachiwonekere adakweza magwiridwe antchito ogonana mwa odwala ochepa 63 , koma izi ziyenera kutsimikiziridwa ndi maphunziro omwe ali ndi odwala ambiri.

N'zovuta kusiyanitsa matenda ndi zotsatira za mankhwala ndikupeza chidziwitso chodalirika kuchokera kwa odwala omwe ali ndi matenda amisala. Chifukwa chake, kusagwira bwino ntchito kwa kugonana komwe kumakhudzana ndi chithandizo cha antipsychotic sikungokhudza ntchito ya erectile, komanso kumachepetsa chilakolako cha kugonana, kumayambitsa kubwereranso kwa umuna ndikuchepetsa chilakolako chogonana komanso kukhutitsidwa kwathunthu kwa kugonana. Ndemanga yaposachedwa ya Cochrane idafufuza mwayi wolowererapo polimbana ndi kusagwira bwino ntchito kwa kugonana mwa odwala omwe akulandira mankhwala a antipsychotics ndipo idati kusintha kugwiritsa ntchito olanzapine kungathandize magwiridwe antchito ogonana mwa amuna ndi akazi 64. Komabe, zotsatirazi zidachokera pa kafukufuku waung'ono wotseguka, ndipo kuthekera kwina ndikuchiza odwala omwe ali ndi schizophrenia ndi ED ndi sildenafil, koma umboniwo ndi wochepa 64.

Buspirone

Buspirone ndi mankhwala ochepetsa nkhawa omwe ali ndi chikondi chochepa pa ntchito yogonana poyerekeza ndi ma SSRI ndipo amathanso kusintha vuto la kugonana lomwe limagwirizanitsidwa ndi chithandizo cha SSRI 65 , 66. Buspirone ndi agonist yochepa pa 5-hydroxytryptamine type 1A (5-HT 1A receptors), koma buspirone ndi main 5-ndi 6-hydroxylmetabolites onse amamangirira ku dopamine D3 ndi D4 receptors ndi maubwenzi ofanana ndi omangirira ku 5-HT 1A receptors, ndipo amagwira ntchito ngati otsutsana pa dopamine D3 ndi D4 receptors 67. Kuyambitsa kwa 5-HT 1A receptors ndi agonists, mwachitsanzo 8-OH-DPAT, kumaletsa kukhazikika kwa mbolo mwa makoswe, pomwe otsutsana ndi receptor iyi amawonjezera mphamvu ya acute pro-erectile ya apomorphine ndi fluoxetine yoperekedwa pansi pa khungu 68 . Chifukwa chake, kuchepa kwa chikondi cha ntchito ya erectile yomwe imapezeka ndi buspirone motsutsana ndi SSRI mwina kungatchulidwe kuti ndi chifukwa cha buspirone yomwe imagwira ntchito ngati mdani pa zolandirira za 5-HT 1A , koma maphunziro ena adzafunika kuti amvetsetse bwino momwe buspirone motsutsana ndi SSRI imakhudzira ntchito ya erectile.

Mankhwala osokoneza bongo akuwonjezera syntaptic dopamine

Kuchuluka kwa dopamine mu synaptic kungawonjezeke mwina mwa kutulutsidwa kwa dopamine kwambiri, mwa kuletsa dopamine reuptake transporter (DAT), kapena mwa kuletsa kusweka kwa dopamine mwa kuletsa catechol- O -methyltransferase (COMT) kapena monoamine oxidase (MAO) type B inhibitors.

Kutulutsidwa kwa dopamine

Amantadine

Mankhwala oletsa mavairasi otchedwa amantadine amalimbikitsa kutulutsidwa kwa dopamine kuchokera ku mitsempha ndipo amaletsa kubwezeretsedwa kwa dopamine mu presynaptic neuron. Kuphatikiza apo, ndi wofooka wotsutsana ndi ma receptors a N -methyl- d -aspartate (NMDA). Ngakhale kuti theka la moyo limakhala la maola 10-15 mwa munthu, zotsatira zake zimaganiziridwa kuti ndi za kanthawi kochepa chifukwa pali kukula kwa kulolera kwa mankhwalawa. M'ma lipoti angapo pomwe amuna ndi akazi anali kulandira mankhwala oletsa mavairasi, mwachitsanzo fluoxetine ndi paroxetine, zanenedwa kuti kuwonjezera chithandizo ndi amantadine kunasintha vuto la kugonana (anorgasm, ED) 10 , 69. Komabe, mayesero osankhidwa mwachisawawa adzafunika kuti awone ngati amantadine ndi yothandizadi pochepetsa vuto la kugonana kwa odwala omwe adalandira mankhwala oletsa mavairasi.

Amphetamine ndi methamphetamine

Methamphetamine yomwa imagwiritsidwa ntchito pochiza vuto la kuchepa kwa chidwi komanso ngati mankhwala osangalatsa. Amphetamine yanenedwa kuti imayambitsa khalidwe logonana . Amphetamine imagwirizana ndi kutulutsidwa kwa dopamine, komanso kutulutsidwa kwa noradrenaline kuchokera ku mitsempha ya sympathetic zomwe zimapangitsa kuti mitsempha ya mbolo ichepetse komanso corpus cavernosum iwonongeke . Chifukwa chake, kugwiritsa ntchito molakwika methamphetamine ndi/kapena kugwiritsa ntchito nthawi yayitali nthawi zambiri kumabweretsa ED, zomwe zimatha kubwerezedwanso m'makoswe . PDE5i, mwachitsanzo tadalafil, imapangitsa kuti erectile igwire bwino ntchito m'makoswe omwe amalandira methamphetamine nthawi zonse , ndipo izi zitha kufotokoza momwe methamphetamine/amphetamine imagwiritsidwira ntchito nthawi zonse, kuphatikiza methamphetamine/amphetamine ndi PDE5i 73 , 74.

Clavulanic acid

Clavulanic acid ndi mankhwala oletsa beta-lactamase ndipo nthawi zambiri amagwiritsidwa ntchito limodzi ndi penicillin kuti aletse kusweka kwa penicillin, mwachitsanzo amoxicillin, ndi bakiteriya beta-lactamase. Clavulanic acid imagwira ntchito pakamwa ndipo imakhala yokhazikika ndipo pafupifupi 25% imafika mumadzimadzi a m'magazi mwa munthu. Kuyesa anyani omwe si anthu ndi clavulanic acid kunapezeka kuti kumawonjezera chilakolako chogonana 75 , motero mankhwalawa adayesedwa m'makoswe aamuna omwe amakumana ndi makoswe aakazi omwe adalowetsedwa mu oestrus yogonana pobayira 50 μg estradiol benzoate, ndipo chiwerengero cha kutuluka ndi kutuluka kwa umuna chinayesedwa 76. Kuchotsa theka la moyo wa clavulanic acid ndi pafupifupi ola limodzi 77 , koma zochita zochepa chabe zolimbikitsa kugonana zidawonedwa pa mlingo wapamwamba kwambiri womwe waperekedwa. Komabe, patatha masiku 7 a chithandizo, clavulanic acid idakulitsa kuchuluka kwa kutuluka ndi kutuluka kwa umuna, pomwe SSRI, paroxetine, idachepetsa zochitika zogonana 76 . Zikuoneka kuti clavulanic acid sinagwirizane ndi ma receptor enaake a neurotransmitter 75 , koma m'maselo a neuronal omwe ali ndi cultured (maselo a PC12 ndi SH-SY5Y) kukondoweza ndi kuchuluka kwa clavulanic acid (100 μM) kunawonjezera kutulutsidwa kwa dopamine, mwina mwa kugwirizana ndi mapuloteni awiri ofunikira kuti neurosecretion ndi vesicle transport 78. Kuchuluka kwa clavulanic acid mu ubongo komwe kumayembekezeredwa ndi zotsatira za anxiolytic ndi erectile kuli pakati pa 1–10 pM 75. Kuti njira imeneyi ingathandize kwambiri kunathandizidwanso ndi zomwe zapezeka kuti dopamine D 2 receptor antagonist imatsutsana ndi pro-erectile effect ya clavulanic acid m'makoswe 79 . Mu kafukufuku womaliza, zotsatira za clavulanic acid zomwe zimaperekedwa kudzera mu jakisoni wamkati mwa peritoneal zinayerekezeredwa ndi apomorphine, ndipo ngakhale apomorphine idapangitsa kuchuluka kwa kukhazikika komwe kumadalira kuchuluka kwa kukhazikika, kukhazikika kwa kuyankha kwa clavulanic acid kunapangidwa ngati belu ndipo zotsatira zake zinali 1 mg/kg kenako kutsika ndi mlingo wokwera 80. Olembawo adati kuwonjezera pa kuchulukitsa kutulutsidwa kwa dopamine, clavulanic acid ingathenso kuwonjezera kutulutsidwa kwa serotonin yomwe imagwira ntchito pa 5-HT 2C receptors, chifukwa mianserin idatsutsanso zotsatira za pro-erectile za clavulanic acid. Kafukufuku wa gawo lachiwiri adakonzedwa kuti awone momwe clavulanic imagwirira ntchito mwa odwala, koma adayimitsidwa 11. Pali mavuto angapo omwe akufunika kuthetsedwa pa clavulanic acid kuphatikiza zomwe zimakhudzidwa ndi pro-erectile effect komanso kufotokozera kwa belu-shaped dose-response curve ya clavulanic acid pa ntchito ya erectile.

Kuletsedwa kwa dopamine kubwezeretsa wogulitsa

Cocaine

Mankhwala osokoneza bongo kuphatikizapo cocaine nthawi zambiri amaganiziridwa kuti amawonjezera dopamine mkati mwa mesotelencephalic reward/reinforcement circuity ya forebrain, makamaka mu nucleus accumbens 81 , koma njira zina zomwe zimawonedwa ndi magnetic resonance image kuphatikizapo subcallosal cortex caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, temporal cortices, parietal cortex, extra-striatal cortices ndi pons zimathandizanso kwambiri pakugwiritsa ntchito cocaine molakwika 82. Kuphatikiza apo, pharmacokinetics ndi kulowa mwachangu ku CNS zimagwira ntchito yofunika kwambiri pakugwiritsa ntchito cocaine molakwika 83. Cocaine imaletsa pre-synaptic transporters za noradrenaline (NET), dopamine (DAT) ndi serotonin (SERT), zomwe zimawonjezera kuchuluka kwa noradrenaline, dopamine ndi serotonin mu synaptic. Cocaine ikhoza kuwonjezera chilakolako chogonana ndikupangitsa kuti mbolo ikwere 84 , koma kugwiritsa ntchito cocaine nthawi zonse kumagwirizanitsidwa ndi ED mwa mwamuna 85 . D1 / D 5 otsutsa monga SCH39166 (ecopipam) amatha kuchepetsa zotsatira za cocaine 86. Cocaine yomwe imaperekedwa pakati ikuwoneka kuti imaletsa kukhazikika kwa mbolo mwa makoswe kudzera mu noradrenergic neurotransmission, ndikuyambitsa α-adrenoceptors mu hippocampus 87. Pamlingo wa peripheral, cocaine-induced endothelial dysfunction yomwe imayambitsa endothelin-1 komanso kuchepa kwa nitric oxide ndi vasoconstriction zinapezeka kuti zimathandizira ku cocaine-induced ED 85. Zomwe zapezekazi zikuwonetsa ubale wabwino pakati pa ntchito yabwinobwino ya erectile ya madera omwe ubongo umayendetsa ndi madera omwe ubongo umayendetsa cocaine, zomwe zikusonyeza kuti mankhwala owongolera erectile ntchito yomwe imakhudza onyamula monoamine ayenera kukhala ndi chisankho cha dopamine transporter. Kuphatikiza apo, mankhwala osayambitsa mwachangu kuletsa dopamine reuptake ayenera kukhala cholinga chopewa kugwiritsa ntchito molakwika monga momwe zawonedwera pa cocaine.

Bupropion

Mankhwala oletsa kuvutika maganizo amagwira ntchito mosiyanasiyana pa ma monoamine transporters. Kusankha bwino kwa mankhwala a SERT ndi SSRI, mwachitsanzo fluoxetine, ndipo mankhwalawa nthawi zambiri amagwirizanitsidwa ndi vuto la kugonana. Kuvutika maganizo kokha kumapangitsa kuti zikhale zovuta kusiyanitsa zotsatira za matenda ndi zotsatira zowonjezera za mankhwala. Matenda a maganizo angayambitse kusowa chidwi ndi kusiya kugonana ndi mnzanu. Mankhwala oletsa kuvutika maganizo amatha kukhala ndi zotsatira zambiri pa ntchito yogonana kuphatikizapo kuchepa kwa chilakolako chogonana, mavuto a kukhwima, komanso mavuto okhudzana ndi kufika pachimake. SSRI ndi venlafaxine zimatha kusokoneza magawo onse a kayendedwe ka kugonana kwa amuna (chilakolako/kudzuka-chisangalalo-orgasm). Monga momwe tafotokozera mwachidule kutengera maphunziro khumi ndi asanu osasankhidwa, bupropion, nefazodone ndi mirtazapine ali ndi kuchuluka kochepa kwa vuto la kugonana kuposa SSRIs9,88 , ndipo bupropion ingagwiritsidwe ntchito kuchepetsa zizindikiro zogonana zomwe zimayambitsidwa ndi mankhwala ena oletsa kuvutika maganizo89,90 . Mpaka pano Bupropion ndiye mankhwala okhawo oletsa kupanikizika omwe ali ndi mwayi wosankha DAT pa NET ndi SERT ndi ma K i values ​​(nM) a, motsatana, 526, 52,600 ndi 9100 kwa onyamula atatuwo. Kulowetsedwa kwa bupropion mu MPOA mwa makoswe kunawonjezera dopamine yoyesedwa ndi microdialysis ndikuyambitsa kukhazikika kwa mbolo mwa makoswe 91 , koma kuchuluka kwakukulu (10 mM) kwa bupropion kunayenera kugwiritsidwa ntchito kuti muwone zotsatira 91 zomwe zikusonyeza kuti MPOA si malo oyamba omwe bupropion imagwira ntchito kapena kuti mankhwalawa panthawi yolowetsedwa mwachangu amayambitsa njira zina zotsutsana ndi erectile. Zoonadi, kupereka bupropion mwachangu kunachepetsa kukhazikika kwa mbolo mwa makoswe, pomwe chithandizo cha bupropion kwa masiku 14 (chithandizo cha nthawi yayitali) sichinagwirizane ndi kusintha kwa kukhazikika kwa mbolo mwa makoswe, zomwe zinali zosiyana ndi chithandizo cha fluoxetine kapena desipramine, choletsa makamaka NET 92 . Zomwe zapezekazi zikusonyeza kuti sikuti kungowonjezera dopamine mu synaptic cleft kokha ndikokwanira kufotokoza zotsatira za pro-erectile. Kusintha kwa kuchuluka kwa dopamine kumagwirizanitsidwa ndi kusintha kwa dopamine receptor expression 35 , 93 ndipo kungafotokoze kusiyana kwa zotsatira zoyipa komanso zosatha pa ntchito ya erectile ya zoletsa zapakati zomwe zimanyamula monoamine.

Kuwonongeka kwa dopamine

Selegiline

Selegiline ndi mankhwala oletsa MAO B osasinthika, osasinthika ndipo amagwiritsidwa ntchito yokha kapena kuphatikiza ndi levodopa pochiza matenda a Parkinson. Kuletsa MAO B kudzachedwetsa kuwonongeka ndikuwonjezera mphamvu ya dopamine. Selegiline imachita kagayidwe ka amphetamine ndi methamphetamine, zomwe zingathandizenso pa zotsatira za mankhwala pa ntchito ya erectile monga tafotokozera pamwambapa pa amphetamine ndi methamphetamine. Selegiline imawonjezera mphamvu ya dopamine mu PVN mwa makoswe 94. Chifukwa chake, selegiline kapena vehicle idagwiritsidwa ntchito kwa milungu itatu pochiza matenda osagwirizana ndi kugonana mwa odwala omwe amalandira chithandizo cha antipsychotic mu kafukufuku woyendetsedwa ndi placebo, crossover. Kupatula kuchepetsa prolactin komwe kumachitika chifukwa cha selegiline, panalibe kusiyana pa ntchito yogonana poyerekeza ndi nthawi ya chithandizo cha placebo 95.

Catechol-O-Methyltransferase inhibitors

Mankhwala oletsa COMT otchedwa entacapone ndi tolcapone amagwiritsidwa ntchito ngati chowonjezera pa levodopa kuti kuchepa kwa mlingo wa mankhwala kuthe mu matenda a Parkinson ndipo amawonjezera kupezeka kwa levodopa mu ubongo. Tolcapone yokha imalowa mu ubongo ndikuwonjezera dopamine mu pre-frontal cortex ndi ventral hippocampus, koma izi zimaonekera kwambiri mwa akazi poyerekeza ndi makoswe aamuna 96. Komabe, sizikudziwika ngati kuletsa kwa COMT komanso kuwonjezeka kwa noradrenaline kudzathetsa zotsatira zazikulu za kuchuluka kwa dopamine pa ntchito yogonana, ndipo izi zikuyenera kufotokozedwabe.

Kusinthasintha kwa njira ya dopaminergic ndi kukwera

Poganizira mankhwala ochizira ED, zotsatira zokhudzana ndi kutaya magazi zimathandizanso kwambiri. Ma physiology ndi pharmacology of ejaculation posachedwapa wasinthidwa kwambiri 97, 98, ndipo apa ndi kufotokozera mwachidule za udindo wa njira za dopaminergic potsegulira. Njira yotchedwa incertohypothalamic yomwe imaphatikizapo MPOA ikuwoneka kuti ikukhudzidwa ndi kuyankhidwa koyankhidwa. Mulimonsemo, kuwonjezeka kwa mazira a extraoplular dopamine mu MPOA ndi jekeseni wa apomorphine mu MPOA imapangitsa kufupikitsa kwa kutalika kwa chiwerengero cha ejaculation ndi kuchuluka kwa mlingo wa makoswe 97. Dopamine D3 phwando likuoneka kuti likugwira ntchito yofunikira, monga D2/D3 receptor agonist 7-hydroxy-N,N-Di-n-Propyl-2-aminotetralin (7-OH-DPAT) imapangitsa khalidwe lodzikweza, pamene kutsekedwa kwa dopamine D3 Odwala omwe ali ndi antchito omwe amamenyana nawo amachititsa kuti anthu asamangokhala ndi nthawi yochepa komanso nthawi yowonongeka. 99. Choncho, D3 Otsutsa amalandiraponso kuti athe kuchiritsidwa msanga 97, ngakhale kuti 7-OH-DPAT inasonyeza kupumula pang'ono pokhapokha muzitsulo zozizwitsa zowonongeka mumtundu wa msana 100. Polymorphism ndi kuchulukanso kwa kubwereza kwa DAT1 transporter gene kunanenedwa kuti ikugwirizanitsidwa ndi kuphulika kwa anthu asanakwane 101, pamene sichidziwikanso ngati inhibitor ya DAT, bupropion, pa matenda achidule amakhudza kumwa. Dapoxetine ndi SSRIs zotsalira ndi zothandiza komanso zotetezeka kuti zithetsedwe mwamsanga msinkhu, komabe zikupitiriza kufufuzidwa mwa munthu ngati pangakhale phindu la dopamine D3 otsutsa antchito. Njira zomwe zimagwiritsidwa ntchito popititsa patsogolo zimakhalabe zomveka bwino 98, komanso kuganizira za mankhwala osokoneza bongo omwe amasintha makamaka njira za dopaminergic zothandizira ED, ziyenera kuwonanso zotsatira zowonongeka kwa thanzi komanso matenda kuti athe kugonana.

Kusinthasintha kwa njira za Dopaminergic ndi Zofunikira Zopanda Pakati pa Odwala ndi Erectile Dysfunction

Ngakhale kuti mankhwala oletsa PDE5 ndi othandiza, palinso odwala ambiri omwe chithandizochi sichikwanira kapena chitha kukonzedwa bwino kuphatikiza odwala omwe ali ndi matenda a shuga, matenda a metabolic syndrome, matenda a neurodegenerative ndi odwala omwe adachitidwa opaleshoni ya radical prostate yomwe imakhudza mitsempha ya cavernous. Mu izi, tayang'ana kwambiri pa matenda a shuga ndi matenda a neurodegenerative komwe timapeza kuti mankhwala osintha njira za dopaminergic adzakhala ofunikira. Zambiri mwa zomwe tikuganiza zokhudzana ndi metabolic syndrome ndizofanana ndi za matenda a shuga, pomwe timapeza kuti zilonda za mitsempha zokhudzana ndi opaleshoni ya radical prostate kapena pelvic zimafuna njira zina ndipo izi zathetsedwa kwina 102.

Matenda a shuga ndi erectile ntchito

Matenda a shuga amagwirizanitsidwa ndi chiopsezo chachikulu cha ED kuposa anthu ambiri 103-105 . M'zipatala zomwe zimathandiza ED, kufalikira kwa matenda a shuga monga matenda ena ndi 20-25% 106. Kuwongolera kwambiri shuga m'magazi kumachepetsa kufalikira kwa ED patatha zaka 10 mwa anyamata omwe ali ndi matenda a shuga amtundu woyamba 107. Komabe, palibe mphamvu ya PDE5 inhibitors mwa 50% ya odwala omwe ali ndi matenda a shuga ndi ED 8 , 108-110 . Izi zikusonyeza kuti kuwonjezera pa chikondi cha minofu ya m'mphepete mwa thupi yomwe imakhudzidwa ndi kukhazikika, matenda a shuga amakhudzanso kuyanjana kovuta kwa mitsempha ya kumva ndi yodziyimira payokha yomwe imakhudzidwa ndi kukhazikika.

Kukonda kwa minofu ya erectile ndi mitsempha ya parasympathetic ya m'magazi mwa matenda a shuga kwafotokozedwa bwino. Mwachidule, kusokonekera kwa maselo a endothelial, kusokonekera kwa minofu yosalala, ndi autonomic neuropathy zafotokozedwa m'makoswe a matenda ashuga komanso m'minofu yosiyana ndi ya amuna odwala matenda ashuga 111 , 112 (onani Ref. 5 ). Kuphatikiza apo, hypogonadism imapezeka kwambiri mwa odwala matenda ashuga ndi ED poyerekeza ndi omwe si odwala matenda ashuga omwe ali ndi ED. Chifukwa cha kusowa kwa mphamvu kwa zoletsa za PDE5, kuwonjezera testosterone ndi mankhwala omwe amayang'ana njira ya Rho kinase kwafufuzidwa ndikuyesedwa mwa odwala omwe ali ndi ED ndi matenda ashuga 113-115.

Chikondi cha matenda a shuga m'njira zapakati zomwe zimakhudzana ndi ntchito ya erectile sichinafotokozedwe bwino. Komabe, kufalikira kwa ED mwa odwala omwe ali ndi matenda a shuga kuli pafupi ndi 100% 116. Mu makoswe omwe ali ndi matenda a shuga omwe amadzipangira okha, makoswe a BB/WOR, omwe ndi apakati komanso a m'mphepete, adapezeka kuti akukhudzidwa ndi vuto la kugonana 117. Kuchepa kwa kuyenda kwa mitsempha yamagazi kwanenedwa kuti kumathandizira pakukula kwa matenda a mitsempha ya m'mphepete omwe amagwirizanitsidwa ndi ED 118. Ma mechanims ena amawoneka kuti nawonso ali ndi gawo. Mu makoswe omwe ali ndi matenda a shuga amtundu woyamba omwe amayambitsidwa ndi streptozotocin, kukhazikika komwe kumayambitsidwa ndi NMDA kunafufuzidwa mwa kubayidwa mwachindunji mu PVN 119. NMDA imalimbikitsa njira zomwezo za oxytocinergic monga dopamine, ndipo panali ED ndi kuchepa kwa kufotokozera kwa neuronal NOS mu PVN 119 . Olembawo adapeza kuti kuchita masewera olimbitsa thupi komanso chithandizo ndi angiotensin II type 1 (AT 1 ) receptor antagonists kumathandizira kuti erectile igwire bwino ntchito mu streptozocin-induced diabetic rat model 120 , 121 , koma zotsatira za mankhwala a dopaminergic pa erectile function zikadali kufufuzidwa m'zinyama zomwe zili ndi matenda a shuga.

Pali umboni wotsimikizira kuti matenda a shuga amakhudza njira zapakati za dopaminergic ndipo amayambitsa matenda. Chiwopsezo cha matenda a Parkinson chinali chokwera ~40% pakati pa odwala matenda a shuga kuposa odwala omwe alibe matenda a shuga 122 , ndipo kukana kwa insulin muubongo chifukwa cha kugwedezeka kwa insulin receptor muubongo kumabweretsa kuchuluka kwa monoaminoxidase mtundu B, kuwonjezeka kwa dopamine turnover ndi kuchepa kwa dopamine release 123. Mu makoswe omwe ali ndi matenda a shuga obwera chifukwa cha mafuta ambiri, pali kutayika kwa dopaminergic neurons 124. Zomwe zapezekazi zikusonyeza kuti kukonda njira za dopaminergic mu matenda a shuga kungathandizenso ku ED. Komabe, dopaminergic agonist, apomorphine, yomwe imagwira ntchito pakati, inayambitsa zotsatira zofanana ndi za placebo mwa odwala 130 omwe ali ndi matenda a shuga ndi ED, ndipo woyankha wamba anali wamng'ono ndipo anali ndi glycemic control yabwino 125. Maphunziro ena adzafunika kuti amvetsetse ngati kusintha kwa njira za dopaminergic osati kokha pakati, komanso pamlingo wapakati kungabwezeretse ntchito ya erectile mu matenda a shuga.

Matenda a Neurodegenerative ndi kulephera kwa erectile

Zotsatira za matenda a neurodegenerative, matenda a Parkinson ndi matenda a Alzheimer's, pa matenda osagwirizana ndi kugonana komanso chithandizo chovomerezeka zawunikidwanso ndi ena posachedwapa . Kusagwirizana ndi kugonana ndikofala kwa odwala omwe ali ndi matendawa, ndipo ED imaonedwa kuti ndi imodzi mwa zovuta kwambiri zokhudzana ndi matendawa . PDE5i ndi apomorphine ndizothandiza kwa odwala ambiri omwe ali ndi matenda a Parkinson ndi ED 42 , ngakhale kuti mlingo wokwera kuposa womwe ukulimbikitsidwa wa apomorphine udzafunika . Monga tafotokozera pokhudzana ndi mankhwala osiyanasiyana a dopaminergic m'magawo omwe ali pamwambapa, hypersexuality yomwe imabwera chifukwa cha mankhwala iyeneranso kuthandizidwa kuti ipereke chithandizo chabwino kwambiri ndi mankhwala a dopaminergic mu matenda a Parkinson.

Zotsatira ndi Zochita

Tayang'ana kwambiri pa kusintha kwa njira ya dopaminergic pochiza ED. Ma dopaminergic agonists angapo amakhudza ntchito ya erectile m'makoswe omwe ali ndi dopamine D2 - like receptors ndipo makamaka ma D1 - like receptors m'minofu ya erectile. Njira yochiritsira ya general dopamine agonist apomorphine ndi yopapatiza ndipo imagwira ntchito makamaka pa ma dopamine receptors apakati. Chifukwa chake, apomorphine idapezeka kuti yalephera mwa odwala omwe ali ndi ED ndi matenda a shuga ndipo sigwira ntchito bwino poyerekeza ndi ma PDE5 inhibitors. MiniReview ya mabukuwa ikupereka lingaliro lakuti kusintha kwa njira za dopaminergic kumapereka mwayi wowongolera chithandizo cha ED. Komabe, izi zingafunike njira yatsopano yolunjika ku njira ya dopaminergic pamlingo wosiyanasiyana wa penile reflex arch. Kuphatikiza apo, kuyesa kwina kwa mankhwala a dopaminergic m'mitundu ya nyama ya matenda a shuga, metabolic syndrome ndi/kapena matenda a neurodegenerative kungakhale kofunikira.

Zothokoza

Ulf Simonsen ndi mbali ya MEMBRANES, University of Aarhus, pomwe Simon Comerma-Steffensen adathandizidwa ndi PhD ku Aarhus University.

Kusamvana kwa Chidwi

Olembawo amanena kuti palibe kutsutsana kwa chidwi.

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