Te kikorangi metilēna me te waikura hauota: NOS, cGMP, me te tuku tohu i ngā ia toto

He māmā te āhua o te pātai: ka aukati rānei te kikorangi metilēna i te waikura hauota? I te taiwhanga, ka wehea te whakautu ki ngā pātai motuhake e whā, ā, he whakamātautau rerekē tō tēnā, tō tēnā. Ko te whakahanumi i ēnei te tino take e rangona ai te māia o ngā kōrero mō te kikorangi metilēna me te waikura hauota, ahakoa kāore i te tino mārama.

Whakaarohia te tohu waikura hauota hei mekameka e whā ōna hononga. Ka tuhia he ira hei hanga i te whākōkī hanga waikura hauota. Ka huri te whākōkī i te arginine hei waikura hauota. Ka tōha te hau ki tōna ūnga i mua i tana tauhohe ki tētahi atu matū. Ka rongo te guanylate cyclase wairewa i a ia, ā, ka hanga i te GMP ā-porowhita. Kua whakaputaina he rangahau mō ngā pānga o te kikorangi metilēna ki ia hononga, engari i ahu mai ngā taunakitanga i ngā takahanga whakamātautau rerekē, ngā kukūtanga rerekē, me ngā momo whākōkī rerekē. Kāore tētahi hua i tētahi hononga e whakaū i te mahi ki tētahi atu.

Te mekameka tikanga, he whakamārama māmā

I te pakitara o tētahi ia toto, koinei te raupapa tikanga. Ka pā tētahi whakaongaonga ki tētahi pūtau endothelium. Ka hanga te whākōkī hanga waikura hauota o te endothelium, e kīia ana ko eNOS, ko NOS3 rānei, i tētahi tukunga iti o te waikura hauota. Ka tōha te hau ki roto i te pūtau uaua māeneene e noho tata ana, ka here ki te heme rino kua whakahekea o te guanylate cyclase wairewa, ā, ka whakatere i te hurihanga o te GTP hei GMP ā-porowhita. Ka whakahohe te GMP ā-porowhita i te protein kinase G, ka rerekē te whakahaere konupūmā, ā, ka whakangā te uaua.

He mekameka tuarua anō me noho wehe. I te wā o te whakapokenga, o te pānga rānei ki ngā cytokine, ka tuhi ngā pūtau i tētahi whākōkī rerekē: te whākōkī hanga waikura hauota ka taea te whakaoho, arā, te iNOS, e kīia ana hoki ko NOS2. He nui ake, he roa ake hoki āna rerenga waikura hauota i ērā o te eNOS. Ko te momo tuatoru, te NOS o ngā pūtau io, arā, te nNOS, nō tētahi atu horopaki anō. Ki te kōrero tētahi tuhinga mō te whākōkī hanga waikura hauota me te kore e tautuhi i te momo, me tū, me tirotiro ko tēhea i inea. He pērā hoki te kōrero a te tirohanga whānui mō te nekehanga irahiko nā te kikorangi metilēna mō ngā ūnga hāora-whakaheke katoa: kāore te pūnaha tuku e mahi takitahi, ā, mā te hoa i ia pito e whakatau te putanga.

Ko te GMP ā-porowhita kua inea he pānuitanga whakakotahi hoki, ehara i te whakamātautau whākōkī tika. Ka whakaata tōna taumata i te hanga a te cyclase, tangohia atu te wāwāhitanga a ngā phosphodiesterase, otirā te PDE5 i ngā uaua māeneene o ngā ia toto. Nō reira, ko te hekenga o te GMP ā-porowhita e tohu ana he iti ake te tohu i tae ki te pūrongo. Kāore taua hekenga anake e tautuhi ko tēhea hononga i rahua.

Hononga 1: he iti ake te whākōkī iNOS ka hangaia

I roto i ngā pūtau horomi o te kiore iti i whakaongaihia ki te lipopolysaccharide huakita, ki te interferon gamma, ki ēnei e rua rānei, nā te kikorangi metilēna i ārai te pikinga i tūmanakohia o te pūmua iNOS, ā, i tino tāmi i te RNA karere iNOS i ngā whakamātautau tuhinga ira o ngā pūtau horomi. Ko te wāhanga whai māramatanga ko ngā mea kāore i rerekē. I noho tata tonu te wāwāhitanga o te pūārai I kappa B alpha, te tāpiritanga phosphate ki te NF kappa B me te STAT1, me te nekehanga o aua tauwehe ki roto i te karihi. Ko te mea i heke ko tō rātou herenga ki te DNA. I whakaūngia tēnei e te whakahekenga ārai-mate o te chromatin, i whakaatu he iti ake te noho ki te kaiwhakatairanga iNOS.

He pānga whakahaere ira tēnei kei mua i te nui o te whākōkī, ehara i te aukati ohorere i tētahi whākōkī kua oti kē te hanga. Nō te tuku tohu mumura tēnei, me here ngā tauwehe tuhinga ira ki tētahi kaiwhakatairanga i mua i te putanga o te pūmua. Kāore tēnei e kōrero tika ana mō te eNOS e mahi pūmau ana i tētahi ia toto e noho whakatā ana, ā, me whakamārama i runga i taua here.

Hononga 2: he pōturi ake te mahi a te whākōkī NOS kua noho kē

I whakamātauria tētahi atu taumata e tētahi rangahau kiore nui. I whiwhi ngā kiore nui tāne e oho ana i te lipopolysaccharide mā te ia toto, kātahi, e toru hāora i muri mai, ka whiwhi i te wairewa tote, i te kikorangi metilēna rānei ki te 3 mg per kg mā te ia toto. I inea te mahi a te whākōkī hanga waikura hauota i te wāhanga takawaenga o raro o te hypothalamus mā te hurihanga o te arginine kua tohua hei citrulline i te rangahau mahi NOS o te hypothalamus. Nā te ahotea me te wairewa tote anake i whakaoho ētahi mahi kāore e whakawhirinaki ana ki te konupūmā, ā, nā te lipopolysaccharide i hiki taua mahi ki te tekau whakareatanga pea o te taumata paerewa. Nā te kikorangi metilēna i whakakore ngā wāhanga e rua i whakaohohia. Kāore i rerekē te mahi pūmau e whakawhirinaki ana ki te konupūmā i taua kiko, i taua rahinga, i taua wā ine.

Me pānui taua hua kia rite pū ki te mea i tuhia: i tāmitia te mahi momo iNOS i inea i raro i aua āhuatanga. Ehara i te inenga o te whakapuakitanga ira, ehara hoki i te taunakitanga mō te whiriwhiri pūmau i te iNOS, kaua i te eNOS, i te nNOS rānei. Ka whakakaha ngā mahi ki ngā whākōkī kua purea i tēnei tūpato. I ngā whakamātautau tika o te whākōkī hanga waikura hauota kua purea, i tino aukati te kikorangi metilēna i te hanganga citrulline ki te 30 micromolar. Ko te kukūtanga aukati haurua i tata ki te 5.3 micromolar ki te kore he hūperōkai dismutase, me te 9.2 micromolar ki te whai i taua whākōkī, e ai ki te whakataurite i te NOS kua purea me te guanylate cyclase. I tohu tētahi rangahau motuhake o te nNOS kua purea ki te hāoratanga o te heme kua herea ki te whākōkī. Ko te akoranga whai take, he tūturu te aukati tika i te NOS i roto i ngā pūnaha kua wehea, engari kāore e taea te whakawhānui i te hua o te hypothalamus hei kerēme whānui ka kore te kikorangi metilēna e pā ki ngā NOS pūmau katoa, i ngā wāhi katoa.

Hononga 3: ka ngaro te waikura hauota i mua i tōna taenga

Ko te whakaaturanga tino mārama ka taea e tētahi mea kē atu i te aukati whākōkī te whakamārama i te hekenga o te GMP ā-porowhita, i ahu mai i ngā pūtau uaua māeneene o ngā iatuku pūkahukahu rapeti i whakatipuria. I hipa rawa te hoahoa whakamātautau i te NOS o roto mā te tāpiri tika i ngā kaituku waikura hauota, kātahi ka pātai mehemea ka tāmi tonu te kikorangi metilēna i te urupare GMP ā-porowhita i te rangahau hūperōkai o ngā uaua māeneene ia toto.

E toru ngā kaituku i whakamātauria mai i te 1 ki te 100 micromolar: S nitroso L cysteine, sodium nitroprusside, me tētahi tairitenga pūmau kua tangohia tōna rōpū amine, e kīia ana ko MPANO. I hiki katoa ēnei i te GMP ā-porowhita ki waenga i te 1.5 whakareatanga me te 12 whakareatanga pea. I aukati te kikorangi metilēna ki te 10 micromolar i ngā mea tuatahi e rua mā te 51 ki te 100 ōrau, engari kāore i whakarerekē i te urupare MPANO. Mehemea e aukati noa ana te kikorangi metilēna i te wāhi whakakōkī o te cyclase, he uaua te whakamārama i taua whiriwhiri kaituku, nā te mea ka ahu katoa ngā mea e toru ki te whākōkī kotahi i muri i te ara.

Kātahi ka herea te tikanga ki te hūperōkai e ngā whakamātautau whakahaere e toru. Tuatahi, nā te whakaputa hūperōkai ki waho o ngā pūtau mā te xanthine me te xanthine oxidase i whakaputa anō taua tauira: i aukatihia te CYSNO me te nitroprusside, engari kāore te MPANO i pāngia. Tuarua, nā te kikorangi metilēna i whakaputa hūperōkai mai i ngā pūtau uaua māeneene, i runga i te rahinga me te roanga wā, ā, i inea mā te whakahekenga o te cytochrome c. Tuatoru, nā te hūperōkai dismutase i tino ārai te aukatinga, engari kāore te catalase i pērā. E tohu ana tēnei ko te hūperōkai, kaua ko te hauwai peroxide, te momo matū take tata i taua takahanga whakamātautau.

He pai te whakamārama i te putanga whakatipu-tahi o te whakamātautau, nā te mea ka tautuhi i te wāhi o te pānga. I whakatipuria tahitia mō tētahi wā poto ngā pūtau endothelium i runga i ngā karāhe uhi me ngā pūtau uaua māeneene. Nā te tauwehe endothelium i tukuna i te āhua taketake i hiki te GMP ā-porowhita o te uaua māeneene ki te toru ki te waru whakareatanga. Nā te maimoatanga o tētahi o aua wāhanga ki te kikorangi metilēna i mua i te whakamātautau i whakaiti taua tohu, ā, nā te hūperōkai dismutase i whakaora tētahi wāhanga o te pānga o te maimoatanga tōmua o te endothelium. Arā, kāore rawa e mate te kikorangi metilēna ki te mahi i roto i te pūtau uaua māeneene e rongo ana i te tohu. Ka taea e ia te whakaiti i te tohu mā te tango i te karere i a ia e haere ana. Ka whakatakotoria tēnei e te aratohu pānui rangahau kikorangi metilēna hei ture whānui: tautuhia te wāhanga i mahia ai te wawaotanga i mua i te whakaingoa i tētahi ūnga rāpoi.

He hē te kī he aukati NOS tēnei. Kāore he hipanga hanga waikura hauota i hiahiatia kia mahi ai ngā kaituku, heoi i heke tonu te tohu.

Hononga 4: he iti ake te urupare a te pūrongo tonu

Kei reira ngā pānga tika ki te guanylate cyclase wairewa, engari he mea nui ngā kukūtanga. I te whakataurite whākōkī kua purea i whakahuatia i runga ake nei, i hiahiatia te 60 micromolar pea o te kikorangi metilēna kia aukatia haurua te cyclase i whakaongaihia e te waikura hauota. Hei whakataurite, i tata te aukatinga haurua o te NOS ki te 5 ki te 9 micromolar, ā, ahakoa te 1 millimolar, he wāhanga noa o te aukatinga mōrahi i puta. He wehenga tēnei e ono ki te tekau mā tahi whakareatanga pea. Nō reira, kāore e taea te tapa i tētahi whakamātautau pūtau ki te kukūtanga micromolar iti e whakaheke ana i te GMP ā-porowhita hei aukati whiriwhiri i te cyclase, mā te nama GMP ā-porowhita anake.

I tāpirihia he tūpato tuarua e tētahi rangahau hāora-whakaheke o muri mai: nā te kikorangi metilēna i whakaweto te cyclase kua whakahohehia e te waikura hauota, mā tētahi tikanga rerekē i te hāoratanga māmā o te rino heme e te hau. Nō reira, ka taea te whakararu i te pūrongo, engari kāore anō te matū o taua mahi kia tau. Nā te āputa kukūtanga, me whakakore tuatahi te tūpono o ngā pānga hūperōkai me ngā pānga NOS i ngā pānga kukūtanga micromolar iti. Kei konei hoki te wāhi mō te whakahaere phosphodiesterase. Ki te kore i inea, i aukatihia rānei te wāwāhitanga, ka taea te whakamārama i te iti ake o te whakaemi GMP ā-porowhita mā te iti ake o te hanga, te tere ake o te wāwāhitanga, ēnei e rua rānei.

He aha tēnei kāore e taea ai te whakaiti ki te kerēme kotahi mō te pēhanga toto

I whakaūngia ia hononga i roto i tētahi pūnaha rerekē. Ehara te tuhinga ira o ngā pūtau horomi i te mahi whākōkī o te hypothalamus. Ehara te mahi hypothalamus i muri i te lipopolysaccharide i te āhua mānukanuka o te endothelium e whakatā ana. Ehara te tauwehe endothelium e tukuna ana i te āhua taketake i te whakatipu-tahi i te whakawhānuitanga ia toto e whakaongaihia ana e tētahi matū whakahohe. Ehara ngā pūtau iatuku pūkahukahu i whakatipuria ki te 10 micromolar o te kikorangi metilēna i te pūnaha rere toto tangata. Ki te whakahanumitia ēnei hei kōrero pēnei i te kikorangi metilēna e hiki ana i te pēhanga toto mā te aukati i te waikura hauota, ka whakarērea ngā rerekētanga tonu i hangaia ai ngā whakamātautau whakahaere hei tiaki.

E toru ngā arowhai e pupuri ana i te tika o te kōrero. Tuatahi, tautuhia te momo whākōkī: eNOS mō te āhua mānukanuka o ngā ia toto e whakatā ana, iNOS mō te rerenga mumura kua whakaohohia, nNOS mō ngā horopaki pūtau io me ētahi horopaki whākōkī kua purea. Tuarua, tautuhia te ara tuku o te tohu waikura hauota: te hanga o roto, te tuku taketake mai i te endothelium, tētahi kaituku motuhake rānei pērā i te CYSNO, te nitroprusside, te MPANO rānei, nā te mea i ātete te kaituku pūmau ki te kikorangi metilēna, engari kāore ngā kaituku ngāwari ki te panoni i pērā. Tuatoru, tautuhia te kukūtanga me te whakaoranga: ka tohu te whakaoranga mā te hūperōkai dismutase ki te hūperōkai; ka whakahē te korenga o te catalase e whakaora i te hauwai peroxide hei take i taua takahanga; ka whakaatu te tāwhai xanthine oxidase e rawaka ana taua tikanga; ā, ka wehe ngā whakamātautau whākōkī kua purea i ngā pānga tika ki te whakakōkī mai i ngā ngaronga i te ara tuku.

Koinei te whakarāpopototanga poto. He pai ake te whakaaro ki te kikorangi metilēna hei matū whakararu i ngā wāhi maha o te tuku tohu mai i te waikura hauota ki te GMP ā-porowhita, kaua hei pūārai whiriwhiri i te cyclase. I runga i te takahanga whakamātautau me te kukūtanga, ka taea e ia te whakaiti i te herenga o ngā tauwehe tuhinga ira iNOS, te aukati tika i ngā whākōkī NOS, te whakaiti i te wāteatanga o te waikura hauota mā te whakaputa hūperōkai, me te whakararu i te cyclase kua whakahohehia e te waikura hauota. Ka whakamārama hōhonu ake te tūranga o te tuku tohu GMP ā-porowhita i ngā rangahau ia toto me te whakataurite i ngā kaituku waikura hauota e whakamahia ana i ngā whakamātautau pūtau i tētahi o aua peka, ā, ka whakamārama ngā tikanga hei wehe i ngā pānga hāora-whakaheke i ngā pānga whākōkī i te take e kitea nuitia ai te hūperōkai dismutase, te catalase, me tētahi whakamātautau whakahaere kaituku pūmau i ēnei tuhinga rangahau.

Ka tohu tētahi uara GMP ā-porowhita iti i muri i te kikorangi metilēna kua motu te mekameka. Mā ngā whakamātautau whakahaere anake e whakaatu ko tēhea hononga i motu.