En dot he li ns (ET) are a group of en do ge nous pep ti des, whi ch ha ve a stro ng and lo ng-las ti ng va so con stric ti ve eff e ct. Three iso for ms of en dot he li ns co ded by three diff e re nt ge nes ha ve been iden ti fi ed to da te. En dot he li n-1 (ET-1) is the mo st po te nt va so con stric ti ve age nt cur ren tly iden ti fi ed, and it was ori gi nal ly iso la ted and cha rac te ri zed from the cul tu re me dia of aor tic en dot he lial cel ls. Two ot her iso for ms, named en dot

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... he li n-2 (ET-2) and en dot he li n-3 (ET-3), we re sub sequen tly iden ti fi ed, alo ng wi th struc tu ral ho mo lo gues iso la ted from the ve nom of Ac trac ta pis en gad den sis known as the sa ra fo toxi ns. The bio lo gi cal eff ec ts of en dot he lin pro duc tion are de ter mi ned via ac ti va tion of one or two G-pro tein coup led re cep to rs, en dot helin re cep to rs A (ETRA) and B (ET R B1 and ET R B2). Re cen tly en dot he lin re cep tor C (ETRC) was dis co ve red, howe ver, its fun ctio ns and dis tri bu tion sti ll re main un clear. The eff ec ts me dia ted by ET-1 via ETRA are va so con stric tion, bron cho con stric tion and sec re tion of al dos te ro ne. Ago nis ts re la ted to the ET R B1 ac ti va tion cau se va so di la ta tion by sti mu la ti ng NO, PGI2 and en dot he liu m-de ri ved hyper po la ri zi ng fac tor (EDHF). In con tra st, coup li ng to ET R B2 causes va so con stric tion. In vol ve me nt of ET has been de mon stra ted in the pat hop hysio lo gy of cer tain di sor de rs. In this re view, we dis cu ss the physio lo gi cal and pat hop hysio lo gi cal ro le of en dot he liu m-de ri ved ET-1, the phar ma co lo gy of its two re cep to rs, fo cu si ng on the ro le of ET-1 in the deve lop me nt of so me pat hop hysio lo gi cal con di tio ns. Key wor ds: en dot he lin 1; en dot he lin re cep tor; en dot he lin re cep tor an ta go ni st; en dot he lin con ver ti ng en zyme Re cei ved: Ap ril 21, 2011 Ac cep ted: Au gu st 15, 2011 En dot he li ns -cli ni cal per spec ti ves Ad ria na Unic*, Lo vor ka De rek, Na ta sa Ho dak, Do ma goj Ma ri jan ce vic, Ma ri na Cep r nja, Ti ha na Ser dar, Ma ja Kr hac, Zelj ko Ro mic Cli ni cal De par tme nt of La bo ra to ry Diag nos ti cs; Dub ra va Uni ver si ty Hos pi tal, Zag reb, Croa tia *Cor res pon di ng aut hor: au nic@kbd.hr En dot he lin con ver ti ng en zymes (ECE) En dothe lin con ver ti ng en zymes are atypi cal en dopep ti da ses (me tal lop ro tea ses), pre do mi nan tly found in the sa me, or in clo se proxi mi ty to, tho se cel ls expres si ng ea ch en dot he lin (7,8). Three for ms of Unic A. et al. En dot he li ns -cli ni cal per spec ti ves Biochemia Medica 2011;21(3):231-42 232 ECE ha ve been des cri bed: ECE-1 (9), ECE-2 (10), and ECE-3 (11), wi th diff e re nt spe ci fi ci ties for the iso forms of big ET. ECE-1 spe ci fi cal ly hydro lyzes the Tr-p21-Val/Ile22 bon ds of bi g-E Ts to pro duce bio lo gical ly ac ti ve ETs (12,13). Four iso for ms of hu man ECE-1 (1a, 1b, 1c and 1d) ha ve been iden ti fi ed to da te (12,14) . The four pro tei ns are en co ded by one ge ne, but ea ch is expres sed from a dis tin ct pro moter that re gu la tes the expres sion of the four unique ami no ter mi ni (12). Si mi lar ly to ECE-1, four diff e re nt iso for ms of ECE-2 ha ve been iden ti fi ed: ECE-2a-1, ECE-2a-b, ECE-2b-1 and ECE-2b-2 (15), al so wi th diffe re nt sub cel lu lar lo ca li za tio ns (16). ECE-3 is spe cifi c for big . Pre vious stu dies in di ca te that ECE-1 is the main en zyme res pon sib le for the transfor ma tion of big ET in to ET (16). Se ve ral stu dies ha ve shown that ECE-1 effi cien tly hydro lyzes a num ber of pep ti de hor mo nes ot her than ETs, these inclu de bra dyki nin, sub stan ce P and neu ro tensin (12, 14) . An exci ti ng no vel sub stra te for ECE-1 is the be ta-a myloid pep ti de that is im pli ca ted in the pat ho ge ne sis of Al zheimer di sea se (12). In hi bi to rs of ECE-1 are con si de red to be va luab le the ra peu tic agen ts and we re de ve lo ped for the treat me nt of va rious di sor de rs li nked to ele va ted ET-1 le ve ls (12, 14) . Nu me rous pep ti des or no n-pep ti dyl ECE-1 in hi bi to rs ha ve al rea dy been pro du ced, but neither is cur ren tly used for the ra peu tic pur po ses, perha ps be cau se of in suffi cie nt knowled ge of the ECE-1 fa mi ly of pro tei ns in na tu ral ly expres si ng cel ls.