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De Radioimmunologische Bepaling Van Vasopressine in Urine

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De Radioimmunologische Bepaling Van Vasopressine in Urine DE RADIOIMMUNOLOGISCHE BEPALING VAN VASOPRESSINE IN URINE ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor in de Geneeskunde aan de Universiteit van Amsterdam, op gezag van de Rector Magnificus dr. D.W, Bresters, hoogleraar in de Faculteit der Wiskunde en Natuurwetenschappen, in het openbaar te verdedigen in de aula der Universiteit (tijdelijk in de Lutherse Kerk, ingang Singel 411, hoek Spui) op donderdag 12 februari 1981 om 16.00 uur precies door MARINUS JOHANNES VAN DER HORN Geboren te Amsterdam I AMSTERDAM 1981 Promotor: Prof.dr. J.L. Touber Coprotnotor: Prof.dr. M. Koster Coreferent: Prof.dr. D.F, Swaab I f Are doctors men of science? George Bernard Shaw Ter nagedachtenis aan mijn vader Aan Noortje, Jeroen en Niels VOORWOOBD Het is niet mogelijk al diegenen te bedanken die een bijdrage heb- ben geleverd bij het tot stand komen van dit proefschrift. Voor een aantal hunner wil ik echter een uitzondering maken gezien hun grote inbreng. Beste Dries Schellekens, jij hebt mij met eindeloos geduld ver- trouwd weten te maken met de radio-lmmunologische bepalingsmetho- dieken en hebt, als ik door mijn onkunde nucleaire rampen dreigde te veroorzaken, dit op tactische wijze weten te voorkomen. Hooggeleerde Swaab, beste Dick, een van mijn sterke punten in dit onderzoek was de keuze van de coreferent. Jouw enthousiasme heeft mij, vooral in de laatste fase, dusdanig gestimuleerd dat ik het onderzoek heb kunnen afronden. Hooggeleerde Koster, naast opleider en copromoter bent U het, tesamen met Prof. Vreeken, geweest die mij in de gelegenheid heeft gesteld dit onderzoek uit te voeren. Zeer geleerde Oosting, beste Hans, met bewondering heb ik ge- zien hoe je op het cijfermateriaal dat ik je ter hand stelde, statistiek bedreef. Slechts ingewijden weten hoeveel werk opgesloten ligt in de zinsnede " is variantie-analyse toegepast". Hooggeleerde Touber, beste Jan, de periode die ik onder jouw leiding heb mogen werken is niet alleen leerzaam geweest, maar vormt ook een prettige herinnering door onze contacten buiten de werksfeer om. Het personeel van het Endocrinologisch laboratorium en in het bij- zonder Marnie Tjon Sackie-Saridjan wil ik danken voor hun hulp bij het uitvoeren van de proeven en Marion Wijnberg voor het geduld wat ze op wist te brengen voor het telkens opnieuw typen van de een na laatste versie van dit proefschrift. Niet in de laatste plaats gaat mijn dank uit naar Noor, Jeroen en Niels voor hun begrip en verdraagzaamheid als ik de weinige tijd die thuis was weer eens op mijn kamer doorbracht. £-; INHOUDSOPGAVE biz. Lijst van afkortingen Hoofdstuk I LITERATUUROVERZICHT 1.1. Historisch overzicht 9 1.2. De relatie tussen chemische structuur en biologische activiteit 12 1.3. Neurofysine 13 1.4. Regulatiemechanisme voor vasopressinesecretie 15 1.5. Perifere werkingen van vasopressine 17 1.6. Metabolisme van vasopressine 20 1.7. Ziektebeelden als gevolg van een gestoorde vasopres- sine huishouding. 21 Hoofdstuk H DOELSTELLINGEN VAN HET ONDERZOEK 27 Hoofdstuk Hl RADIO-IMMUNO-ASSAY VOOR VASOPRESSINE L 3.1. Inleiding 28 •-, 3.2, Anti sera tegen vasopressine 29 ! 3.3. Gebruikte hormoonpreparaten 30 3.4. Koppelingsmethode van vasopressine en thyreoglobuline 31 3.5. Immunisatieprocedure 32 3.6. Associatieconstante 33 3.7. Immunologische karakterisering van antisera 33 '-.'•- 3.8. Resultaten 34 3.9. Bereiding van radio-actief vasopressine 39 3.10. Specifieke activiteit van radio-actief vasopressine 43 ; 3.11. Scheidingsmethode 44 \: 3.12. Uitvoering van de RIA 45 £• 3.13. Resultaten 47 |: 3.14. Discussie 50 3.15. Samenvatting en conclusies 52 biz. Hoofdstuk IV BEPALING VAN VASOPRESSINE IN URINE 4.1. Inleiding 54 4.2. Extractie 55 4.2.1. Extractlemllleu 56 4.2.2. Extractierecovery van radio-actief vasopressine 57 4.2.3. Parallelliteit recovery van koud vasopressine 57 4.2.4. Intra- en inter-assay variatie 58 4.2.5. Storende factoren 63 4.2.6. Eiwithoudende urine 65 4.2.7. Discussie 67 4.3. Invloed van oxytoclnegehalte van urine op meting van van vasopressinesplegels 69 4.4. Urlneklarlng van vasopressine 70 4.5. Samenvatting en conclusies 74 Hoofdstuk V GELDIGHEID VAN DE VASOPRESSINE RIA ! 5.1. Inleiding 75 : 5.2. Ontwikkeling van diabetes insipidus bij gelmmuniseer- ; de konijnen 76 5.3. Neurohypofysalre diabetes Insipidus 77 5.4. Nefrogene diabetes insipidus 83 5.5. Syndroom van 'inappropriate ADH secretion' 83 5.6. Stimulatie en inhibitie van vasopresslnesecretle bij gezonde proefpersonen 85 5.7. Discussie 87 5.8. Samenvatting en conclusies 90 '{ Hoofdstuk VI NORMAALWAARDEN {.' 6.1. De vasopresslne-excretle van gezonde proefpersonen 91 | 6.2. Discussie 95 ï:. 6.3. Samenvatting en conclusies 97 t.. ?-'• I biz. Hoofdstuk VII INVLOED VAN HET NATRIUMGEHALTE VAN DIEET OP DE URINE VASOPRESSINESPIEGE LS 7.1. Inleiding 98 7.2. Protocol 100 7.3. Resultaten 102 7.3.1. Urlnevolume 102 7.3.2. Zoutuitscheiding In urine 102 7.3.3. Urine-osmolaliteU en osmolen excretle 103 7.3.4. Vasopresslne-excretie in urine 106 7.3.5. Bloeddruk 110 7.3.6. Lichaamsgewicht 110 7.3.7 Discussie 110 7.3.8. Samenvatting en conclusie 114 Samenvatting 115 Summary 118 Referenties 120 Appendix 143 i LIJST VAN AFKORTINGEN ACTH - adrenocorticotroop hormoon ADH - anti-diuretiseh hormoon AVP - 8-arginine-vasopressine AVT - 8-arginine-vasotocine cAMP - cyclisch adenosine-mono-fosfaat CDI - ethylcarbodiimide-HCl CBF - corticotropin releasing factor DASP - double antibody solid phase DDAVP - l-deamino-8-D-arginine-vasopressine DG-LVP - desglycinamide-lysine-vasopressine DMC - dimethylchloortetracycline EDTA - (di-natrium-)ethyleen-diamino-tetra-azijnzuur HAK - hypofyse achterkwab HSA - humaan serum albumine LVP - 8-lysine-vasopressine MSH - melanocyten-stimulerend hormoon NPV - nucleus paraventricularis NSO - nucleus supra-opticus OT - oxytocine BAAS - renine-angiotensine-aldosteron-systeem RIA - radio-immuno-assay RSA - runder serum albumine SIADH - syndrome of inappropriate ADH secretion Tg - thyreoglobuline HOOFDSTUK I LITERATUUROVERZICHT 1.1 Historisch overzicht Vasopressine of anti-diuretisch hormoon (ADH) is een peptide dat in de hypothalamus gesynthetiseerd en via de neurohypofyse af- gegeven wordt. Een uitvoerig overzicht van de geschiedenis van het onderzoek naar vasopressine wordt gegeven door Heller (1974). De- ze historie begint in 1895 met Oliver en Schaier, die bij proefdieren een bloeddrukstijging zagen optreden na een injectie van een hypofy- se-extract. Naast bloeddrukverhogende, bleken hypofyse-extracten ook weeënbevorderende (Dale, 1906) en galactokinetlsche eigenschappen (Ott en Scott, 1910) te bezitten. In 1898 ontdekte Howell dat de bloeddrukverhogende substantie (s) uit de hypofyse-achterkwab (HAK) afkomstig moesten zijn. Dit was een opmerkelijke bevinding, daar tot *' dan toe de HAK beschouwd werd als een rudimentair orgaan zonder fysiologische functies (Macalister, 1889). In 1894 deelde Cajal mede, dat hij in de HAK microscopische structuren had waargenomen, die opvallend veel overeenkomst vertoonden met zenuwuiteinden. Het heeft tot 1913 geduurd voor Farini en, onafhankelijk van hem, Von den Velden de antidiuretische werking van HAK-extracten ontdekten en zij waren ook de eersten die patiënten met diabetes insipidus met HAK-extracten behandelden. •': Aanvankelijk werd verondersteld dat de HAK een biologisch ac- ; tieve stof bevatte, die verantwoordelijk was voor bovengenoemde ef- fecten (Abel e£ al_., 1924). Dit hormoon zou dan of in de pars inter- ; media (Herring, 1915) of in de pituicyten van de HAK (Gersh, 1939) L worden gesynthetiseerd. De mening dat de HAK slechts een hormoon | zou bevatten werd gesteund door Van Dyke et^ aJL (1942). Zij isoleer- I den uit runderhypofyses een eiwit met zowel oxytocine-, pressor- als antidiuretische eigenschappen. Daarentegen had Dudley (1919) aanwijzingen gevonden voor de aanwezigheid van twee hormonen in de HAK, hetgeen later bevestigd werd door Kamm et. al. (1928), die uit HAK-extracten twee peptiden isoleerden, namelijk (1) oxytoxine met weeënstimulerende en galactokinetische en (2) vasopressine met pres- sor en antidiuretische eigenschappen. In 1953 gelukte het Du Vig- neaud et .al. oxytocine en vasopressine te synthetiseren. Er zijn op dit moment negen neurohypofysalre hormonen bekend bij vertebraten (zie tabel 1) waarvan drie (8-arglnine-vasopresslne, 8-lysine-va8opresslne en 8-arglnlne-vasotocine) een voornamelijk an- tiduretische en vasopressorwerking hebben. De overige zes peptiden hebben voornamelijk een oxytocine-achtige werking met weinig anti- diuretische en vasopressor eigenschappen (Acher, 1974). Bij alle zoogdieren, behalve de varkensachtigen, is het antidiuretisch hor- moon arginine-vasopresslne. Bij de varkensachtigen Is dat lysine- vasopressine. Bij lagere diersoorten vervult vasotoclne deze rol. Bij enkele diersoorten zou zowel lysine-vasopressine als arginine- vasopressine voorkomen (Acher e£ al.., 1980). • ., De functionele rol van het hypothalamus-neurohypofyse systeem ; werd door Bargmann en Scharrer ontsluierd en later door anderen ; bevestigd (Bargmann, 1949; Bargmann en Scharrer, 1951; Sachs en Takabatake, 1964; Norström en Sjöstrand, 1971; Pickering en Jones, 1971; Pickering et. al.., 1975). Vasopressine en oxytocine en hun respectievelijke dragereiwitten, de neurofysinen, worden in afzonder- lijke cellen als een groot precursor molecuul gesynthetiseerd op de ; ribosomen in de perikarya van de neurosecretoire cellen van de nu- cleus supra-opticus (NSO) en nucleus paraventricularis (NPV) (Swaab et. al.., 1975; Vandesande en Dierickx, 1975; van Leeuwen e£ al., 1976; Dierickx
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