Publikationsserver der Universitätsbibliothek Marburg
Titel:Genetische Suppression endothelialer KCa3.1 und KCa2.3 unterdrückt die EDHF-vermittelte Vasodilatation und erzeugt Hypertonie
Autor:Brähler, Sebastian Paul
Weitere Beteiligte: Köhler, Ralf (PD Dr. )
Veröffentlicht:2009
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0398
URN: urn:nbn:de:hebis:04-z2010-03986
DOI: https://doi.org/10.17192/z2010.0398
DDC: Medizin
Titel (trans.):Genetic Deficit of SK3 and IK1 Channels Disrupts the Endothelium-Derived Hyperpolarizing Factor Vasodilator Pathway and Causes Hypertension
Publikationsdatum:2010-08-02
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Endothel, Hypertonie, Ionenkanal, Kaliumkanal, hypertension, ion channel, Stickstoffmonoxid, potassium channel, endothelium

Zusammenfassung:
Das Endothel nimmt Einfluss auf den Tonus der glatten Gefäßmuskulatur und ist somit wichtig für die adäquate Regulation der Gewebeperfusion und des systemischen Blutdrucks. Zur endothelvermittelten Vasodilatation tragen die diffusiblen Moleküle Stickstoffmonoxid (NO) und Prostazyklin (PGI2) sowie der sogenannte EDHF (endothelium-derived hyperpolarizing factor) bei. Obwohl dieser EDHF insbesondere in kleineren Arterien und Arteriolen eine wesentliche Rolle zu spielen scheint, konnte die molekulare Identität bzw. die physiologischen Mechanismen dieses Faktors noch nicht abschließend geklärt werden. Mittlerweile werden sowohl eine Reihe diffusibler Moleküle als auch elektrophysiologische Prozesse als Ursache für das EDHF-Phänomen diskutiert. Eine der Hypothesen schreibt der Hyperpolarisation durch die endothelialen Ca2+-aktivierten Kaliumkanäle KCa2.3 und KCa3.1 eine wesentliche Rolle bei der EDHF-vermittelten Vasodilatation zu. Zur Klärung der Funktion von KCa2.3 und KCa3.1 im Endothel sollte in dieser Arbeit erstmals ein Mausmodell generiert und untersucht werden, bei dem die Expression beider Ionenkanäle durch genetische Veränderungen beeinflusst wurde. Hierzu sollten zwei bestehende Mausmodelle, die KCa3.1-/- - Maus und die KCa2.3T/T - Maus, miteinander gekreuzt werden. Während es sich bei der KCa3.1-/- - Maus um einen konventionellen Knockout handelte, ließ sich bei dem KCa2.3T/T - Gen die Kanalexpression durch orale Gabe der Antibiotikums Doxyzyklin (Dox) unterdrücken. Ohne die Gabe von Doxyzyklin wurde der Kanal durch das veränderte Gen stark überexprimiert. Die Gene wurden gemäß der Mendelschen Regeln vererbt und der Genotyp der Tiere wurde durch Polymerasekettenreaktion (PCR) bestimmt. KCa3.1-/-/KCa2.3T/T-Tiere zeigten sowohl mit als auch ohne orale Gabe von Doxyzyklin gegenüber Wildtyptieren keine offensichtlichen Auffälligkeiten in Verhalten und Gesundheitszustand. Die elektrophysiologischen Eigenschaften der Endothelzellen dieser Tiere wurden durch die Patch-Clamp-Technik untersucht. Hierbei zeigte sich jeweils eine Halbierung des KCa-Stomes bei KCa3.1-/- - Tieren und KCa2.3T/T - Tieren (+Dox) gegenüber Wildtyptieren und eine nahezu vollständige Unterdrückung des KCa-Stromes bei KCa3.1-/-/KCa2.3T/T -Tieren (+ Dox). Die Sharp-Electrode-Untersuchung des Membranpotenzials der glatten Gefäßmuskulatur ergab, dass der Verlust der KCa-Kanäle im Endothel zu einer signifikanten Reduktion der Hyperpolarisation der Gefäßmuskelzellen auf einen intravasalen Azetylcholinstimulus führte, wobei der Verlust von KCa3.1 einen stärkeren Effekt hatte als der Verlust von KCa2.3. Somit konnte die funktionelle Bedeutung der endothelialen KCa-Kanäle für die Azetylcholin-induzierte Hyperpolarisation der glatten Gefäßmuskulatur und eine funktionelle Interaktion zwischen Endothelzelle und glatter Gefäßmuskulatur bei der EDHF-mediierten Vasodilatation bestätigt werden. Die Vasodilatation der Gefäße wurde durch Myographenexperimente an der Arteria carotis communis der Versuchstiere bestimmt. Der Knockout beider KCa-Kanäle führte zu einer signifikanten Reduktion der Vasodilatation auf intravasale Stimulation mit Azetylcholin. KCa3.1 schien die dominierende Rolle bei der Azetylcholin-induzierten EDHF-vermittelten Vasodilatation einzunehmen. Außerdem war die fluss- und shear-stress- induzierte Vasodilatation ebenfalls signifikant reduziert, wobei der Vergleich der KCa3.1-/-/KCa2.3T/T - Mäuse (+ Dox) mit KCa2.3T/T- Mäusen (+ Dox) für eine dominierende Rolle von KCa2.3 bei der fluss- und shear- stress- induzierten Vasodilatation sprach. Neben den beschriebenen gravierenden funktionellen Veränderungen auf der zellulären und vaskulären Ebene führten die genetischen Veränderungen auch zu einer signifikanten Erhöhung des arteriellen Blutdruckes der KCa3.1-/-/KCa2.3T/T - Mäuse (+Dox) gegenüber den Wildtypmäusen, was die Bedeutung von KCa3.1 und KCa2.3 und der von ihnen initiierten EDHF-vermittelten Vasodilatation für die systemische Blutdruckregulation zeigt. Insgesamt konnte durch die vorliegenden Ergebnisse dieser Studie bestätigt werden, dass die beiden untersuchten KCa-Kanäle bei der Entstehung der EDHF-Antwort eine wichtige Rolle spielen. Offensichtlich tragen KCa3.1 und KCa2.3 über unterschiedliche Mechanismen und Stimuli zur Vasodilatation bei: KCa2.3 scheint die wichtigere Rolle bei der flussinduzierten Vasodilatation zu spielen, während KCa3.1 vor allem für die Azetylcholin-induzierten Vasodilatation verantwortlich zu sein scheint. Die Bedeutung des EDHF als wesentlicher Faktor der Kreislaufregulation konnte durch die Blutdruckuntersuchungen und die Myographenexperimente bestätigt werden. Das bessere Verständnis der physiologischen Funktion des Endothels und des vaskulären Systems liefert den Schlüssel zum Verständnis pathophysiologischer Prozesse und eröffnet neue therapeutische Perspektiven. So ist es vorstellbar, dass spezifische Ionenkanalöffner für KCa3.1 und KCa2.3 zukünftig als Antihypertensiva und Vasodilatatoren eingesetzt werden.

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