title: Activation of arterial KCa3.1 channels with SKA-31
title: Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
Creators: name: Schultz, Tim
Publisher: name: Philipps-Universität Marburg
Year: 2011
Subjects: Endothel
Medizin, Gesundheit
endothelium

description: Die EDHF-Antwort ist neben NO und
      PGI2 der dritte Hauptweg der endothelvermittelten
      Vasodilatation und eine selektive Öffnung des KCa3.1 Kanals
      könnte den Ansatzpunkt für eine neue Strategie zur
      Blutdrucksenkung darstellen (Feletou &amp; Vanhoutte 2006,
      Sankaranarayanan et al. 2009). Im Speziellen wurde an A.c.c.
      von Wildtyp- (KCa3.1+/+) und Knockouttieren (KCa3.1-/-) der
      Einfluss von SKA-31 auf die durch Azetyllcholin induzierte
      Vasodilatation untersucht. Ebenfalls war es Ziel zu
      überprüfen, ob SKA-31 einen Einfluss auf die durch
      Phenylephrin und hohe Kaliumkonzentration induzierte
      Vasokonstriktion hat. Die Ergebnisse der Untersuchungen
      zeigen, dass SKA-31 die EDHF-vermittelte Vasodilatation
      deutlich potenziert und eine hohe Selektivität für den KCa
      3.1 Kanal besitzt. Auf die glattmuskuläre Funktion bestand
      kein Einfluss.
description: Arterial hypertension plays an
      important role in the progress of cardiovascular disorders.
      The pressure level is directly addicted to the total
      peripheral resistance, which is determined by the diameter of
      the small arterioles. The endothelium controls vascular tone
      by different pathways. But not only releasing nitric oxide
      (NO) and prostacyclin dilate the underlying smooth muscle
      cells. Also the hyperpolarization of the endothelium causes a
      hyperpolarization and relaxation. This endothelium-derived
      hyperpolarizing factor (EDHF) is not completely understood
      but the small-conductance calcium-activated channels KCa3.1
      und KCa2.3 play an important role in the hyperpolarisation of
      the endothelium. Sankaranarayanan et al. demonstrate in
      electrophysiological patch-clamp studies that the Riluzole
      derivative SKA-31 is able to open KCa3.1 channels with an
      EC50 of 250 nM and the KCa2.3 channel with an EC50 in the low
      micromolar range. This dissertation has the aim to
      investigate the pharmacological potency of SKA-31 in matters
      of amplifying the EDHF-answer. The studies were accomplished
      with Arteriae carotis communis and a pressure myographe
      system under physiological conditions. The needed KCa3.1
      wildtype and knockout mice were reared and genotyped. SKA-31
      potentiated the
      endothelium-derived-hyperpolarizing-factor-mediated-dilation
      with an EC50 of 93 nmol/L. It also reduced the need
      concentration of acetylcholine, but the contraction behaviour
      was not affected by SKA-31. The sole injection showed no
      dilation effect, so it seems possible that SKA-31 inhibits
      the closing of KCa3.1. Parllel organized experiments showed
      that SKA-31 is able to lower blood pressure in normtensiv and
      hypertensive mice and had no effect to the heart rate or
      toxic attributes. In summary SKA-31 shows the potential to be
      a new drug in the treatment of hypertension.