Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.

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 & Vanhoutte 2006, Sankaranarayanan et al. 2009). Im Speziellen...

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1. Verfasser: Schultz, Tim
Beteiligte: Köhler, Ralf (PD Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2011
Innere Medizin
Ausgabe:http://dx.doi.org/10.17192/z2011.0025
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title_alt Activation of arterial KCa3.1 channels with SKA-31
doi_str_mv http://dx.doi.org/10.17192/z2011.0025
edition http://dx.doi.org/10.17192/z2011.0025
license_str http://archiv.ub.uni-marburg.de/adm/urhg.html
oai_set_str_mv open_access
ddc:610
doc-type:doctoralThesis
xMetaDissPlus
dewey-raw 610
dewey-search 610
genre Medical sciences, Medicine
genre_facet Medical sciences, Medicine
topic_facet Medizin, Gesundheit
topic Medizin, Gesundheit
endothelium
Endothel
spellingShingle Medizin, Gesundheit
endothelium
Endothel
Schultz, Tim
Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
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.
building Medizin
author Schultz, Tim
author2 Köhler, Ralf (PD Dr.)
author2_role ths
ref_str_mv references
language German
title Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
title_short Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
title_full Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
title_fullStr Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
title_full_unstemmed Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
title_sort Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31.
contents 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.
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 & 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.
last_indexed 2011-08-18T23:59:59Z
publisher Philipps-Universität Marburg
first_indexed 2011-02-03T00:00:00Z
institution Innere Medizin
url http://archiv.ub.uni-marburg.de/diss/z2011/0025/pdf/dts.pdf
publishDate 2011
era_facet 2011
format Dissertation
thumbnail http://archiv.ub.uni-marburg.de/diss/z2011/0025/cover.png
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Science 273(5282):1709-14 1996 Smallconductance , calcium-activated potassium channels from mammalian brain Yellen G. 2002. The voltage-gated potassium channels and their relatives. Nature 419(6902):35-42 2002 The voltage-gated potassium channels and their relatives Morimura K, Yamamura H, Ohya S, Imaizumi Y. 2006. Voltage-dependent Ca2+- channel block by openers of intermediate and small conductance Ca2+- activated K+ channels in urinary bladder smooth muscle cells. J. Pharmacol. Sci. 100(3):237-41 2006 Voltage-dependent Ca2+- channel block by openers of intermediate and small conductance Ca2+- activated K+ channels in urinary bladder smooth muscle cells Nelson MT, Quayle JM. 1995. Physiological roles and properties of potassium channels in arterial smooth muscle. Am. J. Physiol 268(4 Pt 1):C799-C822 1995 Physiological roles and properties of potassium channels in arterial smooth muscle Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE et al. 2003. Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Circ. Res. 93(2):124-31 2003 Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure Stocker M. 2004. Ca(2+)-activated K+ channels: molecular determinants and function of the SK family. Nat. Rev. Neurosci. 5(10):758-70 2004 Ca(2+)-activated K+ channels: molecular determinants and function of the SK family Soh H, Park CS. 2001. Inwardly rectifying current-voltage relationship of small- conductance Ca2+-activated K+ channels rendered by intracellular divalent cation blockade. Biophys. J. 80(5):2207-15 2001 Inwardly rectifying current-voltage relationship of smallconductance Ca2+-activated K+ channels rendered by intracellular divalent cation blockade Lacy PS, Pilkington G, Hanvesakul R, Fish HJ, Boyle JP, Thurston H. 2000. Evidence against potassium as an endothelium-derived hyperpolarizing factor in rat mesenteric small arteries. Br. J. Pharmacol. 129(3):605-11 2000 Evidence against potassium as an endothelium-derived hyperpolarizing factor in rat mesenteric small arteries Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure. Mol. Pharmacol. 75(2):281-95 2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure 2011-02-03 Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31. Untersuchung zur pharmakologischen Aktivierung arterieller KCa3.1-Kanäle durch SKA-31. opus:3362 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. 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 & 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. 2011-08-18 2011-02-03 urn:nbn:de:hebis:04-z2011-00250 2011 Schultz, Tim Schultz Tim ths PD Dr. Köhler Ralf Köhler, Ralf (PD Dr.) Philipps-Universität Marburg
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