DARWIN Digitale Dissertationen German Version Strich

FU Berlin
Digitale Dissertation

Joachim Werner :
Contribution of endothelial autacoids to the regulation of arteriolar tone in skeletal muscle in vivo
Die Bedeutung endothelialer Autakoide für die Regulation des arteriolären Gefäßtonus im Skelettmuskel in vivo

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Abstract

The endothelium-derived hyperpolarizing factor (EDHF) mediates vasodilatation via hyperpolarization of smooth muscle cells in addition to endothelial autacoids nitric oxide (NO) and vasodilatory prostaglandins (PG). Several studies suggest that EDHF is a cytochrome P450 product acting on Ca2+-activated K+ (K+Ca) channels of smooth muscle cells. Alternatively it was proposed that EDHF is endothelial K+ hyperpolarizing smooth muscle cells by activating inwardly rectifying K+ (K+IR) channels and Na+/K+ ATPase. The present study assesses the quantitative effect of the EDHF/K+Ca pathway on arteriolar resting tone and on acetylcholine (ACh)-induced vasodilatation in vivo relative to the effects of NO and PG.
The diameter changes of 1215 arterioles in 121 cremaster muscles of anaesthetized rats upon topical application of appropriate blocking agents and their response to ACh (10µM) were analysed by intravital microscopy. Blockade of K+Ca channels (charybdotoxin 3µM, tetrabutylammonium 0.1mM or tetraethylammonium 1mM) or NO synthesis (NG-nitro-L-arginine 30µM) led to diameter reduction by ~13%. A significantly stronger reduction (~30%) was observed upon blockade of PG (indomethacin 10µM). Combined blockade of the three autacoids caused a vasoconstriction of ~67% corresponding to a 100-fold increase in arteriolar flow resistance. Vascular reactions upon blockade of the different autacoid pathways were quantitatively additive and independent. This finding is supported by results of a stochastic simulation model. ACh-induced vasodilatation was diminished by ~40% upon blockade of any of the autacoids and abolished by combined blockade. Blockade of K+IR channels and Na+/K+ ATPase did not change the ACh dilatation preserved after inhibiton of NO and PG.
The present data indicate that continuous release of EDHF activating K+Ca channels contributes to the modulation of resting arteriolar tone in situ in addition to NO and PG. Moreover, EDHF/K+Ca is responsible for the NO/PG-independent component of ACh-induced vasodilatation. Endothelial K+ acting on K+IR channels and Na+/K+ ATPase seems not to be relevant in the in vivo model.

Table of Contents

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TITEL
1. EINLEITUNG 7
2. MATERIAL UND METHODEN 12
2.1. Narkose und Präparation 12
2.2. Versuchsaufbau der Intravitalmikroskopie 16
2.3. Versuchsablauf 16
2.3.1. Versuchsreihe A: Blockade der K+Ca-Kanäle mit ChTX 18
2.3.2. Versuchsreihe B: Dosis-Wirkungsexperimente von TBA und TEA 19
2.3.3. Versuchsreihe C: Funktionelle Endotheldenudierung 20
2.3.4. Versuchsreihe D: Kumulative Blockade zweier Autakoid-Systeme 21
2.3.5. Versuchsreihe E: Kombinierte Blockade von NO, PG und EDHF/K+Ca-Kanäle 22
2.3.6. Versuchsreihe F: Blockade des alternativen EDHF-Stoffwechselwegs 22
2.4. Versuchsauswertung 23
2.5. Statistik 25
3. ERGEBNISSE 27
3.1. Systemische hämodynamische Parameter 27
3.2. Durchmesser und Ruhetonus der untersuchten Arteriolen 27
3.3. Dosis-Wirkungsbeziehung verschiedener K+Ca-Kanal-Blocker 29
3.4. Funktionelle Endotheldenudierung 29
3.5. Autakoid-Effekte auf den arteriolären Ruhedurchmesser 31
3.6. Beeinflussung des arteriolären Strömungswiderstandes durch Autakoid-Effekte 36
3.7. Anteil der einzelnen Autakoid-Systeme an der ACh-induzierten Vasodilatation 37
3.8. Blockade des alternativen EDHF-Stoffwechselweges mit Ba2+ und Ouabain 40
4. DISKUSSION 41
4.1. Methodendiskussion 42
4.2. Arteriolärer Ruhetonus 45
4.3. Effekte von EDHF/K+Ca-Kanäle, NO und PG auf den Ruhetonus 46
4.4. Additivität und Unabhängigkeit der Gefäßreaktionen von EDHF, NO und PG 47
4.5. Acetylcholin-induzierte Vasodilatation 48
4.6. Struktur, Stoffwechselweg und Wirkung von EDHF 49
5. ZUSAMMENFASSUNG 51
6. ANHANG 52
6.1. Mathematisches Simulationsmodell 52
6.2. Liste der verwendeten Abkürzungen 56
7. LITERATURVERZEICHNIS 58

More Information:

Online available: http://www.diss.fu-berlin.de/2001/115/indexe.html
Language of PhDThesis: german
Keywords: Microcirculation, endothelial factors, potassium channels, flow resistance, vasodilatation
DNB-Sachgruppe: 33 Medizin
Date of disputation: 10-Apr-2001
PhDThesis from: Fachbereich Humanmedizin, Freie Universität Berlin
First Referee: Prof. Dr. Axel R. Pries
Second Referee: Prof. Dr. Michael Wiederholt
Contact (Author): jower@web.de
Contact (Advisor): pries@zedat.fu-berlin.de
Date created:06-Jul-2001
Date available:09-Jul-2001

 

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