Small artery tone under control of the endothelium

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1 Small artery tone under control of the endothelium On the importance of EDHF and myogenic tone in organ (dys)function Simone K. Gschwend

2 Publication of this thesis was supported by generous contributions from: Bristol-Myers Squibb, GlaxoSmithKline, the Groningen University Institute of Drug Exploration (GUIDE), Merck Sharp & Dohme, the Rijksuniversiteit Groningen, Sanofi- Synthelabo, Servier. Gschwend S.K. Small artery tone under control of the endothelium. On the importance of EDHF and myogenic tone in organ (dys)function. Dissertation. with Dutch summary Copyright 2003 S.K. Gschwend All rights are reserved. No part of this publication may be reproduced, in any manner or by any means without written permission from the author.

3 RIJKSUNIVERSITEIT GRONINGEN Small artery tone under control of the endothelium On the importance of EDHF and myogenic tone in organ (dys)function Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 29 oktober 2003 om 14:15 uur door Simone Katharina Gschwend geboren op 18 september 1971 te Berlijn, Duitsland

4 Promotores: Prof. dr. D. de Zeeuw Prof. dr. M. Paul Co-Promotores: Dr. H. Buikema Dr. R. H. Henning Beoordelingscommissie: Dr. R. Kreutz Prof. dr. T. J. Rabelink Prof. dr. F. G. Russel ISBN-nummer: x

5 Paranimfen: Annemarieke Loot Soesja Hu Financial support by the Netherlands Heart Foundation for the publication of this thesis is gratefully acknowledged.

6 Contents Chapter 1 General Introduction Vascular tone under control Small arteries and arterioles Diameter control in small arteries and arterioles: an overview Different vascular beds: coronary, mesenteric, and renal arteries The vascular smooth muscle The endothelium Endothelium-derived contracting and relaxing factors Functional assessment of endothelial (dys-)function: the ACh test Endothelium-derived hyperpolarizing factor (EDHF) Role of vascular ion channels in mediating constriction and dilation Ion channels on vascular smooth muscle cells Ion channels on endothelial cells Small artery function in progressive organ disease: a vicious circle This thesis Small artery dysfunction precedes and promotes organ disease Organ disease promotes small artery dysfunction of other organ circulations Increased total peripheral resistance reinforces organ disease progression Endothelium-derived mediators involved: NO versus EDHF Scope Research objectives

7 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Impaired coronary endothelial function in a rat model of spontaneous albuminuria Kidney Int 2002; 62: Endothelial dysfunction and infarct size relate to impaired EDHF response in rat experimental chronic heart failure Eur J Heart Fail 2003; 5: Myogenic constriction is increased in mesenteric resistance arteries from rats with chronic heart failure: Instantaneous counteraction by acute AT 1 receptor blockade Br J Pharmacol 2003; 139: Coronary myogenic constriction antagonizes EDHF-mediated dilation. Role of K Ca channels Hypertension 2003; 41: Endothelial dilatory function predicts individual susceptibility to renal damage in the 5/6 nephrectomized rat J Am Soc Nephrol 2002; 13: Does low sodium diet exert a protective effect on endothelial mediators in normal rats? J Lab Clin Med 2001; 138: Chronic ACE inhibitor therapy differentially modulates mediators of endothelium-dependent dilation in small renal and mesenteric arteries. Effect of dietary sodium restriction Submitted General Discussion Mechanisms of disease-related EDHF impairment Future directions on the therapeutic potential of K Ca channel openers Variability of endothelial dilator function among healthy individuals. Does it predispose some individuals for development of renal damage? Future directions for individual risk assessment, and strategies to prevent renal damage Background and technicalities Summary, Samenvatting & Acknowledgements

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