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Macula Densa Derived Nitric Oxide and Kidney Function

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Macula Densa Derived Nitric Oxide and Kidney Function ! " #$ %% &&'()% %)% *+'(*)%)* ,%&*'* ,,%&% -..- Macula Densa Derived Nitric Oxide and Kidney Function ANNA OLLERSTAM Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Physiology presented at Uppsala University in 2002 ABSTRACT Ollerstam, A. 2002. Macula Densa Derived Nitric Oxide and Kidney Function. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1144. 47 pp. Uppsala. ISBN 91-554-5293-0. The kidney is the major organ regulating the extracellular fluid volume and thereby the arterial blood pressure. The neuronal isoform of nitric oxide synthase (nNOS) in the kidney is predominantly located in the macula densa cells. These cells are sensors for both renin release and the tubuloglomerular feedback mechanism (TGF), which is an important regulator of the glomerular filtration rate and afferent arteriole tone. The aim of this investigation was to elucidate the function of nNOS in the macula densa cells. Acute nNOS inhibition in rats resulted in an increased TGF responsiveness and unchanged blood pressure while, after chronic inhibition, the TGF was normalised and the blood pressure was elevated. The plasma renin concentration was elevated in rats on long- term low salt diet, but was not significantly affected by chronic nNOS inhibition. On the other hand, nNOS inhibition for four days increased plasma renin concentration in rats treated with a low salt diet. The renal vasculature of rats exhibits a diminished renal blood flow and intracellular Ca2+ response to angiotensin II after one week blockade of nNOS while angiotensin II’s effect on the renal blood flow was abolished after four weeks treatment. Acute extracellular volume expansion diminish the TGF sensitivity thus assisting the elimination of excess fluid but after acute addition of nNOS inhibitor to volume expanded rats the TGF sensitivity restored. In conclusion, the results from the present study suggest an important role for nNOS in the macula densa cells in the regulation of the arterial blood pressure and the modulation of the TGF response. Key words: Nitric oxide, rats, kidney, macula densa cells, tubuloglomerular feedback, renin, angiotensin II, blood pressure, hypertension, renal blood flow, neuronal nirtic oxide synthase. Anna Ollerstam, Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Biomedical Centre, P.O. Box 571, SE-751 23 Uppsala, Sweden Anna Ollerstam 2002 ISSN 0282-7476 ISBN 91-554-5293-0 Printed in Sweden by Uppsala University, Tryck och medier, Uppsala 2002 2 This thesis is based on the following papers, which will be referred to in the text by their Roman numerals: I Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase. Ollerstam A, Pittner J, Persson AEG, & Thorup C. 1997 J Clin Invest. 99(9): 2212-8. II Effects of long-term inhibition of neuronal nitric oxide synthase on blood pressure and renin release. Ollerstam A, Skøtt O, Ek J, Persson AEG & Thorup C. 2001 Acta Physiol Scand. 173: 351-8. III Reduced rat renal vascular response to Ang II after chronic inhibition of nNOS. Ollerstam A, Salomonsson M & Persson AEG. 2002 Submitted. IV Neuronal nitric oxide synthase inhibition restores the tubuloglomerular feedback response after volume expansion. Brown R*, Ollerstam A* & Persson AEG. 2002 *equal contribution, Manuscript Reprints are made with permission from the publishers. Paper I is republished with permission of The American Society for Clinical Investigation, Inc.; permission conveyed through Copyright Clearance Centre, Inc. Paper II is republished with permission of Scandinavian Physiological Society. 3 TABLE OF CONTENTS LIST OF ABBREVIATIONS............................................................................................................................... 5 INTRODUCTION................................................................................................................................................. 6 AUTOREGULATION.............................................................................................................................................. 7 Myogenic response ........................................................................................................................................ 8 Tubuloglomerular feedback........................................................................................................................... 8 NITRIC OXIDE...................................................................................................................................................... 9 RENIN-ANGIOTENSIN SYSTEM ........................................................................................................................... 11 AIMS OF THE INVESTIGATIONS................................................................................................................. 13 MATERIALS AND METHODS ....................................................................................................................... 14 ANIMALS........................................................................................................................................................... 14 SURGICAL PREPARATION (STUDIES I, II, III & IV)............................................................................................ 14 TAIL-CUFF BLOOD PRESSURE MEASUREMENTS (STUDIES I & II)....................................................................... 14 WHOLE KIDNEY CLEARANCE MEASUREMENTS (STUDIES I, II & IV)................................................................. 15 STOP-FLOW PRESSURE MEASUREMENTS (STUDIES I & IV)................................................................................ 15 MEASUREMENTS OF SNGFR (STUDIES I & IV) ................................................................................................ 16 ISOLATED BLOOD-PERFUSED JUXTAMEDULLARY NEPHRON PREPARATION (STUDY I) ....................................... 17 SAMPLING AND RENIN ASSAY (STUDY II).......................................................................................................... 17 RENAL BLOOD FLOW MEASUREMENTS (STUDY III) ........................................................................................... 18 MEASUREMENTS OF CYTOSOLIC CALCIUM CONCENTRATION (STUDY III) ......................................................... 18 DISSOLVING 7-NI (STUDIES I, II, III & IV)....................................................................................................... 18 STATISTICAL ANALYSES (STUDIES I, II, III & IV)............................................................................................. 19 EXPERIMENTAL PROTOCOL ............................................................................................................................... 19 Study I.......................................................................................................................................................... 19 Study II ........................................................................................................................................................ 20 Study III ....................................................................................................................................................... 20 Study IV ....................................................................................................................................................... 21 RESULTS AND COMMENTS.......................................................................................................................... 23 STUDY I............................................................................................................................................................. 23 STUDY II ........................................................................................................................................................... 24 STUDY III.......................................................................................................................................................... 25 STUDY IV.......................................................................................................................................................... 26 DISCUSSION ...................................................................................................................................................... 28 CONCLUSIONS ................................................................................................................................................. 36 SUMMARY IN SWEDISH/ SAMMANFATTNING PÅ SVENSKA............................................................. 37 ACKNOWLEDGEMENT.................................................................................................................................. 40 REFERENCES.................................................................................................................................................... 42 4 LIST OF ABBREVIATIONS ∆PSF Maximal TGF response 7-NI 7-Nitro indazole Ang II Angiotensin II Bw Body weight cGMP Cyclic guanosine monophosphate eNOS Endothelial nitric oxide synthase GFR Glomerular filtration rate HS High salt i.p. Intraperitoneal i.v. Intravenous IMCD Inner medullary collecting duct iNOS Inducible nitric oxide synthase JGA Juxtaglomerular apparatus L-Arg L-arginine L-NAME Nω-nitro-L-arginine methyle
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