European Journal of Clinical Investigation

The Journal of the European Society for Clinical Investigation

Editors-in-Chief R. Arnold, M. Brandis, M. Kern Editorial Board 0. L. M. Bijvoet, A. B. Boneu, G. B. Bolli, J. Brodehl, P. van Brummelen, U. Fölsch, E. Harms, R. D. Hesch, D. R. Higgs, K. Hierholzer, U. Keller, G. Klöppel, K. Kühn, S. Lamberts, H. Löffler, S. Matern, F. R. Matthias, K. H. Meyer z. Büschenfelde, S. Moncada, K. J. Netter, C. Nissen, G. Paumgartner, B. A. Peskar, L. B. A. van de Putte, M. J. Rennie, C. Reiger, E. O. Riecken, H. -D. Roher, H. H. Ropers, P. Schauder, G. Schernthaner, H. Scholz, K. Schrör, V. Schusdziarra, M. Sheppard, K. Sikora, M. V. Singer, E. Steiness, B. E. Strauer, K. Unsicker, G. Utermann, P. Verroust, P. v. Wiehert, R. Ziegler, R. Zinkernagel

Volume 18, 1988

Published for the European Society for Clinical Investigation by Blackwell Scientific Publications, Oxford London Edinburgh Boston Palo Alto Melbourne Published by Blackwell Scientific Publications Ltd, Osney Mead, Oxford OX2 OEL, U.K. © 1988 Blackwell Scientific Publications Ltd. Authorization of photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Blackwell Scientific Publications Ltd for libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that the base fee of $3-00 per copy is paid directly to CCC, 27 Congress Street, Salem, MA 01970, U.S.A. Special requests should be addressed to the Editor. 0014-2972/88 $3 00. The use of registered names, trade marks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulation and therefore free for general use. Printed in Great Britain at the Alden Press, Oxford. Contents of Volume 18

Number 1, February 1988 Platelet and vessel associated prostacyclin and Inhibition of secondary bile acid formation in thromboxane A2/ endoperoxide the by lactulose in healthy receptors subjects of two different age groups K. Jaschonek and C. P. Muller 1 F. M. Nagengast, M. P. C. Hectors, W. A. M. Buys and J. H. M. van Tongeren 56 Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization Skeletal muscle and whole body protein K. Scharffetter, B. Lankat-Buttgereit and turnover in disease T. Krieg 9 W. L. Morrison, J.N. A. Gibson, R. T. Jung and M. J. Rennie 62 Serum type III procollagen levels in coronary artery disease (a marker of Hyperiactataemia, hyperkalaemia and atherosclerosis) block in acute iron overload: the fatal role of J. Bonnet, P. E. Garderes, M. Aumailley, the hepatic iron-incorporation rate in rats on C. Moreau, G. Gouverneur, D. Benchimol, Terriq,citrate infusions R. Crockett, J. Larrue and H. Bricaud A. Rosenmund, B. Brand and P. Werner Straub 69 Determinants of kallikrein proteolysis of Urinary excretion of bile acids during acute - apolipoprotein B-100 in human blood plasma administration in man A. Gustaf son, J. P. Kane and R. J. Havel 75 G. Salvioli, R. Lugli, J. M. Pradelli, Anna Frignani and Velia Boccalletti 22 Role of the adrenal cortex in the natriuresis associated with infusion Effects of sodium valproate on haem P. J. T. Drew, J. P. Monson, J. M. P. Holly, biosynthesis in man: implications for seizure F. J. Goodwin and T. D. M. Williams 81 management in the porphyric patient G. M. McGuire, G.J. A. Macphee, Tamm Horsfall glycoprotein interferes with G. G. Thompson, M. R. Moore and bacterial adherence to human cells M. J. Brodie 29 /. Dulawa, K. Jann, M. Thomsen, M. Rambausek and E. Ritz 87 Effects of prolonged administration of two new a-glucosidase inhibitors on blood glucose Studies on calcium exchange in platelets in control, requirements and breath human diabetes hydrogen excretion in patients with insulin- C.-H. Bergh, A. Hjalmarson, G. Holm, dependent diabetes mellitus Eva Angwald and B. Jacobsson 92 G. Dimitriadis, E. Hatziagelaki, S. Ladas, Athena Linos, Ingrid Hillebrand and S. Raptis 33 Stimulation of pancreatic secretion in man by a protease inhibitor (camostate) Prevalence of hypercalcaemia in a health G. Adler, A. Müllenhoff, I. Koop, T. Bozkurt, survey: a 14-year follow-up study of serum B. Göke, C. Beglinger and R. Arnold 98 calcium values M. Palmer, S. Jakobsson, G. Äkerström and Number 2, April 1988 S. Ljunghall 39 Review: Molecular and clinical aspects of Red blood cell sodium and potassium fluxes in connective tissue psoriatic patients Th. Krieg, R. Hein, A. Hatamochi and A. Semplicini, M. G. Mozzato, E. Rigon, M. Aumailley 105 O. Parolin, B. Samä, S. Padovan, P. Degan, A. Peserico and A. C. Pessina 47 Effect of the stable prostacyclin analogue iloprost on water and electrolyte transfer of the Effect of calcium intake on serum levels of rat and colon in vivo 25-hydroxyvitamin D3 K. J. Goerg, R. Wanitschke, U. Becker and T. Berlin and I. Björkhem 52 K.-H. Meyer zum Büschenfelde 124 iii IV CONTENTS The effect of long-term fibre and starch intake Plasma BGP an indicator of spontaneous by man on faecal bile acid excretion bone loss and of the effect of oestrogen Y. Ghoos, P. Rutgeerts, G. Vantrappen, treatment in postmenopausal women M. Hiele and P. Schurmans 128 Julia S. Johansen, B. J. Riis, P. D. Delmas and C. Christiansen 191 Campylobacter pylori: prospective analysis of clinical and histological factors associated with Changes in the lectin-binding pattern of PNA- colonization of the upper gastrointestinal tract agglutinin and UEA| during the DMH- G. Borsch, G. Schmidt, M. Wegener, induced carcinogenesis in the normal appearing M. Sandmann, R. Adamek, F. Leverkus and colonic mucosa of the rat E. Reitemeyer 133 T. Balzer, F. Sandforth, S. Gutschmidt and E.-O. Riecken 196 Gastrointestinal permeability to polyethylene glycol: an evaluation of urinary recovery of an Disturbed relationship between urinary prostaglandin E2 excretion, plasma arginine oral load of polyethylene glycol as a parameter vasopressin and renal water excretion after oral of intestinal permeability in man water loading in early hepatic cirrhosis E. K. Philipsen, W. Batsberg and B, Jespersen, E. B. Pedersen, M. Madsen, A. B. Christensen 139 P. Christensen, H. Eiskjcer, P. P. Leyssac and Peptide in patients with acute S. S. Sorensen 202 leukaemia Low production of procollagen III by skin K.-H. Pflüger, H. Köppler, G. Jaques and fibroblasts from patients with Ehlers-Danlos K. Havemann 146 syndrome type IV is not caused by decreased levels of procollagen III mRNA Bile acid metabolism in heterozygous familial Monique Aumailley, E. Pöschl, G. R. Martin, hypercholesterolemia: a study comparing Y. Yamada and P. K Müller 207 affected and unaffected siblings of four kindreds Density and agonist-promoted high and low B. Angelin 153 affinity states of the jß-adrenoceptor on human B- and T-cells Decrease of plasma potassium due to M. Griese, V. Körholz, D. Körholz, K. Seeger, inhalation of beta-2-agonists: absence of an V. Wahn and D. Reinhardt 213 additional effect of intravenous theophylline M. Deenstra, J. R. E. Haalboom and A. Struyvenberg 162 Number 3, June 1988 Altered bile acid profiles in duodenal bile and Molecular genetics of coronary heart disease urine in diabetic subjects E. Andersen, G. Karlaganis and J. Sjövall 166 D. J. Gallon 219 Insulin stimulates the uptake of chylomicron is a physiological hormonal remnants in cultured rat hepatocytes mediator of fat-induced inhibition of gastric E. Jensen, C.-H. Floren and A. Nilsson 226 emptying in man Cytokine production in patients with newly /. H. Kleibeuker, H. Beekhuis, diagnosed insulin-dependent (type I) diabetes J. B. M. J. Jansen, D. A. Piers and mellitus C. B.H. W.Lamers 173 A. Luger, G. Schernthaner, Agatha Urbanski and T. A. Luger 233 Alternative routes for angiotensin-I conversion: kinetics of the -angiotensin system in Tamm Horsfall glycoprotein in diabetes mouse plasma mellitus: abnormal chemical composition and J. Jacobsen, K. Poulsen and A. Hunding 178 colloid stability M. Rambausek, J. Dulawa, K. Jann and E. Ritz 237 Human hepatocytes exhibit receptors for a2-macroglobulin and pregnancy zone protein- Measures of fat distribution as determinants of proteinase complexes serum lipids in healthy volunteers consuming a C. Munck Petersen, B. S. Christiansen, uniform standardized diet P. H. Jensen, S. K. Moestrup, J. Gliemann, C. Seidell, R. P. Mensink and L. Sottrup-Jensen and J. Ingerslev 184 Martijn B. Katan 243 CONTENTS Glycogen and lactate synthetic pathways in Skin microvascular circulation in the human skeletal muscle in relation to obesity, sympathetic dystrophies evaluated by weight reduction and physical training videophotometric capillaroscopy and laser K. Allenberg, Marianne Nilsson, Kerstin Landin Doppler fluxmetry and Folke Lindgär de 250 L. Rosen, J. Östergren, B. Fagrell and E. Stranden 305 Cholestyramine treatment of type Ha Role of alpha-adrenoceptor subytpes hypercholesterolemia normalizes platelet mediating sympathetic vasoconstriction in reactivity against prostacyclin human digits Petra Löbel, Elisabeth Steinhagen-Thiessen and /. D. Cojfman and R. A. Cohen 309 Karsten Schrör 256 Value of autopsy in internal medicine: Interindividual variability in biliary excretion a 1-year prospective study of hospital deaths of ceftriaxone: effects on biliary lipid M. Boers, A. C. Nieuwenhuyzen Kruseman, metabolism and on intestinal microflora F. Eulderink, J. Hermans and J. Thompson 314 Annie Arvidsson, Barbro Leijd, C. E. Nord and B. Angelin 261 Feedback regulation of stimulated pancreatic Number 4, August 1988 enzyme secretion during intraduodenal perfusion of trypsin in man Review: Clinical applications of heparin- J. Dlugosz, U. R. Fälsch, A. Czajkowski and binding growth factors R. R. Lobb 321 A. Gabryelewicz 267 Abnormal Na+-K+ ATPase kinetics in a Renal lithium handling during water loading subset of essential hypertensive patients and subsequent d-DAVP-induced anti-diuresis A. de la Sierra, A. Coca, M. T. Aguilera and W. H. Boer, H. A. Koomans and A. Urbano 337 E. J. Dorhout Mees 273 Alpha- and gamma-interferon (IFNa, IFNy) Lithium clearance during variations in sodium but not interleukin-1 (IL-1) modulate synthesis intake in man: effects of sodium restriction and and secretion of ^-microglobulin by amiloride hepatocytes W. H. Boer, H. A. Koomans, G. Ramadori, A. Mitsch, H. Rieder and E. J. Dorhout Mees, C. A. Gaillard and K.-H. Meyer zum Büschenfelde 343 A. J. Rahelink 279 Collagen type IV and procollagen type III during granulation tissue formation: a Enhanced secretion in the rat after serological, biochemical, immunohistochemical parathyroidectomy and during chronic calcium and morphometrical study on the viscose deprivation cellulose sponge rat model F. Raue, Ute Wieland, Christine Weiler and K Herslev-Petersen, L. R. Pedersen, R. Ziegler 284 K D. Bentsen, D. Brocks, C. Garbarsch, K Y. Kim, E. G. Hahn, D. Schuppan and Inhibition of human neutrophil migration by I. Lorenzen 352 supernatants from Hodgkin's disease-derived Action of analogue cell lines (SMS 201-995) on the growth-promoting effect E. Schell-Frederick, H. Radtke, H. Sommer, resulting from sustained achlorhydria in rat I. Helbing, H. Burrichter, M. Schaadt and gastric mucosa, with special reference to V. Diehl 290 endocrine cell behaviour G. Cadiot, Therese Lehy and S. Bonfils 360 Platelet serotonin content and plasma tryptophan in peri- and postmenopausal Effects of posture and saline infusion on atrial women: variations with plasma oestrogen and haemodynamics in levels and depressive symptoms patients with Bartter's syndrome and healthy P. Guicheney, D. Leger, J. Barrat, R. Trevoux, controls B. de Lignieres, P. Roques, J. P. Gamier, C. J. Doorenbos, M. R. Daha, F. R. Bühler and P. Boyer, J. Grenier, C. Dreux and P. Meyer 297 P. van Brummelen 369 vi CONTENTS Increased sensitivity to pressor hormones in central diabetes insipidus Number 5, October 1988 T. D. M. Williams, J. F. haycock, S. L. Light man and R. L. Guy 375 Obituary: Albert E. Renold 431 Granulocyte activation during haemodialysis in Review: The molecular and cellular pathology of the absence of complement activation: Chronic Granulomatous Disease inhibition by calcium channel blockers A. W. Segal 433 Marianne Haag- Weber, P. Schollmeyer and W. H. Horl Review: The gap junction: a channel for 380 multiple functions? R. Br uz zone and P. Me da 444 Occurrence of cholesterol monohydrate crystals in gallbladder and hepatic bile in man: Transcutaneous oxygen pressure measurements influence of bile acid treatment in type I diabetic patients for early detection S. Sahlin, J. Ahlberg, B. Angelin, S. Ewerth, of functional diabetic microangiopathy K. Nilsell, E. Reihner and K. Einarsson 386 H.-W. M. Breuer, J. Breuer andM. Berger 454 Intestinal development in the suckling rat: Characterization of a heparin-like activity effect of insulin on the maturation of villus and released in dogs during deep hypothermia crypt cell functions B. Cornillon, M. Mazzorana, G. Dureau and J.-P. Buts, Nadine de Keyser and C. Dive 391 J. Belleville 460 A monoclonal Ro-antibody and the serum of Intraplatelet serotonin in patients with diabetes a Ro-positive patient with subacute cutaneous mellitus and peripheral vascular disease lupus erythematosus (SCLE) react with basal M. A. Barradas, D. S. Gill, V. A. Fonseca, layers of human epidermis D. P. Mikhailidis and P. Dandona 399 W. J. Mayet, M. Bachmann, K. Pfeifer, H. C. Schröder, W. E. G. Müller,' The TSH, T4, T3 and responses to W. Gudat, G. W. Körting and consecutive infusions of a potent and stabilized K H. Meyer zum Büschenfelde 465 thyrotrophin releasing analogue, RX77368, in man Comparison of the effects of two different D. J. A. Eckland and S. L. Lightman 405 doses of alcohol on serum lipoproteins, HDL-subfractions and apolipoproteins A-I and A-II: a controlled study Decreased prostacyclin sensitivity of platelets M. Välimäki, Marja-Riitta Taskinen, in patients with Behcet's syndrome R. Ylikahri, R. Roine, T. Kuusi and A. P. Wilson, J. Efthimiou and D. J. Betteridge 410 E. A. Nikkilä 472

Platelet a2- and leucocyte /^-adrenoceptors in Effect of exercise on plasma atrial natriuretic phaeochromocytoma: effect of tumour removal factor and cardiac function in men and women P. Valet, C. Damase-Michel, B. Chamontin, J. E. Donckier, P. M. de Coster, D. Durand, F. Chollet and J. L. Montastruc 481 M. Buysschaert, P. Levecque, F. M. Cauwe, C. M. Brichant, A. C. Berbinschi and Monocytic production and plasma bioactivities J.-M. Ketelslegers 415 of interleukin-1 and tumour necrosis factor in human cancer Ethanol decreases plasma sulphydryls in man: L. L. Moldauer, C. Drott and K. Lundholm 486 effect of disulfiram Decreased insulin sensitivity and muscle J.-M. Burgunder, J. Nelles and enzyme activity in elderly subjects B. H. Lauterburg 420 Y. T. Kruszynska, G. Petranyi and K. G. M. M. Alberti 493 Role of atrial natriuretic factor, cyclic GMP and the renin- system in acute : a potential hormone from volume regulation of healthy human subjects the distal gut. Pharmacokinetics and effects on A. L. Gerbes, R. M. Arendt, R. Gerzer, gastric acid and insulin secretion in man W. Schnizer, D. Jüngst, G. Baumgartner and B. T. G. Schjoldager, E.G. A. Baldissera, H. Wernze 425 P. E. Mortensen, J. J. Hoist and J. Christiansen 499 CONTENTS vii The effect of ageing on human platelet Atrial natriuretic factor enhances vasopressin- sensitivity to serotonin induced bradycardia in normotensive (WKY) G. Gleerup and K. Winther 504 but not in spontaneously hypertensive (SHR) rats Methodological limitations of the use of M. Lapinski, K. Stepniakowski, A. Januszewicz, intrinsic hepatic clearance of ICG as a measure B. Noszczyk and Ewa Szczepanska-Sadowska 568 of cell function S. Keiding and C. Skak 507 Adipocyte binding and lipogenesis at term in normal pregnancy Asparaginase-induced derangements of O. Andersen and C. Kühl 575 glutamine metabolism: the pathogenic basis for some drug-related side-effects Polymorphism at the 5' end flanking region of G. Ollenschläger, E. Roth, W. Linkesch, the insulin gene is associated with reduced S. Jansen, A. Simmel and B. Madder 512 insulin secretion in healthy individuals S. Cocozza, G. Riccardi, Antonella Mont ice Hi, Effect of cholestyramine on plasma Brunella Capaldo, S. Genovese, V. Krogh, cholecystokinin and E. Celentano, E. Farinaro, S. Varrone and levels, and exocrine pancreatic secretion V. E. Avvedimento 582 /. Koop, A. Fellgiebel, H. Koop, A. Schafmayer and R.Arnold 517 a2-Antagonist compounds and lipid mobilization: evidence for a lipid mobilizing Binding sites for atrial natriuretic peptide on effect of oral yohimbine in healthy male platelets in patients with congestive volunteers cardiomyopathy J. Galitzky, M. Taouis, M. Berlan, D. Riviere, T. M. Strom, J. Weil, F. Braun, K Stangl, M. Garrigues and M. Lafontan 587 A. Timnik, J. M. Heim and R. Gerzer 524 Plasminogen activators and plasminogen Rates of bone loss in normal women: evidence activator inhibitor in malignant and non- of accelerated trabecular bone loss after the malignant ascitic fluid menopause K. Huber, J. Wojta, J. C. Kirchheimer, L. Nilas and C. Christiansen 529 D. Ermler and B. R. Binder 595 Ammonia and glutamine metabolism in human Positive inotropic effects in isolated ventricular liver slices: new aspects on the pathogenesis of myocardium from non-failing and terminally hyperammonaemia in chronic liver disease failing human S. Kaiser, W. Gerok and D. Häussinger 535 M. Näbauer, M. Böhm, L. Brown, F. Diet, M. Eichhorn, B. Kemkes, B. Pieske and Synthesis and secretion of a2-macroglobulin by E. Erdmann 600 human hepatocytes in culture C. Munck Petersen, B. S. Christiansen, Insulin resistance in Graves' disease: L. Heickendorff and J. Ingers lev 543 a quantitative in-vivo evaluation: P. Cavallo-Perin, A. Bruno, Laura Boine, M. Cassader, G. Lenti and G. Pagano 607 Number 6, December 1988 Retention of haematoporphyrin in the aorta Review: Prostaglandin E) and arterial occlusive of hypertensive rats: disease: pharmacological considerations in-vivo and in-vitro studies Th. Simmet and B. A. Peskar 549 G. Scannapieco, P. Pauletto, A. Pagnan, A. Mattiello, G. Jori and C. Dal Palu 614 Copper distribution among serum proteins in paediatric liver disorders and malignancies Serum amyloid A and high density lipoproteins L. Barrow and M. S. Tanner 555 during the acute phase response Linda L. Bausserman, D. N. Bernier, Low dose heparin versus low molecular weight K. P. W. J. McAdam and P. N. Herbert 619 heparin (Kabi 2165, Fragmin®) in the prophylaxis of thromboembolic complications Arginine vasopressin dissociates the diuresis of abdominal oncological surgery and natriuresis due to atrial natriuretic factor J.-P. Fricker, Y. Vergnes, R. Schach, A. Heitz, in man M. Eber, L. Grunebaum, M.-L. Wiesel, /. Mc Murr ay, Mary L. Forsting and A. Kher, P. Barbier and J.-P. Cazenave 561 A.D. Struthers 627 viii CONTENTS Differences between premenopausal women Skeletal muscle and whole body protein and young men in the transamination pathway turnover in cardiac cachexia: influence of of catabolism, and the protection branched-chain amino acid administration against vascular disease W. L. Morrison, J. N. A. Gibson and H. J. Blom, G. H. J. Boers, M. J. Rennie 648 J. P. A. M. van den Ehen, J. J. M. van Roessel, J. M. F. Trijbels and A. Tangerman 633 Characterization of stereomicroscopically Relationships between plasma isotope identified preneoplastic lesions during enrichments of leucine and a-ketoisocaproic dimethylhydrazine-induced colonic acid during continuous infusion of labelled carcinogenesis: leucine F. Sandforth, S. Heimpel, T. Balzer, G. N. Thompson, P. J. Pacy, G. C Ford, S. Gutschmidt and E. O. Riechen 655 H. Merritt and D. Halliday 639 Differences in individual responsiveness of serum cholesterol to fat-modified diets in man Author index 663 M. B. Katan, A. C. van Gastel, C. M. de Rover, M. A. J. van Montfort and J. T. Knuiman 644 Keyword index 665 European Journal of Clinical Investigation (1988) 18, 425-429

Role of atrial natriuretic factor, cyclic GMP and the renin-aldosterone system in acute volume regulation of healthy human subjects A. L. GERBES, R. M. ARENDT*, R. GERZERJ, W. SCHNIZERf, D. JÜNGST, G. PAUMGARTNER & H. WERNZE§, Medizinische Klinik II and *I and flnstitut für Medizinische Balneologie, Klinikum Großhadern, J Medizinische Klinik Innenstadt, University of Munich, and §Medizinische Universitätsklinik, University of Würzburg, FRG

Received 21 October 1987 and in revised form 11 March 1988

Abstract. The role of the atrial natriuretic factor renal sodium and water handling [1]. However, the (ANF), its second messenger cyclic guanosine mono• hormonal mediators by which the heart modifies renal phosphate (cGMP), and the counteracting renin- function have not been satisfactorily defined. With the aldosterone system in acute volume regulation was discovery of the atrial natriuretic factor (ANF), a new investigated in 25 healthy human subjects. Central agent in the concert of volume regulating systems has volume stimulation by 1-h head-out water immersion to be considered in health and disease states [2, 3]. The (WI) into a thermoneutral water-bath increased peptide is stored in granules of atrial myocytes and plasma levels of ANF (mean + SEM) from 6-0 ± 0-6 to released upon atrial distension [4, 5]. There is evidence 13-6 + 2*6 fmol ml-1. This was paralleled by a riseo f for a physiological role of ANF [6], which counteracts plasma cGMP levels from 1-9 + 0-2 to 2-8 + 0-4 pmol sodium-retaining principles, such as the renin-aldo• ml 1, and an increase of urinary cGMP excretion from sterone system [7]. 340 + 64 to 692+ 103 pmol min-1. Water immersion Head-out water immersion (WI) increases central reduced plasma aldosterone concentration (PAC) venous and atrial volume by shifting blood from from 130+1-7 to 6-5 + 0-8 ng 100 ml"1 and plasma peripheral vessels to the intrathoracic venous bed— renin activity (PRA) from 5-3 + 0-9 to 2-4 + 0-3 ng AI thus obviating the necessity of infusing volume ml" 1 h_l. Volume stimulation markedly increased expanders that might alter plasma composition [8]. In diuresis and natriuresis. Whereas the plasma cGMP a preliminary study we had been able to demonstrate increase correlated with plasma ANF stimulation, that WI stimulates ANF release in man [9] and thus neither ANF nor PR A or PAC correlated with basal or seems to be a useful tool to study the physiological role stimulated renal parameters. Water immersion- of ANF in acute volume regulation. Several observa• induced changes in natriuresis and urinary cGMP tions support the contention that cellular actions of excretion were correlated. These data suggest a role of ANF are mediated by cyclic guanosine monophos• ANF and cGMP in acute volume regulation of healthy phate (cGMP) [10]. Administration of pharmacologi• human subjects. cal doses of ANF [11], as well as volume stimulation in the animal [12], have been shown to increase plasma Keywords. Atrial natriuretic factor, volume regulation, concentration and urinary excretion of cGMP. In the water immersion, cyclic GMP, renin-aldosterone sys• present study, the effects of an endogenous ANF tem. release by volume stimulation on cGMP were exam• ined. The aim of the present study was to investigate the Introduction role of ANF and cGMP, as well as its interaction with The atria have long been attributed an essential role in the renin-aldosterone system, in the renal response to the regulation of extracellular volume by influencing acute volume stimulation by water immersion.

Abbreviations: ANF, atrial natriuretic factor; cGMP, cyclic guanosine monophosphate; PRA, ; PAC, Patients and methods plasma aldosterone concentration; cGMPV, urinaiy excretion of Twenty-five subjects, 16 men and nine women, aged cGMP; UV, urinary flow rate; UNaV, urinary sodium excretion; UKV, urinary potassium excretion; CCr, creatinine clearance; WI, 19-65 years, were investigated after their informed head-out water immersion. consent had been obtained. The protocol was Correspondence: Dr Alexander L. Gerbes, MD, Medizinische approved by the Ethical Committee of the Faculty of Klinik II, Klinikum Großhadern, University of Munich, Marchioni- Medicine, University of Munich. The subjects showed nistr.15, D-8000 Munich 70, FRG. no evidence of cardiovascular, renal, pulmonary, 425 426 A. L. GERBES et ai endocrine or urinary tract diseases. They took no analysed for cGMP by radioimmunoassay according medications, were on a regular diet, containing to a method described previously [11]. approximately 150 meq sodium day-1, and were Clearance of creatinine (CCr) was calculated by the prohibited alcohol, tobacco, tea and coffee the day standard formula. before and during the experiment. In the morning after Data are given as means and standard error of the complete emptying of the bladder, an intravenous mean. Following a Kolmogorov-Smirnoff test for cathether was placed into a forearm vein, subjects were random distribution, statistical evaluation was done given 400 ml of water orally and they assumed a seated by Wilcoxon's test or by Student's paired /-tests; a position next to the immersion tank. After 1 h, the probability value of P = 005 or less was considered subjects were immersed to their neck, maintaining the significant. The Pearson correlation coefficient was same seated position, into thermoneutral water determined by the usual linear least-squares method. (34-5±0-2°C) for 1 h. This was followed by a 1-h period of sitting outside the tank. Throughout the investigation, 200 ml water h_1 were given orally to Results ensure adequate urine flow. All the urine voided by spontaneous emptying of the bladder, as well as ANF and cGMP plasma samples, were collected before (baseline), after As shown in Fig. 1, WI significantly increased ANF 1 h WI (immersion) and 1 h subsequent to the end of plasma concentrations from 6-0±0-6 to 13-6±2-6 WI (recovery). fmol ml ~1. Atrial natriuretic factor increased in all but Urine was analysed for sodium and potassium three subjects; mean stimulation was by 117 + 29%. In (flame photometry) and creatinine (Jaffe reaction). the recovery period, ANF decreased to baseline levels. Plasma renin activity (PRA) was measured by The stimulation of ANF was paralleled by an increase radioimmunoassay after 1-h incubation at 37°C, pH of plasma cGMP concentration from 1-9 + 0-2 to 5-9, as described previously [13]. Plasma aldosterone 2-8 + 0-4 pmol ml-1, returning to 2-0 + 0-2 pmol ml-1 concentration (PAC) was determined by use of a in the recovery period. Likewise, urinary cGMP commercial solid-phase radioimmunoassay (Diagnos• excretion rose from 340 + 64 (baseline value) to tic products, U.S.A.). Atrial natriuretic factor was measured in XAD-extracted plasma samples by radioimmunoassay, as described earlier [14]. Briefly, the antibody is mid-molecule- and C-terminal-dir- ected. Cross-reactivity was 70% to rat ANF 99-126, 900 -~ 13% to atriopeptin III, 003% to atriopeptins I or II. It did not cross-react with a wide variety of and proteins, including its immunization conjugate (bovine 600 thyreoglobulin). The final titre was 1:120 000 and the assay sensitivity was 0-5 fmol per assay tube. The 50%- binding intercept of the standard curve was 10 fmol. 300 One-millilitre plasma aliquots were extracted by CL adsorption to pre-rinsed Amberlite XAD-2 adsorbent o resin (particle size 0-3-1-0 mm, Serva, Heidelberg, FRG). Recovery of synthetic human ANF 99-126 was Boso Immersion Recovery approximately 67%. Intra-assay variation was < 10% Figure 1. Plasma concentrations of atrial natriuretic factor (^: ANF) cyclic guanosine monophosphate (•: cGMP) and renal (« = 8), inter-assay variation was < 15% (« = 6). In 18 excretion of cGMP (•) before, during and subsequent to head-out subjects baseline, immersion and recovery plasma water immersion of 25 healthy human subjects. *P<005, samples, and in 15 subjects urine samples, were **P<0-01, significantly different from baseline level.

Table 1. Renal response to acute volume stimulation by water immersion in 25 healthy human subjects

Baseline Immersion Recovery Urinary volume (ml min~') 1-4 + 0-2 5-0 + 0-6*** 2-8 + 0-4* Urinary sodium excretion 0 16 + 002 0-30 + 0-03*** 0 18 + 003 (mmol min~') Urinary potassium excretion 007 + 001 014 + 002*** 007 + 001 (mmol min -') Creatinine clearance (ml min-') 153±26 200 + 32 117±15

* P<005, ***/>< 0-001, significantly different from baseline level. ANF IN VOLUME REGULATION OF HEALTHY HUMANS 427

3 n

4-0-

3-0- " '.I

2-0-

1-0-

—i 1 r- 0-6 K) N4 M3 ?2 ?6 JÖ 2 4 6 cGMP excretion immersion / bosel ine ANF immersion / baseline Figure 2. Correlation of immersion-induced stimulation of ANF Figure 4. Correlation of immersion-induced stimulation of natriure• plasma concentrations with plasma concentrations of cGMP sis (UNaV) with urinary cGMP excretion (immersion/baseline (immersion/baseline ratios); r=0-68, P<0002. ratios); r = 0-61, P<002.

692 + 103 pmol min"', and then returned to 437 + 79 pmol min-1. 6-5 + 0-8 ng 100 ml" \ with recovery values of 8-1 ± 1 -4 While neither basal nor stimulated values of ANF ng 100 ml-1. Basal PAC and PRA values were and cGMP correlated significantly, changes of cGMP significantly correlated (r = 0-56, P<0*01) as were the were closely correlated with changes of ANF (r = 0-68, WI-induced changes of both hormones (r = 0-65, P< 0-002; Fig. 2). />< 0-002).

Renin-aldosterone Renal response The effects of WI on plasma renin activity and plasma Table 1 displays the effects of WI on renal excretion. aldosterone concentration are shown in Fig. 3. Plasma All but five subjects responded to WI with an increase renin activity decreased from 5-3 + 0-9 (baseline) to in sodium excretion. Mean values of sodium excretion 2-4 + 0*3 ng ml-1 h"1, returning to 3-7 + 0-5 ng ml"1 were increased two-fold during immersion. Highly h_l. Similarly, PAC was suppressed from 13-0+ 1-7 to significant enhancements by volume stimulation were also observed for urinary flow rate and for potassium excretion. Increases of creatinine clearance (P>0T) did not reach the level of significance. Relationship of ANF to renin-aldosterone and renal 12 6 _ response Water immersion induced stimulation of ANF as well as suppression of PRA and PAC. However, no I relationship between these hormonal changes could be e 8 found. Tendencies for negative correlations between o 1 basal (r=— 0-37) as well as stimulated (r=— 0-30) values of ANF and corresponding values of PAC did o not reach significance (P>0T). 2 2 Neither basal nor stimulated natriuresis or diuresis correlated with ANF, PRA or PAC values. Changes of a. urinary cGMP excretion correlated with the increase of natriuresis (r = 0-61, P<0-02) (Fig. 4). Boso I Immersion RecoverIy Figure 3. Plasma aldosterone concentration (•: PAC) and plasma Discussion renin activity (^: PRA) before, during and subsequent to immer• sion. **/><001, ***/><0-001, significantly different from baseline The present study demonstrates that acute central level. volume stimulation by water immersion induces a 428 A. L. GERBES et ai highly significant increase of ANF plasma levels in mean increase of ANF plasma levels in non-res• healthy human subjects. However, large variations of ponders was only 4-6 ± 2-0 fmol ml" \ compared with a response were observed, with three of 25 subjects 8-4 + 2-8 fmol ml -1 increase in the responding subjects. exhibiting no stimulation of plasma ANF, despite a In three of the non-responders, urinary cGMP excre• suppression of PRA as an indicator of central volume tion was determined. As opposed to a mean increase of stimulation. In these subjects mean urinary sodium cGMPV by 91%, non-responders showed no stimula• excretion increased less than in the subjects with ANF tion of cGMPV. Furthermore, changes of cGMPV increase (002 vs. 016mmol min-1), possibly suggest• varied significantly with changes of natriuresis by ing a physiological importance of ANF in WI-induced immersion. This may support the hypothesis that natriuresis. urinary GMP, and more so its changes, reflect renal Cyclic GMP is being considered a second messenger action of ANF [21,22]. of cellular ANF action [10]. In this study we investi• Immersion induced an increase of potassium excre• gated cGMP upon endogenous ANF release by tion. This phenomenon has been attributed to an volume stimulation. Basal plasma levels of cGMP were increased distal delivery of filtrate and to an increase of not correlated with basal ANF levels. This finding is in urine flow by WI [23]. A kaliuretic effect of ANF, accordance with unpublished observations in other observed after high dose bolus injection in rats [24], subjects (R. Gerzer et a/.), and might be due to might possibly have contributed to the increase of stimulation of guanylate cyclase by substances other renal potassium excretion. However, several reports than ANF [15-17]. However, as ANF is the only indicate that ANF administration in normal man does hormonal stimulator of particulate guanylate cyclase not significantly affect kaliuresis [20, 25]. In our study, described so far [10], corresponding changes of cGMP potassium excretion was not significantly correlated with ANF stimulation might be expected. Indeed, with ANF plasma levels. The aforementioned studies immersion-induced changes of plasma cGMP levels in man, as well as this observation, do not support the were closely correlated with changes of plasma ANF notion of an ANF effect on kaliuresis. Furthermore, levels. These findings demonstrate that in man endo• diuresis 1 h after the end of WI was significantly higher genous stimulation of ANF in the physiological range than before WI, while ANF concentrations had is accompanied by increases of plasma cGMP, and returned to basal levels. Thus, a role of other mediators support the contention that cGMP acts as a second of volume regulation, apart from ANF, must be messenger of ANF. recognized. Water immersion prompted significant decreases of From the present data it can be concluded that ANF PRA and PAC in all but two subjects. These two is released upon acute volume stimulation in healthy persons, however, exhibited stimulated ANF plasma subjects, inducing increases of both plasma cGMP levels as well as natriuresis and diuresis, indicating that levels and urinary cGMP excretion. suppression of the renin-aldosterone system cannot Whereas immersion suppresses the sodium-retain• fully account for the renal response to WI. Basal ing renin-aldosterone system, together with the stimu• plasma levels of PRA and PAC, as well as changes by lation of ANF, no correlation of any of these hor• volume stimulation, were found to correlate signifi• mones with the renal response was observed. Thus, cantly. Administration of ANF in pharmacological volume regulation may be influenced by complex doses can reduce renin and aldosterone secretion [18, interaction of the ANF system with other humoral 19] and decrease their plasma levels [20]. Therefore, in factors, such as the renin-aldosterone system. Investi• view of WI-induced changes of ANF reciprocal to gation of these hormonal interactions in disease states changes of PRA and PAC, the significance of correla• with impairment of volume regulation might shed tion of these hormonal changes by WI was investi• further light on the pathophysiological importance of gated. However, only trends for negative correlation of ANF. basal as well as stimulated values of ANF with the corresponding PAC values were observed. Therefore these data do not provide strong evidence that a Acknowledgments physiological increase of ANF suppresses PRA or Prof. Dr Neumeier, Department of Clinical PAC, although this possibility cannot be excluded. Chemistry, Klinikum Großhadern (head: Prof. Dr Water immersion caused a significant increase of Knedel), is thanked for determinations of sodium, natriuresis and diuresis, consistent with the renal potassium and creatinine. M. Bauch, V. Gülberg and response observed by others in this standard model of A. Riedel are thanked for technical assistance. volume stimulation [21]. However, in five of the 25 Parts of this study were presented at the Second subjects, at comparable basal sodium excretion, no World Congress on Biologically Active Atrial Pep• increase of natriuresis was induced. Thus, variations of tides, New York, 1987. basal natriuresis, possibly reflecting differences in dietary sodium intake, do not seem to have a major influence on the WI-induced renal response. Observa• References tions in these five non-responders suggested a role for 1 Gauer OH, Henry JP. Circulatory basis of fluid volume control. the ANF system in mediating the renal reaction to WI: Physiol Rev 1963;43:423-81. ANF IN VOLUME REGULATION OF HEALTHY HUMANS 429

2 Arendt RM, Gerbes AL. Atrialer natriuretischer Faktor. Die 14 Arendt RM, Gerbes AL, Ritter D, Stangl E. Molecular weight endokrine Funktion des Herzens. Dtsch med Wochenschr heterogeneity of plasma-ANF in cardiovascular disease. Klin 1986;111:1849-57. Wochenschr 1986;64 (suppl VI):97-102. 3 Gerbes AL, Arendt RM, Paumgartner G. Editorial review. 15 Murad F. Clinical studies and applications of cyclic nucleotides. Atrial natriuretic factor—possible implications in liver disease. J Adv Cyclic Nucleotide Protein Phosphorylation Res Hepatology 1987;5:123-32. 1973;3:355-83. 4 Forssmann WG. Cardiac hormones. Review on the morphology, 16 Reiser G, Walter U, Hamprecht B. regulates the level biochemistry and molecular biology of the endocrine heart. Eur J of cyclic GMP in neural cell lines. Brain Res 1984;290:367-71. Clin Invest 1986;16:439-51. 17 Kurtz A. Adenosine stimulated guanylate cyclase activity in 5 Lang RE, Thölken H, Ganten D, Luft FC, Ruskoaho H, Unger vascular smooth muscle cells. J Biol Chem 1987;262:6296-300. T. Atrial natriuretic factor: a circulating hormone stimulated by 18 Chartier L, Schiffrin E, Thibault G, Garcia R. Atrial natriuretic volume loading. Nature 1985;314:264-5. factor inhibits the stimulation of aldosterone secretion by 6 Naruse M, Obana K, Naruse K et al. Antisera to atrial angiotensin II, ACTH and potassium in vitro and angiotensin II- natriuretic factor reduces urinary sodium excretion and increases induced steroidogenesis in vivo. Endocrinology 1984;! 15:2026- plasma renin activity in rats. Biochem Biophys Res Commun 8. 1985;132:954-60. 19 Goodfriend TL, Elliott ME, Atlas SA. Actions of synthetic atrial 7 Laragh JH. Atrial natriuretic hormone, the renin-aldosterone natriuretic factor on bovine adrenal zona glomerulosa. Life Sei axis, and blood pressure-electrolyte homeostasis. N Engl J Med 1984;35:1675-82. 1985;313:1339-40. 20 Cuneo RC, Espiner EA, Nicholls MG, Yandle TG, Joyce SL, 8 Epstein M. Renal effects of head-out water immersion in man: Gilchrist NI. Renal, hemodynamic and hormonal responses to implications for an understanding of volume homeostasis. atrial natriuretic peptide infusions in normal man, and effect of Physiol Rev 1978;58:529-81. sodium intake. J Clin Endocrinol Metab 1986;63:946-53. 9 Gerbes AL, Arendt RM, Schnizer W et al. Regulation of atrial 21 Epstein M, Loutzenhiser R, Friedland E, Aceto RM, Camargo natriuretic factor release in man: effect of water immersion. Klin MIF, Atlas SA. Relationship of increased plasma atrial natriu• Wochenschr 1986;64:666-7. retic factor and renal sodium handling during immersion- 10 Gerzer R, Weil J, Strom T, Müller T. Mechanisms of action of induced central hypervolemia in normal humans. J Clin Invest atrial natriuretic factor. Clinical consequences. Klin 1987;79:738-45. Wochenschr 1986;64 (suppl VI):21-6. 22 Huang CL, Ives HE, Cogan MG. In vivo evidence that cGMP is 11 Gerzer R, Witzgall H, Tremblay J, Gutkowska J, Hamet P. the second messenger for atrial natriuretic factor. Proc Natl Rapid increase in plasma and urine cGMP after bolus injection Acad Sei USA 1986;83:8015-8. of atrial natriuretic factor in man. J Clin Endocrinol Metab 23 Wright FS. Sites and mechanisms of potassium transport along 1985;61:1217-9. the renal tubule. Kidney Int 1977; 11:415-32. 12 Stasch JP, Hirth C, Kazda S, Wohlfeil S. The elevation of cyclic 24 Shimizu T, Nakamura M. Renal effect of atrial natriuretic GMP as a response to acute hypervolemia is blocked by a polypeptide: comparison with standard saluretics. Eur J Phar• monoclonal antibody directed against atrial natriuretic peptides. macol 1986;127:249-59. Eur J Pharmacol 1986;129:165-8. 25 Weidmann P, Hasler L, Gnädiger MP et al. Blood levels and 13 Wernze H, Speck HJ, Müller G. Studies on the activity of the renal effects of atrial natriuretic peptide in normal man. J Clin renin-angiotensin-aldosterone system in patients with cirrhosis Invest 1986;77:734-42. of the liver. Klin Wochenschr 1978;56:389 97. Author Index

Adamek, R. 133 Burrichter, H. 290 Ford, G.C. 639 Jakobsson, S. 39 Adler, G. 98 Buts, J.-P. 391 Forsling, Mary L. 627 Jann, K. 87, 237 Aguilera, M.T. 337 Buys, W.A.M. 56 Fricker, J.-P. 561 Jansen, J.B.M.J. 173 Ahlberg, J. 386 Buysschaert, M. 415 Frignani, A. 22 Jansen, S. 512 Äkerström, G. 39 Gabryelewicz, A. 267 Januszewicz, A. 568 Alberti. K.G.M.M. 493 Cadiot, G. 360 Gaillard, CA. 279 Jaques, G. 146 Allenberg, K. 250 Capaldo, Brunella, 582 Galitzky, J. 587 Jaschonek, K. 1 Andersen, E. 166 Cassader, M. 607 Galton, D.J. 219 Jensen, E. 226 Andersen, O. 575 Cauwe, F.M. 415 Garbarsch, C. 352 Jensen, P.H. 184 Angelin, B. 153, 261, 386 Cavallo-Perrin, P. 607 Garderes, P.E. 18 Jespersen, B. 202 Angwald, E. 92 Cazenave, J.-P. 561 Gamier, J.P. 297 Johansen, J.S. 191 Arendt. R.M. 425 Celentano, E. 582 Garrigues, M. 587 Jori, G. 614 Arnold, R. 98, 517 Chamontin, B. 481 van Gastel, A.C. 644 Jung, R.T. 62 Arvidsson, A. 261 Chollet, F. 481 Genovese, S. 582 Jüngst, D. 425 Aumailley, M. 18, 105, 207 Christensen, A.B. 139 Gerbes, A.L. 425 Avvedimento, V.E. 582 Christiansen, B.S. 184, 543 Gerok, W. 535 Kaiser, S. 535 Christiansen, C. 191, 529 Gerzer, R. 425, 524 Kane, J.P. 75 Bachmann. M. 465 Christiansen, J. 499 Ghoos, Y. 128 Karlaganis, G. 166 Baldissera, F.G.A. 499 Christensen, P. 202 Gibson, J.N.A. 62, 648 Katan, MB. 243, 644 Balzer, T. 196, 655 Coca, A. 337 Gill, D.S. 399 Keiding, S. 507 Barbier, P. 561 Cocozza, S. 582 Gleerup, G. 504 Kemkes, B. 600 Barradas. MA. 399 CofTman, J.D. 309 Gliemann, J. 184 Ketelslegers, J.-M. 415 Barrat, J. 297 Cohen, R.A. 309 Goerg, K.J. 124 de Keyser, N. 391 Barrow, L. 555 Cornillon, B. 460 Göke, B. 98 Kher, A. 561 Balsberg, W. 139 de Coster, P.M. 415 Goodwin, F.J. 81 Kim, K.Y. 352 Bausserman, Linda L. 619 Crockett, R. 18 Gouverneur, G. 18 Kirchheimer, J.C 595 Becker, U. 124 Czajkowski, A. 267 Grenier, J. 297 Kleibeuker, J.H. 173 Bee.khuis, H. 173 Griese. M. 213 Knuiman, J.T. 644 Beglinger, C, 98 Daha, M.R. 369 Grunebaum, L. 561 Koomans, H.A. 273, 279 Belleville, J. 460 Dal Palu, C. 614 Gudat, W. 465 Koop, H. 517 Benchimol, D. 18 Damase-Michel, C. 481 Guicheney, P. 297 Koop, I. 98. 517 Bernsen, K.D. 352 Dandona, P. 399 Gustafson, A. 75 Köppler, H. 146 Berbinschi, A.C. 415 Deenstra, M. 162 Gutschmidt, S. 196, 655 Körholz, U. 213 Berger, M. 454 Degan, P. 47 Guy, R.L. 375 Körting, G.W. 465 Bergh, C-H.92 Delmas, P.D. 191 Krieg, T. 9 Berl.an, M. 587 DichI, V. 290 Haag-Weber, M. 380 Krieg, Th. 105 Berlin, T. 52 Diet, F. 600 Haalboom, J.R.E. 162 Krogh, V. 582 Bernier, D.N. 619 Dimitriadis, G. 33 Hahn, E.G. 352 Kruszynska, Y.T. 493 Bctteridge, D.J. 410 Dive, C. 391 Halliday, D. 639 Kühl, C 575 Bilzter, M. 420 Dlugosz, J. 267 Hatamochi, A. 105 Kuusi, T. 472 Binder, BR. 595 Donckier, J.E. 415 Häussinger, D. 535 Björkhem, I. 52 Doorenbos, C.J. 369 Hatziagelaki, E. 33 Ladas, S. 33 Blom, H.J. 633 Dorhout Mees, E.J. 273, 279 Havel, R.J. 75 Lafontan, M. 587 Boccalletti, V. 22 Dreux, C. 297 Havemann, K. 146 Lamers, CB.H.W. 173 Boer, W.H. 273, 279 Drew, P.J.T. 81 Hectors, M.P.C. 56 Landin, K. 250 Boers, G.H.J. 633 Drott, C. 486 HeickendorfT, L. 543 Lankat-Buttgereit, B. 9 Boers, M. 314 Dulawa, J. 87, 237 Heim, J.M. 524 Lapihski, M. 568 Böhm, M. 600 Durand, D. 481 Heimpel, S. 655 Larrue, J. 18 Boime, Laura, 607 Dureau, G. 460 Hein, R. 105 Lauterburg, B.H. 420 Bontals, S. 360 Heitz, A. 561 Laycock,J.F. 375 Bonnet, J. 18 Eber, M. 561 Helbing, I. 290 Leger, D. 297 Börs.ch, G. 133 Eckland, D.J.A. 405 Herbert, P.N. 619 Lehy, T. 360 Boyer, P. 297 Efthimiou, J. 410 Hermans, J. 314 Leijd, B. 261 Bozkurt, T. 98 Eichhorn, M. 600 Hiele, M. 128 Lenti, G. 607 Bramd, B. 69 Einarsson, K. 386 Hillebrand, I. 33 Levecque, P. 415 Braun, F. 524 Eiskjasr, H. 202 Hjalmarson, Ä. 92 Leverkus, F. 133 Brown, L. 600 van den Elzen, J.P.A.M. 633 Holly, J.M.P. 81 Leyssac, P.P. 202 Brewer, H.-W.M. 454 Erdmann, E. 600 Holm, G. 92 Lightman, S.L. 375, 405 Breuier, J. 454 Ermler, D. 595 Holst, J.J. 499 de Lignieres, B. 297 Bricaud, H. 18 Eulderink, F. 314 Hörl, W.H. 380 Lindgärde, F. 250 Brichant, CM. 415 Ewerth, S. 386 Herslev-Petersen, K. 352 Linkesch, W. 512 Brociks, D. 352 Huber, K. 595 Linos, A. 33 Brodie, M.J. 29 Fagrell, B. 305 Hunding, A. 178 Ljunghall, S. 39 van Brummelen, P. 369 Farinaro, E. 582 Lobb, RR. 321 Brun o, A. 607 Fellgiebel, A. 517 Ingerslev, J. 184, 543 Löbel, P. 256 Bruzzone, R. 444 Floren, C.-H. 226 Lorenzen, I. 352 Bühler, FR. 369 Fölsen, U.R. 267 Jacobsen, J. 178 Luger, A. 233 Burgunder, J.-M. 420 Fonseca, V.A. 399 Jacobsson, B. 92 Luger, T.A. 233 664 AUTHOR INDEX Lugli, R. 22 Nilsson, Ä. 226 Riis, B.J. 191 Stepniakowski, K. 568 Lundholm, K. 486 Nilsson, M. 250 Ritz, E. 87, 237 Stranden, E. 305 Nord, C.E. 261 Riviere, D. 587 Strom, T.M. 524 Macphee, G.J.A. 29 Noszczyk, B. 568 van Roessei, J.J.M. 633 Struthers, A.D. 627 Madsen, M. 202 Roine, R. 472 Struyvenberg, A. 162 Martin, GR. 207 Ollenschläger, G. 512 Roques, P. 297 Szczepanska-Sadowska, Ewa, 568 Mattiello, A. 614 Ostergren, J. 305 Rosen, L. 305 Mayet, W.J. 465 Pacy, P.J. 639 Rosenmund, A. 69 Tangerman, A. 633 Mazzorana, M. 460 Padovan, S. 47 Roth, E. 512 Tanner, M.S. 555 McAdam, K.P.W.J. 619 Pagano, G. 607 de Rover, CM. 644 Taouis, M. 587 McGuire, G.M. 29 Pagnan,A. 614 Rutgeerts, P. 128 Taskinen, Marja-Riita, 472 McMurray, J. 627 Palmer, M. 39 Thompson, G.G. 29 Meda, P. 444 Parolin, O. 47 Sahlin, S. 386 Thompson, G.N. 639 Mensink, R.P. 243 Pauletto, P. 614 Salvioli, G. 22 Thompson, J. 314 Merritt, H. 639 Paumgartner, G. 425 Samä, B. 47 Thomsen, M. 87 Meyer, P. 297 Pedersen, E.B. 202 Sandforth, F. 196, 655 Timnik, A. 524 Meyer zum Büschenfelde, K.-H. Pedersen, L.R. 352 Sandmann, M. 133 van Tongeren, J.H.M. 56 124, 343, 465 Peserico, A. 47 Scannapieco, G. 614 Trijbels, J.M.F. 633 Mikhailidis, D.P. 399 Peskar, B.A. 549 Schaadt, M. 290 Trevoux, R. 297 Mitsch, A. 343 Pessina, A.C. 47 Schach, R. 561 Urbano, A. 337 Mödder, B. 512 Pelranyi, G. 493 Schafmayer, A. 517 Urbanski, A. 233 Moestrup, S.K. 184 Pfeifer, K. 465 ScharfTetter, K. 9 Moldawer, L.L. 486 Pflüger, K.-H. 146 Schell-Frederick, E. 290 Valet, P. 481 Monson, J.P. 81 Philipsen, E.K. 139 Schernthaner, G. 233 Välimäki, M. 472 Montastruc, J.L. 481 Piers, D.A. 173 Schjoldager, B.T.G. 499 Vantrappen, G. 128 van Montfort, M.A.J. 644 Pieske, B. 600 Schmidt, G. 133 Varrone, S. 582 Monticelli, Antonella, 582 Pöschl, E. 207 Schnizer, W. 425 Vergnes, Y. 561 Moore, M.R. 29 Poulsen, K. 178 Schollmeyer, P. 380 Moreau, C. 18 Pradelli, J.M. 22 Schröder, H.C 465 Wahn, V. 213 Morrison, W.L. 62, 648 Schrör, K. 256 Wanitschike, R. 124 Mortensen, P.E. 499 Rabelink, A.J. 279 Schuppan,D. 352 Wegener, M. 133 Mozzato, M.G. 47 Radtke, H. 290 Schurmans, P. 128 Weil, J. 524 Müllenhoff, A. 98 Ramadori, G. 343 Seeger, K. 213 Weiler, C 284 Müller, CP. 1 Rambausek, M. 87, 237 Segal, A.W. 433 Werner Straub, P. 69 Müller, P.K. 207 Raptis, S. 33 Seidell, J.C. 243 Wernze, H. 425 Muller, W.E.G. 465 Raue, F. 284 Semplicini, A. 47 Wieland, U. 284 Munck Petersen, C. 184, 543 Reihner, E. 386 de la Sierra, A. 337 Wiesel, M.-L. 561 Reinhardt, D. 213 Simmel, A. 512 Williams, T.D.M. 81, 375 Näbauer, M. 600 Reitemeyer, E. 133 Simmet, TH. 549 Wilson, A.P. 410 Nagengast, F.M. 56 Rennie, M. 62 Sjövall, J. 166 Winther, K. 504 Nelles, J. 420 Rennie, M.J. 648 Skak, C 507 Wojta, J. 595 Nieuwenhuyzen Kruseman, A.C. Riccardi, G. 582 Sommer, H. 290 314 Riecken, E.-O. 196 Sorensen, S.S. 202 Yamada, Y. 207 Nikkilä, E.A. 472 Riecken, E.O. 655 Sottrup-Jensen, L. 184 Ylikahri, R. 472 Nilas, L. 529 Rieder, H. 343 Stangl, K. 524 Nilsell, K. 386 Rigon, E. 47 Steinhagen-Thiessen, E. 256 Ziegler, R. 284 Keyword Index

Acetaldehyde 420 Cardiovascular reflexes 375 Familial hypercholesterolaemia Acute leukaemia 146 Ceftriaxone 261 (Ha) 256 Adenylate cyclase 600 Cell coupling 444 Fat distribution 243 Adipocytes 575 Cell movement 290 Feedback regulation 98 ADP 410 Chenodeoxycholic acid 153,386 Ferric citrate 69 ^-adrenoceptor affinity 213 Cholecystokinin 98, 173, 517 Fibre 128 ^-adrenoceptor density 213 Cholesterol 243,261,644 Fibrinogen 512 Ageing 493, 504 Cholesterol crystals 386 Fibroblast 207 Alcohol consumption 472 Cholesterol metabolism 153 Fibrosis 9 Aldosterone 81 Cholesterol saturation 386 Free fatty acids 587 Alpha-adrenoceptors 309 Cholestyramine 256, 517 Free water clearance 202 Amiloride 279 Cholicacid 153 Amino acids 512 Chronic hypocalcaemia 284 Gallstone 386 5-aminolaevulinate synthase 29 Chylomicrons 226 Gastric acid secretion 360 Ammonia metabolism 535 Cirrhosis 535 Gastric anti-secretory drugs 360 a-Amylase 267 Clearance 507 Gastric emptying 173 Analogue 405 Clinical diagnosis 314 Gastric morphometric parameters Angiotensin 178 Clinical study 256 Gastritis 133 Angiotensinases 178 Clinical trial 561 Gastroduodenal mucosa 133 a2-antagonists 587 Cold 75 Gastrointestinal hormones 499 Antibiotics 261 Collagen-IV 352 GLI 499 Anti-thrombin 512 Collagen peptide of procollagen type secretion 607 Apolipoprotein A-I 619 III 18 Glucose clamp 493 Apolipoprotein A-II 619 Collagen synthesis 9 Glucose-6-phosphate 250 Apolipoprotein B 75 Colloid stability 237 Glucose turnover 607 Apolipoprotein C 619 Colon cancer 196, 655 a-glucosidase inhibitors 33 Apoproteins 472 Colonic carcinogenesis 56 Glutamate 512 Aprotinin 267 Colonic pH 56 Glutamine 512 Arginine vasopressin 81, 202, 375, 627 Congestive cardiomyopathy 524 Glutamine metabolism 535 Arteriosclerosis 633 Converting enzyme 178 Glutathione 420 Ascitic fluid 595 Copper 555 Glycogen 250,493 Asparaginase 512 Coronary heart disease 472 Glycogen synthase 250, 493 Atherosclerosis 18 Co-transport 47 Glycosylation 237 Atrial natriuretic factor 415, 425, 568, Countertransport 47 Granulation tissue 352 627 Cyclic GMP 425 Granulocytes 380 Atrial natriuretic peptide 524 Cyclic guanosine monophosphate 524 Gut glucagon 499 Autopsy 314 Cysteine 420 Cytochrome P-450 29 Haematoporphyrin 614 Bacterial adherence 87 Haemodialysis 380 Banter's syndrome 369 d-DAVP 273 Haemodynamics 369 Behcet's syndrome 410 Depression 297 Haem biosynthesis 29 Beta-2-agonist aerosols 162 Diabetes 33,92 HDL-subfractions 472 Bile acids 22, 128, 153, 166, 261, 517 Diabetes mellitus 87, 166, 233, 237, Healthy volunteers 267 Bile acid treatment 386 399, 454 Heart block 69 Bile secretion 261 Dimethylhydrazine 196,655 Heart failure 600, 648 Biliary and faecal secondary bile Distal tubule 279 Heparin 561 acids 56 Disulfiram 420 Heparinization 460 Biliary lipids 153 Diuresis 627 Hepatic cirrhosis 202 ft-blocking agents 587 Dog 460 Hepatocytes 226,343 Blood coagulation factors 75 Early postmenopause 191 Heptanol 444 Blood pressure 369 ECC 460 Histochemistry 655 Body weight 512 ECL and cell densities 360 Hodgkin's disease 290 Bone Gla-protein 191 Ehlers-Danlos syndrome type IV 207 Homocysteine 633 Bone loss 529 Elastase 380 Human 52 Bone turnover 191 Enterogastrone 499 Human adipocytes 587 Branched-chain amino acids 648 Enteroglucagon 499 Human B- and T-cells 213 Epidemiology 39 Human digital blood flow 309 l4C-breath test 128 Erythrocyte 47 Human epidermis 465 Cachexia 648 Erythrocytes 337 Human heart 600 Calcitonin secretion 284 Erythrocyte membrane 47 Human hepatocytes 184, 543 Calcitonin storage 284 Essential fatty acids 644 Human skeletal muscle 250 Calcium 92 Ethanol 420 Hydrodynamic volume 139 Calcium channel blockers 380 25-hydroxyvitamin D3 52 Calcium 1,25-dihydroxyvitamin D 52 Exocrine pancreatic secretion 517 Hypercalcaemia 39 Campylobacter pylori 13 3 Exercise 415 Hyperparathyroidism 39 Cancer 561 Experimental colonic neoplasia 196, Hypertension 337, 399, 568, 614 Cancer cachexia 486 655 Hypokalaemia 162 Capillary circulation 305 FAB classification 146 Hypothermia 460 Cardiovascular disease 1 Hyperthyroidism 607 Familial hypercholesterolaemia 153 666 KEYWORD INDEX

Idazoxan 587 ^-microglobulin 343 Relations to obesity 250 IL-1 486 Molecular cloning 444 Renin 178 Iloprost 124 Monoclonal antibody 465 Renin-aldosterone system 425 499 Morphometry 655 Renin-angiotensin system 375 Individuality 644 mRNA 207 Renin kinetics 178 Indocyanine green 507 Muscle 648 Ro-antibody 465 Indomethacin 124 Inositol triphosphate 92 Na + -K+ ATPase 337 In-situ hybridization 9 Na + transport 337 Scleroderma 9 Insulin 226, 391,444 Natriuresis 627 98 Insulin gene 582 Neutrophil 290 Secretion amylase 444 Insulin insensitivity 493 Non-ulcer dyspepsia 133 Secretory component of Insulin receptors 575 Noradrenaline 375 immunoglobulins 391 Insulin release 587 Serotonin 399, 504 Insulin resistance 607 Obesity 243 Serum lipids 243 Insulin secretion 582, 607 Oestrogens 75,297 Serum lipoproteins 472 Insulin sensitivity 575 Organic anions 261 Skeletal muscle 493 Interferons 343 191 Skin microcirculation 305 Interleukin 1 233, 343 Osteoporosis 529 Smooth muscle cells 614 Interleukin 2 233 Sodium intake 279 Internal medicine 314 Paediatrics 555 Sodium metabolism 81 Intestinal brushborder membrane Pancreatic feedback regulation 267 Sodium-potassium ATPase 47 enzymes 391 Pancreatic polypeptide 517 Sodium transport 273 Intestinal microflora 261 Pancreatic secretion 98, 267 Sodium valproate 29 Intestinal permeability 139 Peptic ulcer 133 Stable isotopes 62, 639 Intestinal water and electrolyte Peptide hormones 146 Starch 128 transfer 124 Perfused 444 Stepwise logistic regression 133 Intrinsic clearance 507 Phaeochromocytoma 481 Stool 128 Iron overload 69 Pharmacokinetics 261 Sub-acute cutaneous LE 465 Iron toxicity 69 Phenylalanine 267 Sympathetic dystrophies 305 Photodynamic therapy 614 Sympathetic vasoconstriction 309 Kallikrein 75 Physical exercise 587 Keratinocytes 465 Physical training 250 Tamm Horsfall glycoprotein 87, 237 a-ketoisocaproic acid 639 Plasma atrial natriuretic peptide 369 Theophylline 162 Ketonic bile acid 166 Plasma catecholamines 369, 481 Thrombosis 561 Kidney function 202 Plasma gastrin 360 Thromboxane 256 Kinetics 507 Plasma noradrenaline 81 Thromboxane A2 I Plasminogen activator inhibitor 595 [3H]-Thymidine labelling 360 Lactate 69 Platelet a2-adrenoreceptors 481 Thyroid disease 62 Lactate dehydrogenase 250 Platelet aggregation 410 Thyrotrophin 405 Lactoferrin 380 Platelet function 256 Thyrotrophin releasing hormone 405 Lactulose 56 Platelet 5-HT 297 Thyroxine 405 Laser Doppler fluxmetry 305 Platelets 1, 92, 399, 410, 504, 524 Tissue plasminogen activator 595 Lectins 196 Polyethylene glycol 139 TNF cancer 486 Leg and whole body metabolism 62 Polymorphism 582 Toxicity of acetaldehyde 420 Leucine 639 Porphyria 29 Toxicity of ethanol 420 Leucocyte fo-adrenoreceptors 481 Positive inotropic effects 600 Transamination 633 Leucocyte migration inhibitory Postnatal development 391 Transcutaneous oxygen pressure 454 activity 290 Prazosin 309 Transsulphuration 633 Leukaemia 512 Pregnancy 575 Treatment 33 LH 297 Pregnancy zone protein 184, 543 405 Lipase 98,267 Prevalence 39 Tryptophan 297 Lipid mobilization 587 Procollagen 207 Lipogenesis 575 Procollagen-III 352 Unsaturated fatty acids 644 Lipolysis 587,607 Prolactin 405 Urinary excretion 22 Lipophilicity 139 Prophylaxis 561 Urinary tract infection 87 Lipoproteins 226,243 Propranolol 587 Urine 166 Lipoproteins LDL, 75 Prospective study 39 Lithium clearance 273, 279 Prostacyclin 1, 124, 256 Urokinase-type plasminogen Liver 226,512,535 Prostacyclin sensitivity 410 activator 595 Liver diseases 555 Prostaglandin E2 202 Ursodeoxycholic acid 386 Liver function 507 Prostaglandin endoperoxides 1 Low calcium diet 284 124 Vascular disease 399 Low density lipoprotein 153 Protease inhibitor 98 Vascular smooth muscles 1 Low molecular weight heparin 561 Protein metabolism 639 Vasomotor reflexes 305 Protein turnover 62, 648 Vasopressin 273, 568 a2-Macroglobulin receptors 184 Proximal tubule 279 Videophotometric capillaroscopy 305 a2-Macroglobulin synthesis 543 Psoriasis 47 Volume regulation 425 Man 173 Pyelonephritis 87 Membrane channels 444 Pyruvate dehydrogenase 493 Water immersion 425 Membranes 337 Water loading 202, 273 Menopause 297, 529 Rat 52 Weight reduction 250 Methanethiol 633 Receptors 1, 524 Wilson's disease 555 Methionine metabolism 633 a-receptors 587 Microangiopathy 454 Receptor high and low affinity Yohimbine 309, 587 Microcirculation 454 states 213