ANTIHYPERTENSIVE THERAPY

PRINCIPLES AND PRACTICE

AN INTERNATIONAL SYMPOSIUM

PROCEEDINGS EDITED BY

F. GROSS WITH THE ASSISTANCE OF

S. R. NAEGELI AND A. H. KIRKWOOD BASLE

WITH 225 FIGURES

S PRINGER- VERLAG BERLIN · HEIDELBERG · NEW YORK

1966

The Symposium took place at Siena, Italy 28th June- Jrd July, 1965

under the chairmanship of

C. Bartorelli, Siena and was sponsored by

elBA

ISBN 978-3-642-50240-8 ISBN 978-3-642-50238-5 (eBook)

DOlI 0.1 007/978-3-642-50238-5

AU rights, especially that of translation into foreign languages reserved. It is also forbidden to reproduce this book, either whole or in part, by photomechanical means (photostat, micro­fUm and/or microcard) or by any other procedure without written permission from Springer Verlag. © by Springer-Verlag' Berlin· Heidelberg 1966. Library of Congress Catalog Card

Number 66·17 551.

Softcover reprint of the hardcover 1 st edition 1966

The reproduction of general descriptive names, trade names, trade marks, etc. in this publication, even when there is no special identification mark, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Law,

may accordingly be freely used by anyone.

Title No. 1329

Preface

Hypertension has certainly been one of the topics most fre­quently discussed at symposia, meetings, and congresses during recent years. There may be several reasons for this; three of them are obvious: firstly, the fact that a large proportion of the world's population is suffering from various forms of hypertensive disease; secondly, increasing knowledge of the pathogenesis of hypertension and of the disturbances underlying it; and, thirdly, the marked progress which has been made in antihypertensive therapy over the past fifteen years. When plans for the present symposium were being drawn up, it was felt that it should not simply bring forth just another meeting on hypertension, but should place particular emphasis on those aspects which had not been adequately discussed at previous symposia of this kind. Curiously enough, the topic which appeared to have received least attention in the past was therapy, although from the practical point of view this is by far the most important. The choice of therapy as the main theme of the whole symposium also seemed to be warranted in view of the relatively long period that had elapsed since effective antihyper­tensive treatment became available; the time had in fact come now to pass judgement on the benefits as well as the shortcomings of drug treatment as available today.

An assessment of the value of antihypertensive therapy must of necessity be based to a substantial degree on work undertaken some time ago - work which has therefore to some extent already been published. Nevertheless, although some of the data contained in this volume may previously have appeared in print elsewhere, there is much to be said for looking at them again in the context of a symposium at which all the different aspects of the subject have been treated. For once, it is also useful to have the numerous data assembled in a single volume, instead of scattered throughout the abundant literature.

Long-term therapy of hypertension, to which much of this volume is devoted, has undergone various modifications during the one and a half decades since the first antihypertensive drugs ap­peared. It is not so much the individual compound, but rather the beneficial effect of lowering elevated blood pressure by drug treat­ment, which is responsible for the better chance of survival that

IV Preface

the patient suffering from hypertension has today. For this reason no special treatment schedules for the various drugs are given. It is evident from some of the papers read at this symposium that the hypertensive patient whose blood pressure is brought down to within normal limits has the best life expectancy and that this aim can now be achieved by the most active of the drugs at present available.

There remains the question whether it is worth while to publish the proceedings of such a meeting. During the symposium, one evening, one of the participants expressed the opinion in the course of an informal chat that their pUblication would be unnecessary and that those attending the gathering would be only too glad not to have to face the burden of preparing a manuscript for printing or of revising what they had said during the discussions. Recently, however, the Editor was gratified to receive a letter indicating that the speaker in question had meanwhile become "converted" to the idea of printing the proceedings: "When I was in Siena I made a comment that perhaps publication of papers was not necessary. Mter thinking it over I realise that these publications are very important not only as a reference for the participants but even more so to those who were unable to attend."

The success of a meeting of this type depends to a decisive degree upon the organiser, upon the man who, together with his advisers, determines who should speak about what and is respon­sible for all the necessary preparations. Prof. BARTORELLI and Prof. ZANCHETTI, working in close collaboration, drew up an ex­cellent programme and, together with their young and enthusiastic collaborators, proved most charming and attentive hosts.

In a place like Siena, where the working sessions and the many discussions following them were held in most beautiful surround­ings and in a congenial and stimulating atmosphere, fascinating impressions and exciting episodes to which participants at the symposium were treated may bewitch the critical intellect. The book which contains the proceedings provides a more sober record than may the memories of those who had the pleasure of participat­ing at the meeting - and it is up to the reader to decide what it has achieved and whether or not it has made a valuable contribution to the chosen subject. Between the picture and its frame there has to be a well balanced relationship. The small group who had the privilege of being in Siena on this occasion saw both the picture and the frame, whereas the great majority to whom this book is addressed can only imagine the blue sky of Tuscany, the slender tower of La Mangia rising majestically above the warm brick

Preface v

faQades of Siena brown, and the magnificent, colourful spectacle of the Palio. It remains to be seen, however, whether the proceed­ings of the symposium and the scientific progress achieved by it stand the test of deframing as well as the unforgettable La Maesta by Duccio in the Museo dell'Opera del Duomo.

The Editor of such a volume tends, alas, to prove a rather unpopular person - at least during the period when he has to remind the authors to submit their manuscripts, corrected galley proofs, summaries, etc. Moreover, in trying to "edit" he may do too much of a good thing and inflict additional strain on authors whose patience and goodwill have already been sorely taxed. He apologises for any annoyance he may inadvertently have caused them and expresses his warmest thanks to all contrib­utors to the volume who so patiently dealt with his many queries and requests. Without their understanding help it would not have been possible to publish the volume so soon after the meeting.

We should also like to extend our sincerest thanks to Dr. R. DEGUILLAUME, who translated the summaries into French, to Dr. WILTRUD HATZINGER, who prepared the subject index, and - last but by no means least - to Springer-Verlag, who, as in former years, did their utmost to ensure rapid publication of the volume and whose staff made every effort to meet all our wishes.

Basle, November 1965 F.G.

Contents

Participants in the Symposium.

Opening remarks by C. BARTORELLI . . . . .

Experimental basis of antihypertensive treatment

Pharmacology of the sympathetic nervous system by A. CARLSSON . . . . . . . . . .

Mode of action of antihypertensive drugs

x

1

5

by H. J. BEIN and H. BRUNNER . 15 Discussion: Carlsson, Page, Smirk 29

Pharmacology of diuretics by G. PETERS . . . . . . . . . . . . . . . . . . . . . . . . 31 Discussion: Hood, Peters . . . . . . . . . . . . . . . . . . . 58

Functional, biochemical, and morphological changes produced by hypo­tensive drugs by ELEANOR ZAIMIS . . . . . . . . . . . . . . . . . . .. 59 Discussion: Carlsson, Dollery, Gross, Page, ·Wilson, Zaimis. . .. 71

Influence of sleep on circulation in normal and hypertensive animals by A. ZANCHETTI, M. GUAZZI, and G. BACCELLI 74 Discussion: Bock, Pickering, Smirk. . . . . . . . . . . . .. 96

General Discussion: Introduction by A. C. TAQUINI. . . . . . . . . . . . 101

Bein, Brunner, Carlsson, Pickering, Zaimis. 107

Hypertension and vascular disease

Experimental atherosclerosis and hypertension by Q. B. DEMING. • . • • . . . . • • .

The vascular crisis in hypertension

HI

by F. B. BYROM . . . . . . . . . . . . . . . . . . . . . . . 125 Discussion: Bein, Byrom, Carlsson, Deming, Dengler, Dollery, Gross, Hood, Page, Peart, Pickering ................. 132

Vascular disease and hypertension by G. W. PICKERING • . . . • . . • • • . . . . . . . . . • • 135 Discussion: Cottier, Dustan, Kincaid-Smith, Kirkendall, Page, Pick­ering, Smirk. . . . . . . . . . . . . . . . . . . . . . . . . 150

Contents

Retinal vascular alterations in hypertension by C. T. DOLLERY, P. S. RAMALHO, and J. W. PATERSON ..... Discussion: Brod, Byrom, Cottier, DoUery, Gross, Page, Peart, Pick-ering, Taquini . . . . . . . . . . . . . . . . . . . . . . . .

The heart and hypertension by W. M. KIRKENDALL .

General Discussion: Introduction by V. PUDDU . . . . . . . . . . . . . . . . . .

Hood, Kirkendall, Page, Pickering, Reubi, Smirk, Ta-quini, Werko, Wilson ............ .

General principles in antihypertensive treatment

Assessment of antihypertensive therapy

VII

152

164

170

178

180

by W. I. CRANSTON. . . . . . . . . . . . . . . . . . .. 184 Discussion: Cranston, Deming, Freis, Gross, Lee, Page, Peart, Peters 193

Selection of patients for antihypertensive therapy by M. HA!lIILTON. . . . . . . . . . . . . . . . . . . . . . . 196 Discussion: Bock, Brod, Dollery, Dustan, Hamilton, Hoobler, Lee, Leishman, Mach, Smirk, Wilson, Zaimis. . . . . . . . . . . . . 207

lUethodology of blood-pressure recording by S. B. HUMERFELT. . . . . . . . . . . . . . . . . . . . . 212 Discussion: Dollery, Humerfelt, Pickering, Puddu, Smirk, Taquini . 222

Spontaneous blood-pressure variations in hypertension; the etJeet of antihypertensive therapy and eorrelations with the incidenee of com­plications by K. D. BOCK and W. KREUZENBECK . . . . . . . . . . . . . 224 Discussion: Bock, Brod, Dontas, Hoobler, Pickering, Taquini, Werko, Zanchetti . . . . . . . . . . . . . . . . . . . . . . . . . . 238

EtJect of a simple therapeutic regimen on blood pressure and its varia-bility in mild hypertension 242 by H. SCHWARTZ, G. A. EADIE, R. D. REMINGTON, and S. W. HOOBLER Discussion: Brod, Cottier, Cranston, Dengler, Freis, Hoobler, Page, Peart, Taquini. . . . . . . . . . . . . . . . . . . . . . . . 254

General Discussion: Introduction by J. BROD . . . . . . . . . . . . . . . . . . . 257

Brod, Cranston, Deming, Dustan, Hoobler, Hood, Kin­caid-Smith, Lee, Page, Peart, Peters, Pickering, Reubi, Smirk, Taquini, Wilson . . . . . . . . . . .. 262

Clinical pharmacology and short-term treatment

Haemodynamic analysis of some principles applied in the treatment of arterial hypertension by R. SANNERSTEDT, G. SCHRODER, and L. WERKO ........ 268 Discussion: Brod, Cottier, Gross, Hartmann, Hoobler, Humerfelt, Page, Peart, Reubi, Taquini, Werko .............. 282

VIII Contents

Some biochemical aspects 01 treatment and diagnosis of hypertension by A. SJOERDSMA. . . . . . . . . . . . . . . . . . . . . . . 286 Discussion: Carlsson, Dengler, Dollery, Hoobler, Kirkendall, Sjoerdsma299

Advantages and disadvantages of combined drug treatment by A. N. BREST . . . . . . . . . . . . . . . . . . . . . . . 302 Discussion: Bock, Brest, Carlsson, Dustan, Freis, Hoobler, Kincaid­Smith, Page, Peters, Smirk . . . . . . . . . . . . . . . . . . 309

1\ianagement 01 hypertensive crisis byR. E. LEE ....... . 313 Discussion: Dustan, Freis, Hamilton, Hood, Kirkendall, Lee, Leish-man, Reubi, Sjoerdsma, Smirk, Wilson ............. 319

Hypertension in pregnancy and its treatment by N. F. MORRIS . . . . . . . . . . . . . . . . . . . . . . . 324 Discussion: Brod, Deming, Freis, Kincaid-Smith, Morris, Smirk, Zanchetti . . . . . . . . . . . . . . . . . . . . . . . . . . 335

General Discussion: Introduction by H. LAGERLOF . . . . . . . . . . . 338

Bein, Page, Peart, Smirk, Taquini, Wolff 340

Long-term treatment

Organization 01 a long-term multielinie therapeutic trial in hypertension by E. D. FREIS . . . . . . . . . . . . . . . . . . . . . . . 345

Prognosis in retinal Grade I and II patients by F. H. SMIRK .......... . 355

Analysis 01 mortality and survival in actively treated hypertensive disease by B. HOOD, M. AURELL, T. FALKHEDEN, and S. BJORK ...... 3iO Discussion: Brod, Freis, Hood, Pickering, Puddu, Reubi, Smirk, Wilson ........................... 38i

The present status 01 symptomatic surgical treatment lor arterial hyper­tension by P. TCHERDAKOFF, J. VAYSSE, M. LACOMBE, P. OUDEA, J. MOURAD, F. TARRETTE, and P. MlLLIEZ ................. 394 Discussion: Brest, Brod, Dustan, Hoobler, Hood, Page, Reubi, Smirk, Tcherdakoff, Wilson ..................... 419

Potassium loss and potassium replacement during long-term diuretic treatment in hypertension by C. BARTORELLI, N. GARGANO, and G. LEONETTI. . . . . . . . 422

Disturbances in carbohydrate and uric-acid metabolism during diuretic treatment by F. HARTMANN and V. HEIMSOTH .............. 436

Comparison of long-term effects 01 salureties and 01 anabolic steroids on renal lunetions by A. S. DONTAS, N. T. PAPANICOLAOU, and C. S. COTTAS ..... 448 Discussion: Brest, Cottier, Dollery, Hartmann, Lagerlof, Leonetti, Mach, Peters, Reubi, Smirk . . . . . . . . . . . . . . . . . . 463

Contents

Diagnosis and treatment of renovascular and other forms of renal hypertension

Diagnosis of renal artery stenosis by W. S. PEART . . . . . . . . . . . . .

The diagnostic value of renal biopsy in renovascular and other forms of renal hypertension

IX

468

by PRISCILLA KrNCAID·SlIUTH . . . . . . . . . . . . . . . . . 485 Discussion: Byrom, Gross, Hood, Kincaid·Smith, Peart, Tcherdakoff, Wilson. . . . . . . . . . . . . . . . . . . . . . . . 499

Diagnostic value of selective renal arteriography in hypertension by A. LIBRETTI and S. GRAZI . . . . . . . . . . . . . . 503 Discussion: Page, Peart. . . . . . . . . . . . . . . . . 516

Diagnostic significance of humoral factors in renovascular hypertension by J. GENEST, G. Y. TREMBLAY, R. BOUCHER, J. DE CHAMPLAIN, J. M. ROJO ORTEGA, R. LEFEBVRE, P. RoY, and P. CARTIER. . . . 518 Discussion: Dollery, Dustan, Genest, Kincaid·Smith, Peters, Taquini, Tcherdakoff. . . . . . . . . . . . . . . . . . . . . . . . . 541

Conservative treatment of renovascular hypertension by HARRIET P. DUSTAN, T. F. MEANEY, and 1. H. PA.GE ..... 544

Some observations on the filtration fraction, on the transport of sodium and water in the ischemic kidney, and on the prognostic importance of R.P.F. to the contralateral kidney in renovascular hypertension by T. A. STAMEY. . . . . . . . . . . . . . . . . . . . 555 Discussion: Brod, Dustan, Genest, Hood, Lee, Smirk, Stamey 580

Hypertension and nephritis by C. WILSON . . . . . . . . . . . . . . . . . . . . . . . . 584

General Discussion: Introduction by F. C. REUB!. . . . . . . . . . . . . . . . . . 594

Brod, Dollery, Genest, Hartmann, Hood, Kirkendall, Pe~rt:, Reubi, Smirk, Stamey, Tcherdakoff, Wilson, ZalmlS ..................... 597

Drug treatment of hypertension Public lecture by I. H. P A.GE, delivered on the occasion of the bestowal of an honorary doctorate from the Medical Faculty, University of Siena 602

Closing remarks by C. BARTORELLI

List of authors .

Subject index .

615

619

621

Participants in the Symposium

BARTORELLJ, C ..

BEIN, J. H.

BLOCH, H •.

BOCK, K. D.

BREST, A. N ..

BROD, J ....

BRUNNER, H ..

BYROM, F. B •.

CALIFANO, L ..

CARLSSON, A ..

COTTIER, P. T.

CRANSTON, W. I.

DEMrNG,Q.B ••

DENGLER, H. J ..

DOLLERY, C. T ..

DONTAS, A. S. .

DUSTAN, HARRIET P.

Istituto di Patologia Speciale Medica e Metodo­logia Clinica, UniversitA di Siena, Siena (Italy)

Forschungslaboratorien der CIBA Aktiengesell­schaft, Basel (Switzerland)

Forschungslaboratorien der CIBA Aktiengesell­schaft, Basel (Switzerland)

Medizinische Klinik und Poliklinik, Klinikum Essen der Wilhelms-Universitat Munster, Es­sen (Germany)

Department of Medicine, Hahnemann Medical College and Hospital, Philadelphia, Pa. (U.S.A.)

Ustav pro Choroby Obehu Krevniho, Praha-Krc (Czechoslovakia)

Forschungslaboratorien der CIBA Aktiengesell­schaft, Basel (Switzerland)

Medical Unit, The London Hospital, London (Great Britain)

Istituto di Patologia Generale, S. Andrea delle Dame, Napoli (Italy)

Farmakologiska institutionen, Goteborgs univer­sitet, Goteborg (Sweden)

Medizinische Abteilung, Bezirksspital, Interlaken (Switzerland)

Department of Medicine, St. Thomas's Hospital Medical School, London (Great Britain)

Department of Medicine, Albert Einstein College of Medicine, Bronx, N. Y. (U.S.A.)

Medizinische Universitats-Klinik, Heidelberg (Germany)

Department of Medicine, Postgraduate Medical School, London (Great Britain)

Department of Clinical Therapeutics, University of Athens, Athens (Greece)

Research Division, Cleveland Clinic Foundation, Cleveland, Ohio (U.S.A.)

FREIS, E. D.

GENEST, J ..

GROSS, F.

HilIILTON, M.

HARTMANN, F.

HOOBLER, S. \V.

HOOD, B .....

HUMERFELT, S. B.

IMHOF, P .....

Participants in the Symposium XI

Veterans Administration Hospital, Washington, D. C. (U.S.A.)

Departement de recherches cliniques, Hotel-Dieu de Montreal, Montreal (Canada)

Forschungslaboratorien der CIBA Aktiengesell­schaft, Basel (Switzerland)

Chelmsford and Essex Hospital, Chelmsford, Essex (Great Britain)

Medizinische Klinik der Medizinischen Hoch­schule Hannover, Hannover (Germany)

Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Mich. (U.S.A.)

Medicinska kliniken I, Goteborgs universitet, SaWgrenska sjukhuset, Goteborg (Sweden)

Medisinsk avdeling A, Universitetet i Bergen, Haukeland sykehus, Bergen (Norway)

Forschungslaboratorien der CIBA Aktiengesell­schaft, Basel (Switzerland)

KINCAID-SMITH, PRISCILLA Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Mel­bourne, Victoria (Australia)

KIRKENDALL, 'V. M ..

LAGERLOF, H.

LEE, R. E. ..

LEISHMAN, A. \V. D ..

LEONETTI, G ..

LmRETTI, A.

MACH, R. S.

MlLLrEZ, P ..

MORRIS, N. F.

Department of Medicine, University of Iowa Hospitals, Iowa City, Iowa (U.S.A.)

Medicinska kliniken, Karolinska sjukhuset, Stockholm (Sweden)

Department of Medicine. Cornell University Me­dical Center, The New York Hospital, New York, N. Y. (U.S.A.)

United Sheffield Hospitals, Sheffield (Great Brit­ain)

Istituto di Patologia Speciale Medica e Metodo­logia Clinica, Universita di Siena, Siena (Italy)

Istituto di Patologia Speciale Medica e Metodo­logia Clinica, Universita di Siena, Siena (Italy)

Clinique universitaire de therapeutique, Hopital cantonal, Geneve (Switzerland)

Hopital Broussais, Paris (France)

Department of Obstetrics and Gynaecology, Charing Cross Hospital Medical School, Lon­don (Great Britain)

MORUZZI, G. . . . . . . Istituto di Fisiologia, Universita di Pisa, Pisa (Italy)

XII

}IULL, R. P.

PAGE,I.H.

PEART, W. S ..

Participants in the Symposium

Chemical Research Department, CIBA Pharma­ceutical Company, Summit, N. J. (U.S.A.)

Research Division, Cleveland Clinic Foundation, Cleveland, Ohio (U.S.A.)

Medical Unit, St. Mary's Hospital, London (Great Britain)

PETERS, G.. . Institut de Pharmacologie de l'Universite, Lau-sanne (Switzerland)

PICKERING, SIR GEORGE The Radcliffe Infirmary, University of Oxford, Oxford (Great Britain)

PLUMMER, A. J.. Macrobiology Department, CIBA Pharmaceuti-

PUDDU, V ..

REUBI, F. C.

SJOERDSlVIA, A.

S~IIRK, SIR HORACE

STAMEY, T. A.

TAQUINI, A. C.

TCHERDAKOFF, P ..

TRAEGER, J.

WERKO, L ..

WILSON, C ..

WOLFF, H. P ..

ZAIMIS, ELEANOR

cal Company, Summit, N. J. (U.S.A.)

Divisione Cardiologica A. Cesalpino, Ospedale San Camillo, Roma (Italy)

Medizinische Universitatspoliklinik, Bern (Swit­zerland)

National Heart Institute, National Institutes of Health, Bethesda, Md. (U.S.A.)

Wellcome Medical Research Institute, University of Otago Medical School, Dunedin (New Zea­land)

Division of Urology, Stanford University School of Medicine, Palo Alto, Calif. (U.S.A.)

Centro de Investigaciones Cardiol6gicas, Facul­tad de Ciencias Medicas, Universidad de Bue­nos Aires, Buenos Aires (Argentina)

H6pital Broussais, Paris (France)

Service des maladies metaboliques et renales, Hopital de l'Antiquaille, Lyon (France)

Medicinska kliniken I, Goteborgs universitet, Sahlgrenska sjukhuset, Goteborg (Sweden)

Medical Unit, The London Hospital, London (Great Britain)

II. Medizinische Universitatsklinik und Poli­klinik, Homburg/Saar (Germany)

Department of Pharmacology, The Royal Free Hospital School of Medicine, London (Great Britain)

ZANCHETTI, A. . . . . . Istituto di Patologia Speciale Medica e Metodo­logia Clinica, Universita di Siena, Siena (Italy)