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Hypertension prelims 16/10/08 16:25 Página iii

An Atlas of Investigation and Management

HYPERTENSION
Edward D Frohlich
Alton Ochsner Medical Foundation
New Orleans, USA

Hector O Ventura
Alton Ochsner Medical Foundation
New Orleans, USA

CLINICAL PUBLISHING
OXFORD
Hypertension prelims 16/10/08 16:25 Página iv

Clinical Publishing
an imprint of Atlas Medical Publishing Ltd
Oxford Centre for Innovation
Mill Street, Oxford OX2 0JX, UK

Tel: +44 1865 811116

Fax: +44 1865 251550
E mail: [email protected]
Web: www.clinicalpublishing.co.uk

Distributed in USA and Canada by:

Clinical Publishing
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© Atlas Medical Publishing Ltd 2009

First published 2009

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical
Publishing Ltd

Although every effort has been made to ensure that all owners of copyright material have been acknowledged
in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought
to our attention

A catalogue record for this book is available from the British Library

ISBN-13 978 1 904392 15 6

ISBN-10 1 904392 15 6
ISBN e-book 978 1 84692 524 5

The publisher makes no representation, express or implied, that the dosages in this book are correct.
Readers must therefore always check the product information and clinical procedures with the most
up-to-date published product information and data sheets provided by the manufacturers and the most
recent codes of conduct and safety regulations. The authors and the publisher do not accept any
liability for any errors in the text or for the misuse or misapplication of material in this work

Project managed by Prepress Projects Ltd, Perth, UK

Typeset by Initial Typesetting Services, Edinburgh, UK
Printed by T G Hostench, s.a.
Hypertension prelims 16/10/08 16:25 Página v

Contents

Preface and a brief apologia vi

Abbreviations vii

Dedication viii

Introduction ix

1. Pathophysiology: disease mechanisms 1

2. Evaluation of the patient 15

3. Clinical pharmacology of antihypertensive agents 37

4. Uncomplicated essential hypertension 55

5. The heart in hypertension 73

6. The kidney in hypertension 89

7. Renal arterial disease 113

8. Concluding comments 123

Epilogue 125

Index 127
Hypertension prelims 16/10/08 16:25 Página vi

vi

Preface and a brief apologia

In a textbook of this nature, it is in order to provide the Another concern (as a past Editor-in-Chief of two major
prospective reader and potential reviewer with a brief journals and the author of several textbooks and many
overview of the goals, limits and editorial guidelines that we papers) was related to our selection of reference material.
set for ourselves in preparing the material for this atlas. In The purpose of this text was to present neither a literature
the Introduction we provide some personal remarks related review nor a current state of the art. We therefore chose to
to our agreement to organize and present our repertoire of provide ‘suggested reading’ so that the reader can consult in
visual material, but, perhaps, a few words might be in order the peer-reviewed literature the primary references for the
here to explain our selection. clinical and experimental material we use to support our
First, a number of friends and colleagues encouraged us to pictorial, tabular and diagrammatic material.
publish the material for many of our lectures over the years. With these comments, we sincerely hope that the atlas
Our publisher further supported these comments although material, the accompanying discussion and suggested
he raised the concern that some material and references reading are of value to the reader. We hope that this book
might seem to be dated. We agreed and exerted particular will be of value to readers who are clinicians and students of
effort to select only that pictorial and diagrammatic material hypertension and who are interested in the pathophysiology
which we strongly believed was currently pertinent for of hypertensive disease.
presentation and for pedagogic purposes.
Hypertension prelims 16/10/08 16:25 Página vii

vii

Abbreviations

ACE angiotensin-converting enzyme LV left ventricle

ACEI angiotensin-converting enzyme inhibitor LVH left ventricular hypertrophy
ARB angiotensin receptor blocker LVS left ventricular strain
AT angiotensinogen MAP mean arterial pressure
AV arteriolar–venular MI myocardial infarction
BB beta blocker L-NAME nitro-L-arginine methyl ester hydrochloride
CBC complete blood count NSAID non-steroidal anti-inflammatory drug
CCB calcium channel blocker PKD polycystic kidney disease
CHD coronary heart disease PRA plasma renin activity
CHF congestive heart failure PSA prostate-specific antigen
COPD chronic obstructive pulmonary disease PV plasma volume
CPV cardiopulmonary volume PWT pulmonary wall thickness
DBP diastolic blood pressure RA renal afferent
ECG electrocardiogram RE renal efferent
ERBF estimated renal blood flow RHD rheumatic heart disease
ESRD end-stage renal disease SHR spontaneously hypertensive rat
FF filtration fraction SBP systolic blood pressure
GFR glomerular filtration rate SNFF single-nephron filtration fraction
HCTZ hydrochlorothiazide SNGFR single-nephron glomerular filtration rate
HCVD hypertensive cardiovascular disease SNPF single-nephron plasma flow
HHD hypertensive heart disease SMA smooth muscle actin
IP3 inositol triphosphate TPR total peripheral resistance
ISA intrinsic sympathomimetic activity TSH thyroid-stimulating hormone
IVU intravenous urography UPE urinary protein excretion
WKY Wistar–Kyoto rat
Hypertension prelims 16/10/08 16:25 Página viii

viii

Dedication

We dedicate this textbook to our wives, Sherry Frohlich and added dimension to nurture family as well as our pro-
Laurie Ventura, and to our children, who share with us the fessional colleagues. This is the long-standing commitment
very honest and warm thirst for knowledge, whether in the of the well-rounded physician, and it is the obligation of all
medical or in other academic environments. It is this teachers and professionals to impart a better life to man
understanding of the need to impart one’s personal or within our professional careers.
professional knowledge and experience which provides an
Hypertension prelims 16/10/08 16:25 Página ix

ix

Introduction

Producing an atlas on hypertension was not at the forefront hypertensive patient; an elucidation of the mechanisms of
of my thinking until I was approached by Jonathan Gregory, action of the varied modes of therapy including non-drug as
commissioning editor at Clinical Publishing, who was well as pharmacological entities; and my personal overview
interested in publishing such a textbook. Indeed, in recent and investigative and clinical experience with two vital areas,
years, I have questioned the importance of hypertension as the heart and kidney in hypertension.
a discipline. Institutions such as mine no longer maintain a Most national and international guidelines present a
separate hospital service for admitting patients with the straightforward concept for the evaluation and treatment of
diagnosis of hypertension; and the numbers of patients with patients with hypertension; and they presently suggest a
primary problems relating to hypertension have diminished clear-cut course of action with respect to treatment unless
considerably. This is in striking contrast to the early days of there are complicating considerations. For the most part, we
my academic career, when a large majority of hospitalized agree with this presentation; but, of course, as is the case
patients were admitted with hypertensive emergencies or with most consultants, consideration must be focused on the
hypertension associated with myocardial infarction, patient in whom complicating factors suggest specific
congestive heart failure, angina pectoris, stroke or renal problems. To my way of thinking, the major areas that
involvement. Today, a patient with hypertension who is require more specific attention relate to the hypertensive
hospitalized because of myocardial infarction, acute patient with cardiac or renal involvement. Indeed, cardiac
coronary syndrome or renal failure is immediately sent to a and renal failure continue to increase in frequency despite
specialized unit. Yes, we have certainly come a long way over the reduction in deaths from stroke or coronary heart
the past five decades. disease and the fact that hypertensive emergencies are today
On the other hand, the number of patients with rather rare. Patients with hypertension who are hospitalized
hypertension continues to increase all over the world. with myocardial infarction or with end-stage renal disease,
Clearly, this is partly the result of what I have termed the as well as patients with an acute stroke, require very
‘numbers game’ of disease. That is to say, the limits of specialized hospital services. And so we are left with the
normal – whether of blood pressure, blood sugar need to consider in detail the heart in hypertension and the
concentration or body weight – continue to converge, and so kidney in hypertension. Both deserve very specific
the number of potential patients with hypertension or discussions in a textbook for the primary care physician or
diabetes mellitus or obesity continues to rise. And as a internist, cardiologist or nephrologist, all of whom deal with
consequence, the increasing attention demanded by these a large number of such patients who are not covered
diseases falls on the shoulders of the primary care physician, adequately by current clinical guidelines. Moreover, over the
and with this responsibility comes a greater need for a clear past few years I have on several occasions been invited to
understanding of the pathophysiology of these diseases and present my thoughts on this matter to such physicians, and
their management. Related to the increased attention these so I was convinced that now might be an appropriate time
diseases receive, and the increase in the number of such to share my personal thoughts in an ‘atlas’ format. It became
patients seen in any physician’s day-to-day practice, are apparent to me that in such a book I would be able to impart
remarkable innovations in diagnosis and management. And not only my personal clinical experience, but also the
so the subject arose of yet another textbook about hyper- ongoing work in my laboratories, which focuses primarily on
tension. I was won over by the need to confine the text to the heart and kidney. At this point in my thinking about the
just these subjects: classification of the disease; a clear subject, I discussed the merits of the task with my long-time
insight into the pathophysiology and initial evaluation of the friend and colleague, Hector Ventura. Hector convinced me
Hypertension prelims 16/10/08 16:25 Página x

x Introduction

of the potential ‘need’ for such an undertaking, and when he To complete our task we want to express our appreciation
‘volunteered’ to assist me I readily agreed. Thus, the to Jonathan Gregory for stimulating our thinking about how
concept and the format for this atlas of hypertension to present the very common problem of hypertension in the
developed and we thereupon began this job. practice setting. We also want to express our warm and
Not infrequently, we are invited to write a book review. heartfelt appreciation to our wives and children, first and
Often, one of the major pitfalls for an author is to clearly foremost, for their abiding understanding of our need to
identify what the book is trying to achieve; and so we were spend more time away from home and family in order to
very careful to ensure that we express our thinking clearly. meet yet another deeply personal commitment. It is to them,
We did not want to write a textbook that deals with the our dear families, that we dedicate this endeavour. In
hypertensive patient who presents with problems that con- addition, we want to express our appreciation to our office
stitute an emergency or those who require hospitalization in staff (Lillian Buffa, Caramia Fairchild and Pamella
a special care unit. Nor did we want to discuss the patient Tadesco), whose continuous support of our daily
whose demographic characteristics are such that specific professional activities permitted us to pursue yet another
chapters need be dedicated to a discussion of the role of the job.
patient’s age, race or gender, or the patient who suffers from It would be totally remiss of me not to mention a few
a new popular syndrome. In the final analysis, when the stumbling blocks that I encountered along the way during
physician is confronted by a particular patient, the relation- the preparation of this book: the sudden striking of
ship is one-on-one, and the decision about diagnosis and Hurricanes Katrina and Rita; the associated flooding and
therapy for that person is very specific and unique for that loss of my home and long-to-be remembered library
clinical situation. (including ‘saved’ copies of completed chapters on hard
Thus, we accepted Jonathan Gregory’s invitation and drives and disks), records and recollections; an enforced
presented to him our revised thinking. We proposed a evacuation from New Orleans to our daughter’s home in
textbook that would present our personal opinions about Chicago; and conversation and support from my son in New
hypertensive disease and its cardiac and renal complications Jersey whereby personal refocusing was made possible. And,
as it relates to everyday pathophysiological assessment and finally, I want to express my (our) appreciation to our
about the choice of therapy not only for the relatively colleagues and institution, who continue to provide the
uncomplicated patient but also for the frequently ambience and culture required to pursue an academic
encountered patient with complications affecting the heart dimension to the overall healthcare effort (especially in the
and kidneys. This material would, we believe, best be past difficult times).
presented as tables or figures that would hopefully clarify
our thinking on patient management as suggested by our Edward D. Frohlich, MD
clinical as well as laboratory experience. New Orleans, LA
May 2008
Hypertension ch1 16/10/08 14:51 Página 1

Chapter 1 1

Pathophysiology:
disease mechanisms

Introduction

Systemic arterial hypertension is one of the most common Moreover, hypertension is a key determinant risk for
cardiovascular diseases of industrialized populations. It premature cardiovascular morbidity and mortality end-
affects approximately 20% of adults in these societies, and a points (Table 1.2). It is, therefore, necessary to understand
much higher proportion in certain demographic groups (e.g. the nature of the disease pathophysiologically; by doing so,
blacks, the elderly). The disease is the major treatable risk it is then possible to conceive, develop, and select. This,
factor underlying coronary heart disease (Table 1.1), and then, is the mission of this atlas.
exacerbates and accelerates the atherosclerotic process.

Table 1.2 Complications and end-points promoted

Table 1.1 Risk factors underlying coronary heart
by hypertension that result in premature
disease
cardiovascular morbidity and mortality

Brain
Not treatable
• Haemorrhagic stroke
• Advancing age
• Thrombotic stroke
• Male gender
• Embolic stroke
• Black race
• Positive family history
Heart
• Angina pectoris involving coronary arterioles
Treatable
• Occlusive epicardial coronary arterial diseases
• Hypertension
• Congestive heart failure
• Hyperlipidaemia
• Left ventricular diastolic dysfunction
• Tobacco consumption
• Obesity
Kidney
• Diabetes mellitus
• Renal arterial disease
• End-stage renal disease
Unresolved (as to whether treatment reverses risk)
• Embolic renal disease
• Left ventricular hypertrophy
• Exacerbation of diabetic renal disease
• Hyperinsulinism
• Hyperuricaemia
Other hypertensive emergencies
• Indices of inflammation (e.g. C-reactive protein)
• Dissecting aortic aneurysm
• Accelerated and malignant hypertension
• Crisis from phaeochromocytoma
• Eclampsia
• Other pressor emergencies
Hypertension ch1 16/10/08 14:51 Página 2

2 Pathophysiology: disease mechanisms

The mosaic Altered haemodynamics

It was approximately 60 years ago that Irvine H. Page To understand the pathophysiological alterations associated
described his concept of the mosaic of hypertension (see with the systemic arterial hypertensive diseases, there must
Further reading). Inherent in his thesis was the belief that first be a clear-cut understanding of the haemodynamic
hypertension is multifactorial in causation. This is because alterations associated with a persistent elevation of arterial
all of the mechanisms that serve to control arterial pressure pressure. By definition, hypertension is a haemodynamic
in normal individuals as well as in those patients with disorder in which the elevated arterial pressure may be
hypertensive disease relate to each other in a kaleidoscopic associated with an increased cardiac output and/or total
fashion, each with the others. Thus, all mechanisms are peripheral resistance (11.2).
critical for maintaining homeostasis, physiologically or In most patients with essential hypertension, the elevated
pathophysiologically (1 1.1A, B ). arterial pressure is associated with an increased total
The factors depicted in Page’s mosaic clearly are not all- peripheral resistance. In some patients, however, an elevated
inclusive but serve to satisfy the underlying model cardiac output may also participate. The relationship
suggesting that many (if not most) diseases are multif- between arterial pressure, cardiac output, and total
actorial in causation. In the case of hypertension, the funda- peripheral resistance is discussed more extensively in
mental driving physiological purpose is to maintain normal subsequent chapters. However, when one considers the
tissue perfusion. In hypertension, this is accomplished at the magnitude of the elevated pressure, changes in blood
expense of an increased vascular resistance and, hence, the viscosity do not have major importance. Nevertheless,
elevated arterial pressure which is the primary clinical intravascular rheological changes may alter local tissue
characteristic of hypertensive disease. blood flow dynamics in the major target organs. Thus, it is
possible that some degree of increased viscosity promotes
changes in blood rheological characteristics which could

A B
Chemical Chemical
Racial Aging
Elasticity Reactivity Elasticity factors factors Reactivity

Hormonal Reno-
pressor
Tissue Tissue
Cardiac perfusion Vascular perfusion
(pressure/ Neural (pressure/ Volume
output calibre resistance)
resistance)

Sodium Excess

Neural Volume Cardiac Vascular

output Associated Sexual
diseases factors calibre
Viscosity Viscosity

1.1 Page’s mosaic theory of hypertension. A: the original theory; B: including additional factors as modified by the author.
Each of these (and other) factors interrelate with one another in order to maintain normal tissue perfusion in response to
an increasing vascular resistance and at the expense of the abnormally elevated arterial pressure. (Modified from Frohlich
ED: Clinical classifications of hypertensive diseases. In: Atherosclerosis and Coronary Artery Disease. V Fuster, R Ross,
E Topol (eds.). Lippincott-Raven, Philadelphia, 1996.)
Hypertension ch1 16/10/08 14:51 Página 3

Pathophysiology: disease mechanisms 3

exacerbate the haemodynamic alterations in the coronary, distributed throughout the various organ circulations. The
renal, and brain circulations. mechanism responsible for this resistance increase is an
For the most part, however, the increased total peripheral augmented vascular smooth muscle tone, primarily in the
resistance (or, in organ circulations, their corresponding precapillary arterioles, and accounts for the state of increased
vascular resistances) is the established haemodynamic arteriolar tone (i.e. arteriolar constriction) that is implicit in
hallmark of the hypertension and is more or less uniformly the multifactorial nature of the disease (Table 1.3).

Table 1.3 Active and passive mechanisms that alter vascular resistance

I. Constriction II. Dilatation

Active Active
• Adrenergic stimulation (i.e. increased neural input or • Acetylcholine
increased vascular responsiveness to normal neural • Nitric oxide
input) • Kinins: bradykinin, kallidin
• Catecholamines: norepinephrine (noradrenaline), • Prostaglandins (some)
epinephrine (adrenaline), dopamine • Catecholamines: low-dose epinephrine (adrenaline),
• Renopressor: angiotensin II dopamine
• Cations: Ca2+, K+ (high concentration) • Histamines
• Other humoral substances: vasopressin, serotonin, • Peptides (atrial natriuretic peptide, insulin, secretin,
certain endothelins, certain prostaglandins vasoactive intestinal polypeptide, parathormone,
calcitonin gene-related peptide, substance P,
Passive endorphins, enkephalins)
• Oedema: extravascular compression • Renal medullary phospholipid substance (medullin)
• Vessel wall waterlogging • Cations: K+ (low concentration), Mg2+
• Increased blood or plasma viscosity • Vasoactive metabolites: adenosine, Krebs intermediate
• Obstruction (proximal): thrombosis, embolus, metabolites, acetate
rarefaction
• Hyposmolarity Passive
• Temperature: cold • Reduced blood or plasma viscosity
• Increased plasma tonicity
• Hyperosmolarity
• Temperature: heat

Arterial pressure

Total peripheral resistance Cardiac output Viscosity

Organ/vascular resistances Heart rate Stroke volume Vessels Blood

Oragan 1 + organ 2 + organ 3 etc.

1.2 The haemodynamic concept inherent in hypertension.

Hypertension ch1 16/10/08 14:51 Página 4

4 Pathophysiology: disease mechanisms

This book emphasizes those mechanisms that have been clinical forms of hypertension. Consideration of the pertinent
related to essential hypertension, since this primary form of underlying pressor mechanisms in those secondary forms of
hypertension occurs in approximately 95% of all patients with hypertension provides a basis for a more comprehensive
systemic arterial hypertension. Moreover, this pathophysio- insight into the overall mechanisms that could participate in
logical discussion is also relevant to other (i.e. secondary) patients with essential hypertension (Table 1.4).

Table 1.4 Classification of the various forms of systemic arterial hypertension

Primary (essential) hypertension Renal parenchymal disease Drugs, chemicals, and foods
(hypertension of undetermined cause) • Chronic pyelonephritis • Excessive alcohol intake
• Borderline (labile) or ‘high normal’ • Acute glomerulonephritis • Excessive dietary sodium intake
hypertension or prehypertension • Chronic glomerulonephritis • Exogenously administered adrenal
(essential hypertension) • Polycystic renal disease steroids
• Essential hypertension: systolic • Diabetic nephropathy • Birth control pills
pressures >139 mmHg and diastolic • Others: amyloidosis, ureteral • Adrenal steroids for asthma,
pressures >89 mmHg obstruction malignancies, anabolic steroids
• Isolated systolic hypertension: • Liquorice excess (imported primarily
systolic pressures >139 mmHg with Hormonal disease from the Netherlands not synthetic
diastolic pressures <89 mmHg • Thyroid in USA, UK)
• Hyperthyroidism • Cold preparations:
Secondary hypertension • Hypothyroidism phenylpropanolamine, nasal
• Aortic coarctation • Hashimoto's thyroiditis decongestants
• Snuff and tobacco
Central nervous system diseases Adrenal cortical hypertension • Street drugs (e.g. cocaine)
• Increased spinal fluid pressure • Cushing's disease or Cushing's
• Tumours syndrome Complications from specific therapies
• Diencephalic syndrome • Primary hyperaldosteronism • Antidepressant therapy (tricyclic
• Bilateral hyperplasia antidepressants, MAO inhibitors)
Renal arterial disease (renovascular • Adrenal enzymatic deficiencies • Chronic steroid administration
hypertension) • Cyclosporine (transplantation and
• Non-atherosclerotic (fibrosing): Adrenal medullary hypertension (i.e. certain disease immunosuppressive
intimal fibroplasia, medial phaeochromocytoma) therapy)
fibroplasia, fibromuscular • Beta-adrenergic receptor agonists
hyperplasia, subadventitial Other endocrine (e.g. for asthma)
fibroplasia • Ectopic production of hormones • Radiation nephritis and arthritis
• Atherosclerotic (tumours) • Lithotripsy therapy for renal calculi
• Aneurysm(s) of renal artery • Growth hormone excess (e.g.
• Embolic acromegaly, gigantism) MAO, monoamine oxidase.
• Extravascular compression (of renal • Hypercalcaemic diseases (e.g.
artery): tumour, fibrosis hyperparathyroidism, milk-alkali
• Perinephric hull (Page kidney) syndrome, hypervitaminosis D,
• Exacerbation of diabetic renal metastatic bone disease, idiopathic
disease hypercalcaemia)
• Oral contraceptive-exacerbated
hypertension
Hypertension ch1 16/10/08 14:51 Página 5

Pathophysiology: disease mechanisms 5

Arteriolar constriction results in enhanced phosphorylation of myosin light chains.

Arteriolar (and, for that matter, venular) smooth muscle This increased calcium ionic milieu may be achieved either
tone is increased in hypertension, although all of the through an inflow of calcium ions through calcium- or
mechanism(s) responsible are not entirely known. No other receptor-activated membrane channels or by a release
doubt, this relates to the many pressor and depressor factors of calcium ions from intracellular organelles, although
that normally participate in regulating vessel tone and calcium may be released from the mitochondria or from
calibre and, hence, arterial pressure (Table 1.3). It follows binding with protein substrates through secondarily
that these factors also participate in the increased vascular activated biochemical processes. The net increase in
resistance in most patients with essential hypertension. intracytoplasmic calcium ion concentration promotes the
Lessons concerning regulation of increased vascular formation of inositol triphosphate (IP3) and diacylglycerol.
resistance have been learned from the variety of secondary IP3 serves as the second messenger, mediating the calcium
forms of hypertension in which specific pressor and ion release and the resulting mechanical coupling that
depressor mechanisms are involved (Table 1.4). permits an enhanced state of contractility of vascular
It is likely that the increased vascular resistance in most smooth muscle.
patients with essential hypertension may be mediated
through more than one pressor mechanism. Some of these Arteriolar structure
mechanisms are predetermined by inborn genetic factors, Another factor participating in the increased vascular
since it has become increasingly apparent that the resistance of hypertension is an increased wall-to-lumen
pathophysiological alterations in essential hypertension are ratio of the arteries and arterioles. This structural alteration
polygenetic in origin. Furthermore, many of the pressor and in hypertension serves to amplify the arteriolar responsive-
depressor mechanisms that seem to be operative have been ness to constrictor stimuli that maintains the hypertensive
well documented to increase actively vascular smooth disease process. Recent investigations have suggested that
muscle tone. Many new mechanisms are elucidated with the haemodynamic stress of vessel stretch may be an
each passing year. Thus, vascular smooth muscle tone is important additional mechanism responsible for the vessel
abnormally increased as a result of one or more of those wall thickening, or even of myocytic hypertrophy of the left
factors that participate in the underlying disease process and ventricle. Several reports have indicated that upon stretch of
are then expressed in the clinical manifestations of that the ventricular or arteriolar (e.g. renal, coronary) myocyte,
patient’s disease. As a consequence of the increased total one or more of a vast array of ‘early genes’ or proto-
peripheral resistance, arterial pressure rises in order to oncogenes participate in initiating DNA-directed myocytic
maintain tissue perfusion; this occurs at the expense of the and collagen (and likely other) growth. Some of these
vascular and cardiac systems, and the specific indices of growth factors are themselves vasoconstrictors (e.g.
organ damage and functional impairment that secondarily angiotensin II, norepinephrine [noradrenaline], endothelin),
result. and they may even be generated within the arteriolar or
As suggested in Tables 1.2 and 1.3, the increased tone of ventricular endothelium or wall itself. Intriguingly, they may
the arteriolar or venular smooth muscle occurs no matter also participate in the separate but related process of
what mechanism(s) participate. Thus, for example, the atherogenesis. Hence, this may explain the close relationship
vascular myocyte is constricted by enhanced adrenergic of these two common and comorbid diseases (i.e.
input or elevated circulating levels of catecholamines; hypertensive vascular disease and atherosclerosis).
alterations in circulating or local autocrine/paracrine effects
of humoral substances; local or systemic participation of Pre- and postcapillary constriction
vasoactive peptides (e.g. angiotensin II, endothelin); ions; For the most part, all patients with hypertension have an
and growth factors. Alternatively, increased vascular increased arterial pressure that is associated with an
resistance may also be produced by reduced local or increased contractile state of vascular smooth muscle in
systemic amounts of vasodilating agents, local vasoactive both the arterioles and venules. The movement of plasma or
peptides or ions, and vasoactive metabolites (Table 1.3). interstitial fluid across the capillaries follows Starling
Whatever the myocytic stimulus, there is a resultant rise in mechanics, and depends upon the hydrostatic and colloid
cytoplasmic free calcium ions from their resting state that osmotic pressures in the intravascular and interstitial
Hypertension ch1 16/10/08 14:51 Página 6

6 Pathophysiology: disease mechanisms

compartments, respectively (1 1.3). Additionally, the wall-to- 1.4). This intravascular volume redistribution phenomenon
(1
lumen ratio of the arterioles, which is increased in has been demonstrated clinically in patients with essential
hypertension, further increases vascular resistance and hypertension as well as in naturally occurring or other
arterial pressure (i.e. the Folköwian hypothesis). The experimental forms of hypertension. Thus, early in the
increased tone of the smooth muscle in the arteriolar wall is development of hypertension, systemic venoconstriction
responsible for the increased arteriolar constriction. As a may not be associated with intravascular volume contraction
result of the constriction and, consequently, the increased 1.4). However, as arteriolar and venular constriction
(1
total peripheral resistance and arterial pressure, left progresses, capillary hydrostatic pressure increases and
ventricular afterload increases pari passu, providing the circulating intravascular volume diminishes. This is
major haemodynamic determinant for the structural probably the consequence of two factors: movement of
ventricular adaptation of left ventricular hypertrophy and plasma from the circulation into the extravascular
the associated events of hypertensive heart disease. These compartment and renal excretion of some of the circulating
precapillary changes are associated with generalized volume as arterial pressure increases (i.e. the Guytonian
constriction of the postcapillary venules, which reduces total phenomenon of pressure natriuresis). The intravascular (i.e.
body venous capacity. The simultaneous events of arteriolar plasma) volume contraction results in other recognizable
and venular constriction relate to several pathophysiological factors (Table 1.5). Thus, as diastolic and mean arterial
phenomena and consequences of hypertensive disease (1 1.4). pressures or total peripheral resistance increase in
hypertensive patients with essential hypertension or with
Venoconstriction 1.5A , B , C)
renal arterial disease, plasma volume contracts (1
The reduced venous capacity resulting from postcapillary and renal parenchymal disease.
venular constriction diminishes the overall venular capacity In contrast, patients with parenchymal disease of the
of the peripheral circulation. As a result, the circulating kidney demonstrate an increased plasma volume as diastolic
intravascular volume is redistributed from the periphery to pressure increases (11.6) due to renal mechanisms subserving
the central circulation to increase venous return to the heart volume expansion.
(i.e. cardiopulmonary volume) and, hence, cardiac output

Colloid
Hydrostatic osmotic
pressure pressure
TPR CPV

Precapillary Postcapillary
arterioles venules
Interstitial fluid Capillary
PV

1.3. The four pressure determinants of transcapillary fluid 1.4. The role of pre- and postcapillary tone in regulating
migration elucidated by Starling. plasma volume. TPR, total peripheral resistance; PV,
plasma volume; CPV, cardiopulmonary volume.
Hypertension ch1 16/10/08 14:51 Página 7

Pathophysiology: disease mechanisms 7

32 25

Plasma volume (ml/cm)

22
21
20
20
Plasma volume (ml/cm)

19
15
18
17
16
90 100 110 120 130 140 150 160 170 180
15 Mean arterial pressure* (mmHg)
14
*MAP – diastolic BP + 1/3 pulse pressure
13 B
r = –0.468
12 P = <0.001
80

Total peripheral resistance (units)

80 90 100 110 120 130
Systolic arterial pressure (mmHg) 70
A
corrected for BSA
60
1.5 Relationship between plasma volume and arterial
pressure. Contraction of plasma volume in men with
50
essential hypertension as diastolic (A) or mean arterial
(B) pressures increase or as total peripheral resistance
40
increases in male hypertensive patients with essential
hyprtension or renal arterial disease (C).
30

20
–30 –25 –20 –15 –10 –5 0 5 10 15 20
Total blood volume (% normal)
C

Table 1.5 Clinically recognizable correlates of contracted

intravascular (plasma) volume

• Elevated haemoglobin concentration and haematocrit

• Increased plasma protein concentration (e.g. albumin, fibrinogen)
• Increased blood (and plasma) viscosity
• Hyperuricaemia
Hypertension ch1 16/10/08 14:51 Página 8

8 Pathophysiology: disease mechanisms

High haematocrit and haemoglobin Table 1.6 Forms of hypertension associated with
The higher haematocrit and haemoglobin levels in essential alterations of intravascular (plasma) volume
hypertension explain the clinical term ‘reactive’ or ‘relative’
polycythaemia. This entity is frequently detected in patients
with essential hypertension and was first described by Contracted plasma volume
Gaisböck at the turn of the twentieth century. Unlike • Increasing severity of essential hypertension
polycythaemia rubra vera, there is neither a leucocytosis or • 'High-renin' essential hypertension
thrombocytosis, nor is there associated splenomegaly. The • Renal arterial disease
elevated haemoglobin and haematocrit in Gaisböck
• Phaeochromocytoma
syndrome is classically described in the ‘ruddy’ patient with
essential hypertension with contracted plasma volume. This
relative increase in red cell mass with a reduced plasma Expanded plasma volume
volume has been measured in a large number of patients • Volume-dependent essential hypertension
with essential hypertension. In contrast, some patients have – Low plasma renin activity
a volume-dependent essential hypertension in whom the
– Hypertension in black patients
magnitude of plasma volume is directly related to the height
of arterial pressure (Table 1.6). • Steroid-dependent hypertension
This, then, provides an explanation why those patients – Primary hyperaldosteronism
with essential hypertension have plasma volume contraction – Cushing’s disease or syndrome
may lose effective control of arterial pressure when they are • Renal parenchymal disease (including end-stage
treated only with an adrenergic inhibitor or a direct acting, renal disease)
smooth muscle relaxing vasodilators (e.g. sodium
• Left ventricular failure
nitroprusside in the intensive care situation). Thus, plasma
volume expands as pressure is reduced with treatment and, • Patients with prior contracted plasma volume treated
under these conditions, blood pressure control can then be with smooth muscle vasodilators and alpha-
restored with diuretic administration. Indeed, this explains adrenergic receptor blocking agents
the phenomenon of ‘pseudotolerance’ (1 1.6).

A 185 B

175
Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

165 120

110
155
100
145
90
135
80

125 70

115
70 80 90 100 110 120 PV (% normal)
PV (% normal)

1.6 Expansion of plasma volume in patients with essential hypertension as systolic and diastolic pressures increase when
adrenergic inhibitors or direct-acting smooth muscle relax vasodilators are used.
Hypertension ch1 16/10/08 14:51 Página 9

Pathophysiology: disease mechanisms 9

Oedema hydrostatic pressure in patients with hypertensive

A second clinical example of coincident pre- and nephrosclerosis (i.e. the Brenner hypothesis). Thus, both
postcapillary vasoconstriction may be demonstrated in those afferent and efferent glomerular arteriolar constriction
patients with severe hypertensive retinopathy. It provides an occurs in patients with prolonged systemic arterial hyper-
explanation for the transudation of protein through the tension, with renal parenchymal involvement favouring
retinal capillary bed in patients with accelerated elevated glomerular hydrostatic capillary pressure,
hypertension as well as those with papilloedema associated glomerular ultrafiltration of protein, and consequent
with malignant hypertension (see Chapter 2). A third hyalinosis and glomerulosclerosis. With therapeutic
example relates to development of oedema in patients reduction of afferent and efferent arteriolar resistance (with
receiving calcium antagonists. This oedema is the angiotensin-converting enzyme inhibitors or angiotensin II
consequence not of renal-mediated fluid retention but, receptor blockade), glomerular hydrostatic pressure will also
rather, of the potent drug-induced precapillary arteriolar diminish in association with reduced filtered protein and
dilatation associated with reflex postcapillary constriction. reversal or inhibition of further progression of glomerular
This is particularly experienced with prolonged standing or sclerosis (see Chapter 6). These findings provide credibility
when seated for a long time with the legs dependent. to the concept that angiotensin II participates in the
progression of nephrosclerosis in essential hypertension as
High cardiac output hypertension well as in diabetic renal disease; they also strongly suggest
A fourth example of the phenomenon of pre- and post- that inhibition of angiotensin II confers significant benefit to
capillary constriction provides, in part, a pathophysiological these patients.
explanation for the increased cardiac output and hyper-
dynamic circulation observed during development of Fluid volume partitions
essential hypertension. Thus, early in the elaboration of As originally postulated by Starling, local haemodynamic
hypertension (i.e. patients with borderline or ‘labile’ and other pressure alterations are responsible for the
hypertension), when blood pressure is elevated only at times movement of water across the major body fluid
but is normal at other times, cardiac output is increased. compartments (1 1.3 ). These factors include the local
This increased output is related to the translocation of the capillary hydrostatic and local tissue pressures as well as the
circulating intravascular volume from the periphery to the protein oncotic pressures, intravascularly and extra-
central circulation as a result of the postcapillary (i.e. vascularly. In general, total body water is normal in essential
venular) constriction. Although the total peripheral hypertension and seems to be normally distributed between
resistance at this stage is said to be ‘normal’, it has been the extracellular and intracellular fluid compartments.
suggested that it is ‘inappropriately so’, since, should cardiac However, although there is much epidemiological evidence
output become elevated to the same extent in normotensive suggesting deranged sodium handling in patients with
individuals, their total peripheral resistance would be slightly hypertension, there is little evidence supporting the concept
reduced. With progression of the hypertensive vascular that total body sodium is increased in hypertensive disease
disease and, as the pre- and postcapillary vasoconstriction or that it is associated with expanded total body water or,
increase further, the intravascular (i.e. plasma) volume even, increased blood pressure sensitivity. In contrast,
progressively contracts as described above. This contraction emerging data suggest other effects of sodium excess on
in circulating intravascular volume proportionally heart, aorta, kidney, and vessels. In addition, there is good
diminishes the cardiopulmonary volume, decreases right clinical investigative evidence that the extracellular fluid
atrial venous return and, thus, the cardiac output is reduced volume may be maldistributed in hypertension. Thus, as
to a more normal level than the output observed earlier in intravascular (i.e. plasma) volume becomes contracted in
the disease. patients with essential hypertension, it may be associated
with greater interstitial fluid volume. This movement of
Nephrosclerosis fluid from the intravascular to the extravascular (including
A fifth example, which has more recently become appreci- interstitial) fluid compartments has specific pathophysiological
ated clinically, relates to the increased intraglomerular implications (1 1.7).
Hypertension ch1 16/10/08 14:51 Página 10

10 Pathophysiology: disease mechanisms

(i.e. salt) loading. The major problem lies in the elusive

Body fluid compartments
ability to define just which patients with essential hyper-
Extracellular Intracellular
tension are sodium sensitive and those which are not. The
Plasma best proof in the individual patient is to restrict sodium
RBC Interstitial
intake to see if blood pressure becomes reduced. The sub-
ject currently remains one of great controversy. As we
59Fe describe later, salt excess is associated with structural and
functional derangements of the target organs of the disease.
51Cr

T1824 Hormonal alterations

Because of the controversial role of sodium in essential
131I
hypertension, many studies have focused upon the role of
Inulin adrenal corticosteroids and their regulatory genes in the
Substances used

SO4 pathogenesis of hypertension in at least some patients.

82Br There have been very few patients with essential
42K
hypertension who have demonstrated an abnormality of
24Na
steroidal mechanisms underlying the hypertension disease
D 2O process. In general, aldosterone seems to be synthesized,
THO released, and excreted in proportion to the levels of
Antipyrine stimulation of the renin–angiotensin system in patients with
essential hypertension; there does not seem to be any clear-
cut derangement in adrenal steroid biosynthesis in such
patients. In those patients with abnormalities in steroidal
biosynthesis and release, the derangements are due to
1.7 Extracellular and intracellular body fluid compartments specific adrenal diseases (Cushing’s syndrome and disease,
and the various labels used to determine them primary hyperaldosteronism, hydroxylase and other enzyme
quantitatively. deficiencies). Recent studies in many of these secondary
hypertensions have demonstrated specific genetic enzymatic
abnormalities that account for the steroidal defect.
Hormonal alterations have been demonstrated in other
Sodium metabolism patients with hypertension (Table 1.4).
As suggested above, many epidemiological studies have
demonstrated a direct correlation between the magnitude of Neural mechanisms
dietary sodium intake and the prevalence of hypertension in The autonomic nervous system normally participates in the
many populations. Other studies have shown that in those control of arterial pressure; this role may be altered in
societies with daily sodium dietary intakes of <60 mmol patients with essential hypertension. One would normally
(mEq), hypertension is practically non-existent and these expect that, as arterial pressure increases, heart rate should
populations fail to show a rise in arterial pressure with slow. However, most patients with essential hypertension
ageing. Furthermore, still other epidemiological studies demonstrate a faster resting heart rate than normal. This is
have demonstrated that there may be genetically determined but one manifestation of the phenomenon of the ‘resetting’
alterations in sodium transport across cell membranes in or altered baroreceptor sensitivity in hypertension. In
different populations of patients with essential hypertension. addition, increased release, sensitivity, and excretion of
Notwithstanding the abundance of the above epidemi- norepinephrine (noradrenaline) has been repeatedly
ological data supporting an important role for the sodium demonstrated in patients with essential hypertension and,
ion in essential hypertension, there is a relative paucity of more frequently, in patients with borderline or earlier stages
pathophysiological data confirming this thesis clinically. of the disease. These findings have been supported by the
Indeed, only about one-third of patients with hypertension demonstration of increased serum catecholamine con-
demonstrate increased pressure responsiveness to sodium centration in proportion to the altered haemodynamics in
Hypertension ch1 16/10/08 14:51 Página 11

Pathophysiology: disease mechanisms 11

these patients. The elevation of serum catecholamine normal levels in patients with essential hypertension but not
concentration in these patients, however, is not nearly as in those with phaeochromocytoma.
high as in patients with phaeochromocytoma.
It is of interest that in patients with less severe essential Renopressor system
hypertension, particularly those with a hyperdynamic beta-
adrenergic circulatory state (with or without idiopathic The enzyme renin is released from the juxtaglomerular
mitral valve prolapse syndrome), serum norepinephrine apparatus of the kidney through several mechanisms (Table
(noradrenaline) concentration is frequently elevated. This 1.7). Renin acts on its circulating peptide substrate
finding provides one explanation for the altered haemo- angiotensinogen, produced in the liver, resulting in the
dynamic findings as well as the augmented myocardial generation of the pressor octapeptide angiotensin II (1 1.8). The
contractility, the idiopathic mitral valve prolapse, and the octapeptide apparently generates other peptides whose actions
associated cardiac dysrhythmias. In general, there have been are under active investigation. Angiotensin II has a number of
no alterations reported in catecholamine biosynthesis or in sites of action, most notably in blood vessels and adrenal
release or reuptake of these substances, although increased cortex, to produce vasoconstriction and aldosterone release,
responsiveness of beta-adrenergic receptor sites has been respectively. In addition, angiotensin is also generated locally
reported (see Chapter 5). Furthermore, the reported altered in heart, vessels, kidneys, and other organs with specific local
responses to upright tilting, Valsalva manoeuvres, and actions (Table 1.8). The precise roles for these local systems are
tyramine stimulation of norepinephrine (noradrenaline) not yet clearly known but intracellular generation of
release from nerve endings may provide a useful indication angiotensin II affects muscle protein synthesis, with inherent
of adrenergic neural participation in certain patients with implications relating to the development or reversal of vascular
essential hypertension. and ventricular hypertrophy. Local generation of angiotensin
Several years ago, the clonidine suppression test was II may be of particular importance in: (a) the function of the
introduced to differentiate patients with phaeochromo- cardiac or arteriolar myocyte which produces the peptide (an
cytoma from those patients with essential hypertension (who intracrine function); (b) the effect on neighbouring cells (an
demonstrate smaller elevations of plasma catecholamines). autocrine function); or (c) association with other hormones
Clonidine (a centrally acting adrenergic inhibitor) admini- (e.g. kinins, catecholamines, atrial natriuretic peptide,
stration will suppress elevated catecholamine levels to endothelin) within that organ (a paracrine function) (1 1.9).

Table 1.7 Mechanisms of increased Table 1.8 Sites of action of angiotensin II

renin release from the kidney

Site Action
• Reduced renal blood flow and/or Vascular smooth muscle Vasoconstriction
perfusion pressure Adrenal medulla Release of catecholamines
Adrenal cortex Aldosterone
• Contracted intravascular volume
Medulla of brain Thirst
• Dietary sodium restriction (<100 mmol Medullary centres Augment adrenergic outflow
[mEq]/day) Paravertebral ganglia Augment norepinephrine
• Increased beta-adrenergically mediated (noradrenaline) release
neural input Local synthesis of angiotensin II in:
• Reduced aldosterone levels in blood Heart Myocytic hypertrophy, fibrosis,
• Upright posture apoptosis
Brain Adrenergic outflow
• Hormones or humoral agents (e.g.
Arteries Myocytic hypertrophy, fibrosis
catecholamines)
Other organs (uterus, liver, To be resolved
• Drugs (e.g. diuretics) salivary glands)
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