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least four are influenced beneficially by moderate salt

restriction and high potassium intake: (1) the renin-
angiotensin system and (2) the aldosterone system which are
brought back into their regulatory range where they can help
to control sodium balance ;21 (3) the sympathetic nervous
system (said to be overactive in hypertensive subjects, CORTICAL NEPHRON CONTROL?
especially those with borderline hypertension), which would
raise blood pressure to a lesser extent than would be reached KEITH E. BRITTON
after the usual high sodium/low potassium diet; and (4) the
St Bartholomew’s Hospital, London EC1
baroreceptor reflex which becomes more sensitive. Only very
simple preventive measures can be put into practice on a large Summary Intrarenal plasma-flow distribution has
scale. Since compliance with sodium restriction alone is poor,
been determined non-invasively in man.
and since additional benefits may be expected, replacement of
The reduction in effective renal plasma flow in essential
sodium by potassium deserves a long-term trial for
preventing hypertension. Further studies will be required to
hypertension is due to a reduction in flow to the cortical
confirm whether there indeed exists a salt-sensitive nephrons only; the juxtamedullary nephrons maintain their
flow. A disorder of the autoregulatory control of cortical-
normotensive group who would benefit more from the
nephron flow is postulated to be the genetic defect in essential
regimen than would the population as a
This work was supported partly by the Fonds zur Forderung der wissen-
schaftlichen Forschung, Austria, and by the Jubilaumsfonds der

Correspondence should be addressed to F. S., Universitatsklinik fur IT is not fashionable to seek a single aetiology for essential
Innere Medizin, A-6020 Innsbruck, Austria. hypertension; several interacting factors are preferred. Many
of the findings in essential hypertension may be the results of
readjustments made in response to the raised blood pressure.
REFERENCES The search for a single cause of essential hypertension is
1. Meneely GR, Battarbee HD High sodium-low potassium environment and based on the agreement that there is genetic predisposition to
hypertension Am J Cordiol 1976; 38: 768-85. the disorder. De Wardener and MacGregorl argued, on the
2. Gros G, Weller JM, Hoobler, SW. Relationship of sodium and potassium intake to
blood pressure. Am J Clin Nutr 1971; 24: 605-08. basis of cross-transplantation experiments between
3. Dahl LK. Salt and hypertension Am J Clin Nutr 1972; 25: 231-44.
4. Swales JD. Dietary salt and hypertension. Lancet 1980; i: 1177-79. hypertensive and normotensive strains of rats/-4 that the
5. Morgan T, Adam W, Gillies A, et al. Hypertension treatment by salt restriction. Lancet genetically determined disorder resides in the kidney and
1978; i: 227-30. concluded that the renal abnormality caused the rise in blood
6. Burstyn P, Hornall DEE, Watchorn C. Sodium and potassium intake and blood
pressure. Br Med J 1980; 281: 537-39. pressure in the hypertensive rats and was related to a
7. Parfrey PS, Vandenburg MJ, Wright P, et al. Blood pressure and hormonal changes
following alteration in dietary sodium and potassium in mild essential hypertension
difficulty in the rats’ ability to eliminate sodium, possibly
Lancet 1981; i: 59-63.
caused by a saluretic Na/K ATPase inhibitor. They
8. Brown JJ, Lever AF, Robertson JIS, Schalekamp MADH. Renal abnormality of suggested that in essential hypertension there is continuous
essential hypertension. Lancet 1974; ii: 320-22.
correction of a slightly raised extracellular fluid volume and
9 Omvik P, Tarazi RC, Bravo EL Regulation of sodium balance in hypertension
Hypertension 1980, 2: 515-23 hence the increased response to a saline load. De Wardener
10. Davies MH. Is high blood pressure a psychosomatic disorder? A critical review of the and MacGregor’s hypothesis’and other hypotheses based on
evidence. J Chronic Dis 1971, 24: 239-58
11. Cochrane R. High blood pressure as a psychosomatic disorder- a selective review Br J primary retention of salt and water by the kidneys5-’ postulate
Soc Psychol 1971; 10: 61-72 that the extracellular fluid volume is raised, yet Dickinson8
12. Esler M, Julius St, Zweifler A, et al. Mild high-renin essential hypertension
has pointed out that "blood and plasma volumes in early
Neurogenic human hypertension? N Engl Med J 1977; 296: 405-11.
13. Sleight P Neurophysiology of the carotid sinus receptors in normal and hypertensive essential hypertension have almost invariably been found to
animals and man. Cardiology 1976; 61 (suppl. 1): 31-45.
be slightly less than normal in large series" and that, in
14. Korner PI, West MJ, Shaw J, et al ’Steady state’ properties ofthe baro-receptor-heart
rate reflex in essential hypertension in man. Clin Exp Pharm Physiol 1974; 1: 65-76. keeping with a reduced circulating volume, the heart rate in
15. Skrabal F, Aubock J, Hörtnagl H, et al Effect of moderate salt restriction and high essential hypertension is slightly increased.
potassium intake on pressor hormones, response to noradrenahne and baroreceptor
function in man Clin Sci 1980; 59: 157s-160s There is, however, agreement that two abnormalities are
16 Boyd GW, Adamson AR, Fitz AE, et al Radioimmunoassay determination of plasma- found in most patients with essential hypertension, a
renin activity Lancet 1966; i: 213-17.
17. Ito T, Woo J, Haning R, et al. A radioimmunoassay for aldosterone in human
reduction in renal plasma flow and a -rise in peripheral
peripheral plasma including a comparison of alternate techniques. J Clin Endocrinol resistance. Blaustein9 suggested that the rise in peripheral
1972; 34: 106-12. resistance may be due to increased intracellular salt and thus
18. Robertson GL, Mahr EA, Athar S, et al. Development and clinical application of a new
method for the radioimmunoassay of arginine vasopressin in human plasma J Clin calcium concentrations which would augment the tension in
Invest 1973; 52: 2340-52 the arteriolar wall. Other workers believe that vasconstriction
19. Hörtnagl H, Benedict CR, Grahame Smith DG A sensitive radioenzymatic method
for adrenaline and noradrenaline in plasma Br J Clin Pharmacol 1977; 4: 533-58. may be augmented by circulating or intramural substances
20. Parfrey PS, Condon K, Wright P, et al. Blood pressure and hormonal changes
following alteration in dietary sodium and potassium in young men with and
without a familial history of hypertension. Lancet 1980; i 13-17.
21. Skrabal F Aldosterone and in vivo mineralocorticoid activity in normotensive and
hypertensive man. J Roy Soc Med 1979; 72: 252-59 25. Sullivan JM, Ratts TE, Taylor Ch, et al. Hemodynamic effects of dietary sodium in
22. Fujita T, Henry WL, Banter FC, et al Factors influencing blood pressure in salt- man. A
preliminary report. Hypertension 1980, 2: 506-14
sensitive patients with hypertension. Am J Med 1980; 69: 334-44. 26. Liddle GW, Bennett LL, Forsham PH. The prevention of ACTH-induced sodium
23. Ames RP, Borkowski AJ, Sicinski AM, et al Prolonged infusions of angiotensin II and retention by the use of potassium salts a quantitative study. J Cim Invest 1953, 32:
norepinephrine on blood pressure electrolyte balance and aldosterone and cortisol 1197-201
secretion in normal man and in cirrhosis with ascites J Clin Invest 1965; 44:
27. Rocchini AP, Cant JR, Barger
AC. Carotid sinus reflex in dogs with low- to high-
sodium intake. Am Physiol 1977; 233: H 196-202
24 Luft FC, Rankin LI, Henry DP, et al. Plasma and urinary norepinephrine values at 28. Kunze DL, Saum WR, Brown AM. Sodium sensitivity of baroreceptors mediates
extremes of sodium intake in normal man Hypertension 1979; 1: 261-66. reflex changes of blood pressure and urine flow Nature 1977; 267: 75-78
29. Saum WR, Ayachi S, Brown AM. Actions of sodium and potassium ions on
baroreceptors of normotensive and spontaneously hypertensive rats Circ Pes 1977.
41: 768-74

such as angiotensin, 10,1 I vasopressin,I2

or adrenaline, either JUXTAMEDULLARY NEPHRONS
alone13 in association with increased efferent sympathetic
Juxtamedullary nephrons do not have thick-walled afferent
activity,14 or by the absence of the vasodilator properties of arterioles, do not have the juxtaglomerular apparatus, and do
certain substances such as prostaglandinsls or kinins.I6 not autoregulate. Therefore, with a rise in blood pressure
However, the maintenance of raised blood pressure requires their flow increases and tends to wash out the osmolar
some resetting of the renal control of salt and water to prevent
concentration gradient in the medulla and reduce the
a pressure-induced diuresis.17 concentrating ability of the kidney. Indeed, nocturia is found
TWO POPULATIONS OF NEPHRONS early in many patients with essential hypertension. Because
of the reduced concentrating ability, the extracellular and
Renal plasma flow in essential hypertension is reducedl8 plasma volumes may not increase despite the retention of salt
but the specific feature of flow that is reduced is not known. by the kidneys. Thus at homoeostasis in essential
No hypothesis of the cause of essential hypertension has hypertension there is relative salt retention, due to the lower
taken account of the range of nephrons in the kidney, which afferent-arteriolar flow and the reduced peritubular capillary
may be classified into two main populations, the cortical pressure of the cortical nephrons, and a relative reduction in
nephrons and the juxtamedullary nephrons. This is partly plasma volume, due to the increased pressure and increased
because there was no rigorous method for measuring non- post-glomerular flow of the juxtamedullary nephrons. The
invasively the relative functioning of these two populations of retained salt is distributed through all parts of the body
nephrons in man until our technique was developed.I9 It is including the afferent arterioles.26 The tendency for tissues to
based on the fact that cortical nephrons have short loops and retain salt may be enhanced by a circulating sodium-transport
therefore shorter transit times for a non-reabsorbable solute, inhibitor.27
123I-orthoiodohippurate (OIH), than the long-looped The diuretic response to a saline load in essential
juxtamedullary nephrons. The proportion of the total OIH hypertension may also be attributed to the failure of a
that takes the shorter transit time gives the proportion of relatively higher juxtamedullary-nephron flow to maintain
effective renal plasma flow to the cortical nephrons. We have adequate urine-concentrating ability. Before intrarenal flow
shown that the reduction in renal plasma flow that occurs in distribution could be measured, it was apparently assumed
essential hypertension is caused solely by a reduction in flow that the reduction of renal plasma flow in essential
to the cortical nephrons (table 1), the juxtamedullary
hypertension meant that the juxtamedullary-nephron flow
nephrons maintain normal or relatively increased post- was reduced; such an explanation was, therefore, discounted.
glomerular flow. I postulate here that there is an over-contraction of cortical-
CORTICAL NEPHRONS nephron afferent arterioles in response to a physiological rise
in blood pressure in the genetically hypertensive and that the
Cortical nephrons are autoregulatory-i.e., they maintain insidious effects of this over-contraction lead to the changes in
the constancy of their plasma flow and glomerular filtration salt homoeostasis and to essential hypertension. A minimum
rate during blood pressure changes in the physiological salt intake of 60 mmol/day may be needed for the expression
range. They have thick-walled afferent arterioles with renin- of this postulated disorder of cortical-nephron auto-
containing granular cells which form, with the macula densa regulation.’ Dependence on salt intake would help to grade
segment of the early distal tubule, the juxtaglomerular the response in the disorder, consistent with the gradation of
apparatus. This is a control system which responds to sodium normotension through to hypertension found in most
chloride in the cortical-nephron early distal tubule21and, populations.
through the local renin-angiotensin system, adjusts cortical-
nephron afferent-arteriolar tone. A rise in perfusion pressure EFFECT OF DRUGS
increases the salt content of the macula densa segment,
releases renin locally in the juxtaglomerular apparatus and, Certain drugs have been shown to improve cortical-
through local production of angiotensin II, increases nephron plasma flow. For example, nadolol administration
increases effective renal plasma flow and cortical-nephron
cortical-nephron afferent-arteriolar tone to subserve
autoregulation.zz,a3. plasma flow in essential hypertension in spite of a fall in
Consider a genetically determined disorder of this control cardiac output28 (table II). It is possible that nadolol might
have a beneficial effect on essential hypertension if
system such that a physiological rise in blood pressure in the
course of every-day activities gives an over-compensatory
introduced early in its course.
increase in cortical-nephron afferent-arteriolar tone, Normotensive subjects and patients with essential
reducing cortical-nephron plasma flow and peritubular hypertension show proportionally the same response to
capillary pressure and thereby enhancing the passive captopril,29 which suggests that this inhibitor of angiotensin
component of proximal tubular water and reabsorption of converting enzyme interferes with a normal mechanism
electrolytes,24,25 notably salt and calcium. Plasma and working normally in both groups of subjects. Our recent
extracellular volume would tend to increase but would be
for by the continuing flow to the TABLE 11-THE EFFECT OF NADOLOL ON CORTICAL-NEPHRON FLOW
juxtamedullary nephrons.

BP =blood pressure. BP= blood pressure; ERPF effective renal plasma flow; NS not significant.


Reviews of Books

Hyperviscosity in Hypertension
Leopold Dintenfass, University of Sydney. Rushcutter’s Bay, Australia,
and Oxford: Pergamon. 1981. Pp. 250.$38.50; 17.50.
BP= blood pressure, Dosages of captopril=25-75mg, three nmes daily. ARTERIAL pressure is determined by cardiac output and by total
peripheral resistance, which in turn is dependent on both arteriolar
work with captopril suggests that the drug, which would be calibre and blood viscosity. This monograph aims to "convince
expected to inhibit the renin-angiotensin-dependent specialists in the field of hypertension that rheology of blood plays a
autoregulatory response of the cortical nephrons, increases crucial, if so far a very neglected, role". To this end it marshals
"hidden information from the literature" suggesting that the links
their fraction of renal plasma flow as blood pressure is between hypertension and haematocrit/blood viscosity are causal
reduced (table III). rather than coincidental. It then goes on to present material which
suggests to the author that the body has a system of regulating blood
CONCLUSION viscosity and that hypertension results from a breakdown of this
feedback mechanism. Dr Dintenfass considers that there are visco-
The hypothesis suggests that the genetically determined
defect in essential hypertension is a defect ofcortical-nephron receptors in vessel walls which can bring about changes in viscosity
by modifying red-cell rigidity. Whatever judgment posterity and his
autoregulatory control in the juxtaglomerular apparatus present readers may pass on this concept, it is true that there is
which causes a reduction in cortical-nephron flow, changes in increasing interest in abnormalities of sodium/potassium flux across
salt homoeostasis, and a rise in peripheral resistance and red cell membranes in hypertensive subjects and that some of the
blood pressure in consequence. Therapeutic correction of drugs used to manage high blood pressure, such as beta-blockers,
this defect may influence the natural progression of essential reduce blood viscosity as well as alter cardiac output and peripheral
hypertension. resistance.
The book has been produced direct from typescript and many of
The technique for intrarenal blood flow measurement in man was developed
the figures have been over-reduced to the point of illegibility.
with Cyril Nimmon and Simon Gruenewald, whose work is gratefully
Dintenfass’ conviction that viscosity plays a central role in many
acknowledged. vascular diseases and the way he has pursued this belief with single-
minded dedication over a working lifetime may also deter some
readers and detract from the very real merits of his case. Despite the
1. De Wardener HE, MacGregor GA. Dahl’s hypothesis that a saluretic substance may element of personal involvement, as illustrated by the fact that ten of
be responsible for a sustained rise in arterial pressure: its possible role in essential
the forty-eight pages of references consists of papers in which the
hypertension. Kidney Int 1980; 18: 1-9.
2. Dahl LK, Heine M, Thompson K. Genetic influence of the kidneys on blood pressure: author is the first-named contributor, the book deserves careful
evidence from chronic renal homografts in rats with opposite predispositions to scrutiny by anyone working in this area.
hypertension. Circ Res 1974; 34: 94-101.
3. Dahl LK, Heine M. Primary role of renal homografts in setting chronic blood pressure Department of Medicine,
levels in rats. Circ Res 1975; 36: 692-96. University of Nottingham J. R. A. MITCHELL
4. Fox U, Bianchi G. The primary role of the kidney in causing the blood pressure
difference between the Milan hypertensive strain and normotensive rats Clin Exp
Pharmacol Physiol 1976; 3 Suppl 3: 71-74.
5. Borst JGG, Borst de Geus A. Hypertension explained by Starling’s theory of Current Hematology
circulatory homeostasis. Lancet 1963; i: 677-82.
6. Ledingham JM, Cohen RD. Changes in the extracellular fluid volume and cardiac Vol. 1. Edited by V. F. Fairbanks, Mayo Medical School, Minnesota. New
output during the development of experimental renal hypertension. Canad Med York and Chichester: John Wiley. 1981. Pp. 673. ;C38.50.
Assoc J 1964; 90: 292-94. THE contributors to this ingenious hybrid of reference textbook
7. Coleman TG, Guyton AC. Hypertension caused by salt loading in dogs. Circ Res 1969;
25: 153-60. and up-to-date specialist review were asked "to review the literature
8. Dickinson CJ. Neurogenic hypertension revisited. Clin Sci 1981, 60: 471-77. of the last few years and to indicate where notable progress has been
9. Blaustein MP. Sodium ions, calcium ions, blood pressure regulation and hypertension:
made" and to give a "critical interpretive review of the most
a reassessment and a hypothesis. Am J Physiol 1977; 232: C165-73.
10. Dickinson CJ, Lawrence JR A slowly developing pressor response to small recently published articles". 80% of the 3000 or so papers reviewed
concentrations of angiotensin, its bearing on the pathogenesis of chronic renal were published during 1977-81. The material selected is biased
hypertension. Lancet 1963; i: 1354-56. strongly in favour of the biological, immunological, or molecular
11. Laragh JH. The renin system in high blood pressure from disbelief to reality:
basis of haematological disease. The book starts with an account of
converting enzyme blockade for analysis and treatment. Prog Cardiovasc Dis 1978;
21: 159-66. the application of restriction endonuclease mapping to globin gene
12. Khokhar AM, Slater JDH. Increased renal excretion of arginine—vasopressin during
mild hydropenia in young men with mild essential benign hypertension. Clin Sci
Mol Med 1976; 51: 691S-94S.
13. Engelman K, Portnoy B, Sjoerdsma A. Plasma catecholamine concentrations in
patients with essential hypertension. Circ Res 1970; 27 (Suppl I): 141-45. 22. Britton KE. Renin and renal autoregulation. Lancet 1968; 329-33.
14. Dickinson CJ. Neurogenic Hypertension. Oxford: Blackwell, 1965.
23. Thurau K, Dahlheim H, Gruner A, Mason J, Granger P. Activation of renin m the
15. Vane JR, McGriff JC. Possible contributions of endogenous prostaglandins to the
control of blood pressure. Circ Res 1975; 37 (suppl I): 68-75.
single juxtaglomerular apparatus by sodium chloride in the tubular fluid at the
macula densa. Circ Res 1972; 31 (Suppl II): 182-86.
16. Keiser HR. The kallikrein-kmin system in essential hypertension. Clin Exp 24. Fromter E, Rumrich G, Ullrich KJ. Phenomenologic description of Na+ Cl - and
Hypertension 1980; 2: 675-91. HCO3- absorption from proximal tubules of the rat kidney. Pflugers Arch 1973.
17. Guyton AC. Arterial Pressure and Hypertension. Philadelphia: WB Saunders, 1980.
343: 189-220.
18. Chasis H, Redish J. Effective renal blood flow in the separate kidneys of subjects with
essential hypertension. J Clin Invest 1941; 20: 655-61.
25. Earley LF, Friedler RM. Effects of combined renal vasodilatation and pressor agents
on renal hemodynamics and tubular reabsorption of sodium J Clin Invest 1966; 45:
19. Britton KE. The measurement of intrarenal flow distribution in man. Clin Sci 1979;
56: 101-04.
26. Tobian L, Binion JT. Tissue cations and water in arterial hypertension. Circulation
20. Gruenewald SM, Nimmon CC, Britton KE. A non invasive gamma camera technique
1952; 5: 754-58.
for the measurement of intrarenal flow distribution in man. Clin Sci 1981; 61:
27. Poston L, Sewell RB, Wilkinson SP, et al. Evidence for a circulating sodium transport
inhibitor in essential hypertension. Br Med J 1981; ii: 847-49.
21. Schnermann J. Regulation of filtrate formation by feedback. In: Giovannetti S,
28. Britton KE, Gruenewald SM, Nimmon CC. Nadolol and renal haemodynamics In
Bonomim V, D’Amico G, eds. 6th International Congress of Nephrology. Basel: S.
International Experience with Nadolol. International Congress Symposium series
Karger, 1975: 230-34. London: Royal Society of Medicine, 1981; 37: 77-86.
29. MacGregor GA, Markandu ND, Roulston JE, Jones JC. Essential hypertension effect
of an oral inhibitor of angiotensin-converting enzyme. Br Med J 1979, ii 1106-09