225
ClinicalScience(1986)71, 225-230
HYPOTHESIS
Ion transport in hypertension: are changes in the cell membrane
responsible?
ROBERT F. BING, ANTHONY M. HEAGERTY, HERBERT THURSTON
JOHN D. SWALES
Department of Medicine, University of Leicester, Leicester, U.K.
Summary
Disturbances in several, distinct cell membrane ion
transport processes have been demonstrated in
essential hypertension but their variable relationship to blood pressure in different populations
has made it difficult to achieve a unifying hypothesis. We suggest that altered composition of the lipid
fraction of the cell membrane is the common underlying factor. This would produce many of the
reported perturbations of cell membrane properties
and function, not all of which relate directly to the
development of hypertension, but which act as
markers for the underlying abnormality. However,
functions such as phosphoinositol turnover, calcium
binding and Ca2+,Mg2+-ATPasedependent calcium
efflux, which are influenced by the lipid composition of the membrane, provide a possible link
between the membrane disturbance, intracellular
calcium, vascular smooth muscle contraction and
blood pressure. Alteration in the lipid content of the
cell membrane not only provides an explanation for
the variability in the ion transport abnormalities
between populations but perhaps also for some of
the variability in blood pressure within a single
population. It also provides a potential means of
influencing blood pressure by dietary intervention.
Introduction
High blood pressure can be regarded as a manifestation of the biological variability of a characteristic
that in most populations shows a continuous, unimodal distribution, but which assumes unique
importance because of its association with cardiovascular morbidity [l]. Perhaps it is not unexpected
that for a multifactorial condition such as essential
hypertension no single underlying mechanism to
Correspondence: Dr R. F. Bing, Department of Medicine, Clinical Sciences Building, Royal Infirmary
Leicester,P.O.Box 65, Leicester LE2 7LX, U.K.
AND
explain the blood pressure rise has been identified.
Nevertheless elucidation of the physiological and
biochemical mechanisms that hnderly this variability in blood pressure may Lad to a greater
understanding of blood pressure control and to the
development of new ways of lowering blood pressure.
The first step is to identify abnormalities that are
associated with high blood pressure. The increasing
number of reports of alterations in cellular cation
transport in blood cells in hypertension [Z-51 suggests such changes may reflect an aspect of cell
membrane function that influences blood pressure
by involvement of tissues directly concerned with
blood pressure control. The fact that multiple,
distinct transport systems appear to be altered
makes interpretation difficult. In addition, the relationship between such alterations and blood pressure seems to vary in different populations.
The central question is whether a umfying
hypothesis can be put forward to account for these
disparate findings and, if so, can this explain the
development of hypertension?
Membrane sodium/potassium transport
Increased erythrocyte sodium content in essential
hypertension has been reported by the majority of
workers although by no means all [2-51, and a similar change has been demonstrated in the leucocyte
[6, 71. This would imply a disturbance in the relationship between sodium influx, sodium pump
activity and intracellular sodium. Many groups have
observed enhanced sodium and potassium influx in
erythrocytes from hypertensive patients, using a
variety of methods [2, 3, 5, 8-12]. In some cases, a
rise in cell sodium with a fall or no change in the
rate constant for sodium efflux suggests the
sodium pump is not responding adequately. This
has been most consistently observed in the leucocyte [2,3,5,6,13,14].
R. F. Bing et al.
226
Circulating factors
Stress
Diet
I
I
Ill
Ca*+,MgzC-ATPase
calcium binding
Phosphoinositol
I i""
lntracellular
calcium
I
lntracellular
sodium
Smooth muscle
contraction
FIG. 1. Relationship between environmental and
genetic factors, the cell membrane and ion transport with smooth muscle contraction.
There is other evidence that the disturbances of
blood cell ion transport are multiple and only
loosely associated with hypertension. Thus,
sodium-potassium co-transport first reported to be
reduced has in other studies been normal or
increased [2, 3, 5, 15-17]. Also sodium-lithium
counter-transport has been reported to be raised in
the majority although not all of populations studied
[2,3,5, 17-21]. This measurement is thought to reflect predominantly sodium-sodium exchange; however, its true physiological role is unknown. These
discrepancies probably partly reflect differences in
methodology but perhaps more importantly differences in the composition of the populations
studied [2, 3, 15, 16, 22, 231. Another significant
point is that abnormalities in for instance
sodium-sodium counter-transport are unlikely to
produce a net change in intracellular sodium [24,
251. It is therefore difficult to see their relevance to
blood pressure elevation through a sodium dependent mechanism, although they may reflect a more
generalized membrane defect [3,26].
Explanatory hypothesis
The direct link. Blaustein [27] proposed that
accumulation of intracellular sodium in vascular
smooth muscle inhibited a postulated sodium-cal-
cium exchange mechanism, resulting in a rise in free
intracellular calcium and vascular contractility.
Other groups have suggested that intracellular
sodium is raised as a consequence of inhibition of
the sodium pump by a circulating factor produced
in response to an inherited defect in renal sodium
excretion [28, 291. These explanations have not
been generally accepted for the following reasons.
(a) Doubts about the existence of sigmficant
sodium-calcium exchange in vascular smooth
muscle [30]. (b) Failure to isolate or characterize a
specific sodium transport inhibitor from plasma
and thus to differentiate it from other factors in
plasma, such as noradrenalie, that can influence
sodium transport [31] and are altered in hypertension [32]. (c) Difficulty in demonstrating inhibition
of the sodium pump as a consistent result of chronic
sodium loading [12, 33, 341. (d) The presence of
abnormalities in sodium transport pathways other
than the sodium pump, referred to above, and the
inability to demonstrate raised intracellular sodium
as the final common pathway with these abnormalities.
The lipid hypothesis. An alternative explanation
attributes disturbances of ion transport to an intrinsic abnormality in the physicochemical structure of
the cell membrane associated with essential hypertension [ 13, 261. Since the cation transport systems
that are altered in hypertensive populations are, as
far as is known, independent of each other and of
cell membrane permeability [35], it is necessary to
postulate either multiple abnormalities or a global
disturbance which influences several pathways.
This suggests that the phospholipid bilayer may be
implicated since the transport systems are located
in that structure. The proportion of different lipids
in the cell membrane is known to influence both the
physical properties and active processes of the
membrane and disturbances in several of these
functions have been reported in essential hypertension. Thus an alteration in cell membrane lipids in
this condition could explain disturbances in ion
transport and in other membrane functions which
independently increase vascular smooth muscle
activity.
Evidence for the lipid hypothesis
The lipid hypothesis yields a series of testable predictions: (1)Alterations in membrane lipids in vivo
should influence cation transport. (2) Changes in
cell membrane lipids should be demonstratable in
those tissues from hypertensive subjects where
cation transport is altered. (3) It should be possible
to define a physiological process which links plasma
membrane disturbance to elevated blood pressure.
(4) Therapeutic interventions which modlfy plasma
Zon transport in hypertension
membrane lipids should influence blood pressure as
well as ion transport in vivo.
Effect of alterations in membrane lipids
The composition of the lipid bilayer is not fixed
and changes in its chemical and physical structure
readily occur, for instance when catecholamines
bind to adrenoceptors in a target tissue [36].
Similarly, alterations in the proportion of unsaturated to saturated fatty acids in the acyl sidechains of membrane phospholipids have been
shown to influence membrane fluidity, transport of
ions and Na+,K+-ATPaseactivity [37-391. Ouabain
resistant ion fluxes can also be modified by changes
in the physicochemical properties of the erythrocyte membrane both in vivo and in vitro [38,
40-421. Thus, increasing membrane linoleic acid by
dietary intervention produces an increase in
erythrocyte ouabain resistant fluxes in normal individuals [43]. Also a relationship between plasma
lipids, in particular high density lipoproteins, and
sodium-lithium exchange has been reported in nor- motensive and hypertensive individuals [44, 451.
Another approach is to induce a change in the
micellar structure of the erythrocyte membrane by
altering its electrostatic charge. This can be
achieved by substituting the permanent anion
nitrate for chloride in the suspension medium [46].
When this is done permeability is increased
together with intracellular sodium and absolute
sodium efflux rate, although the sodium efflux rate
constant for active sodium pumping (i.e.the component of the sodium pump to respond to increased
sodium) is decreased [47]. This constellation of
changes resembles that described by some groups
in essential hypertension [2-51.
Membrane lipids in hypertension
As in the case of ion transport the erythrocyte
has been most frequently studied because of its
accessibility. Decreased erythrocyte membrane
fluidity, which reflects membrane lipid composition,
has been reported in essential hypertension [48]and
in the spontaneously hypertensive rat [49]. A cell
membrane lipid disturbance has been associated
directly with altered ion transport in a study by
Levy et al. [18].When the ambient temperature is
reduced, cell membrane lipids undergo a change in
physical state. At this temperature (the phase transition temperature) lipid dependent membrane functions show an abrupt change. The phase transition
temperature for erythrocyte sodium-lithium counter-transport is sigrhcantly altered in hypertensive
patients and their relatives. There is also some
direct evidence of alteration in membrane lipids in
227
essential hypertension: sialic acid content has been
reported to be increased [50]and the content of the
polyunsaturated fatty acid, linoleic acid, decreased
[5 11.In addition the linoleic acid content of adipose
tissue and platelets has been shown to be negatively
correlated with blood pressure [52,53].
Plasma membrane and hypertension
Haemodynamically most forms of hypertension
are characterized by raised peripheral resistance.
An essential participant in the control of vascular
smooth muscle contraction, and thereby vascular
tone, is the intracellular calcium ion concentration
[54].Those abnormalities that could influence intracellular ionized calcium may therefore be of particular relevance to the development of
hypertension. This could be altered secondarily as a
result of membrane depolarization caused by
increased permeability [55]. Alternatively, calcium
handling could be influenced directly [56]. Three
membrane functions of relevance to calcium handling are altered in essential hypertension: phosphoinositol turnover, calcium binding and
Ca2+,Mg2+-ATPasedependent calcium efflux [37,
57-59]. Hydrolysis of membrane lipid phosphinosito1 produces inositol triphosphate. This system has
recently been recognized to be important as a
second messenger in the release of intracellular calcium stores [60].Erythrocyte phosphoinositol turnover is abnormal in essential hypertension [61].
Phospholipidsmay also contribute to the decreased
calcium binding to the inner surface of the cell
membrane found in hypertension [48,62], which is
also influenced by membrane lipid composition
[63]. Ca2+,Mg2+-ATPase
dependent calcium efflux
has been shown to be reduced in erythrocytes in
hypertension, particularly in the presence of calmodulin [64]. The activity of this enzyme and its
responsiveness to calmodulin can be modified by
the type of phospholipid in the adjacent bilayer [59].
The measurement of intracellular calcium has
until recently been difficult in human cells. Two
reports of elevated levels have been made: using ion
selective electrodes to measure calcium activity in
disrupted erythrocytes [65] and using the fluorescent indicator Quin-2 to measure ionized calcium
in intact platelets [66].In the latter study intracellular ionized calcium was positively correlated with
blood pressure. However, studies using human
leucocytes have failed to confirm these findings [67,
681, and the role of abnormalities in calcium handling in essential hypertension will have to await
studies of human vascular smooth muscle. Nevertheless there is evidence that changes in blood cells
do reflect similar alterations in more relevant tissues. Thus, analogous abnormalities of sodium
228
R. F. Bing et a[.
influx, sodium efflux, phosphoinositol turnover and
calcium handling in vascular smooth muscle and
other tissues have been reported in the spontaneously hypertensive rat [3,4,26, 56,60,62,69,70].
This supports the view that these membrane defects
are widespread and that circulating blood cells may
be analogous to vascular smooth muscle.
Therapeutic iriterventiori
Although some aspects of cell membrane composition may be inherited and therefore account for
the differences in blood pressure between individuals and for the altered cellular responses to factors such as circulating hormones and stress, they
are amenable to modification by environmental factors such as diet. Whilst study of dietary influences
on blood pressure has been focused upon electrolyte intake, it is possible that dietary lipids may
account for the lower blood pressures repeatedly
reported in vegetarians [711. Increasing polyunsaturated fat intake, or the ratio of unsaturated to saturated fat, has produced a fall in blood pressure in
several studies in man [72-7.51 and in the rat [76,
771. The relevant dietary change has not been
adequately defined. In one study when dietary
unsaturated to saturated fat ratio was altered without an overall change in fat intake no blood pressure fall was observed [78].O n the other hand, in a
recent double-blind trial linoleic acid supplementation produced a significant fall in systolic
blood pressure and an increase in leucocyte
ouabain sensitive sodium efflux in normal man [43].
Moreover, exercise induced changes in plasma
lipids have been associated with changes in
sodium-lithium exchange [44]. T h e possible manipulation of cell membrane composition by dietary
intervention is an attractive one which deserves
further study.
To test this hypothesis two major criteria need to
be met. Firstly the demonstration that changes in
leucocyte and erythrocyte cation transport and/or
plasma membrane composition reflect a global
change in all cells but in particular the vascular
smooth muscle cell. In man data on this are poor
but a relationship between ouabain sensitive
sodium efflux in leucocytes and mesenteric resistance vessels has recently been reported [79].
Secondly that induced changes in the cell membrane physical properties or lipid composition are
associated with changes in blood pressure and
membrane cation transport, that reflect the differences described between hypertensive and normotensive subjects. Also the relationship between the
distribution of blood pressure and the distribution
of cell membrane properties such as fluidity or lipid
composition in a single population will show how
much of the variability in blood pressure can be
attributed to changes in the cell membrane.
Conclusions
Changes in cell membrane lipid composition provide an explanation not only for the multiple disturbances of monovalent cation fluxes in essential
hypertension, but also for alterations in vascular
smooth muscle contractility through changes in
intracellular ionized calcium and partial depolarization of the cell. Because of the number of permutations of lipid, content possible, this explanation
would account for the variability in the associations
reported between blood pressure and ion transport
abnormalities in different populations, which has
been a feature of the extensive and conflicting
studies in this field. Further, it is possible to account
for changes in ion fluxes (such as sodium-sodium
counter-transport) which would not be expected to
change intracellular composition. Such abnormalities can be considered as loosely associated
markers for the underlying cell membrane defect.
Differences in cell membrane lipids may be inherited but could also be the result of environmental factors such as diet and stress. Further
elucidation of the role of cell membrane composition in the control of intracellular mechanisms may
not only explain some of the puzzling changes
reported in hypertension but also provide a rational
basis for public health measures to lower blood
pressure.
References
1. Pickering, G.W. (1986) High Blood Pressure, 2nd
edn. J. & A. Churchill, London.
2. Parker, J.C. & Berkowitz, L.R. (1983)Physiologically
instructive genetic variants involving the human red
cell membrane. Physiological Reviews, 63, 26 1-3 13.
3. Swales, J.D. (1983) Abnormal ion transport by cell
membranes in hypertension. In: Handbook of Hypertension, pp. 239-266. Ed. Robertson, J.I.S. Elsevier
Press, Amsterdam.
4. Friedman, S.M. (1983)Cellular ionic perturbations in
hypertension.Journal of Hypertension, 1, 109-1 14.
5. Hilton, P.J. (1986) Cellular sodium transport in
essential hypertension. New England Journal of
Medicine, 314,222-229.
6. Edmondson, R.P.S., Thomas, R.D., Hilton, P.J.,
Patrick, J. & Jones, N.F. (1975)Abnormal leucocyte
composition and sodium transport in essential hypertension. Lancet, i, 1003-1005.
7. Ambrosioni, E., Costa, E.V., Montebugnoli, L.,
Tartagni, F. & Magnani, B. (1981) Increased intralymphocytic sodium content in essential hypertension: an index of impaired Na cellular metabolism.
Clinical Science, 6 1,181-186.
8. Birks, R.I. & Langlois, S . (1982)Ouabain-insensitive
net sodium influx in erythrocytes of normotensives
and essential hypertensive humans. Proceedings of
the Royalsociety London, Series B, 216,53-69.
9. Cole, C.H. (1983) Erythrocyte membrane sodium
transport in patients with treated and untreated
essential hypertension. Circulation, 68, 17-22.
10. Talib, H.K.,
Chipperfield, A.R. & Semple, P.F. (1984)
Potassium influx into erythrocytes in essential hypertension. Journal of Hypertension, 2,405-409.
Ion transport in hypertension
11. Boon, N.A., Aronson, J.K., Hallis, K.F., Raine,
A.E.G. & Graham-Smith, D.G. (1985) An in vivo
study of cation transport in essential hypertension.
Journal of Hypertension, 3 (Suppl. l),457-459.
12. Feig, P.U., Mitchell, P.P. & Boylan, J.W. (1985)
Erythrocyte membrane transport in hypertensive
humans and rats. Hypertension, 7,423-429.
13. Heagerty, A.M., Milner, M., Bing, R.F., Thurston, H.
& Swales, J.D. (1982) Leucocyte membrane sodium
transport in normotensive populations: dissociation
of abnormalities of sodium efflux from raised blood
pressure. Lancet, ii, 894-896.
14. Forrester, T.E. & Alleyne, G.A.O. (1981) Sodium,
potassium and rate constants for sodium efflux in
leucocytes from hypertensive Jamaicans. British
Medical Journal, 283,5-8.
15. Adragna, N.C., Canessa, M.L., Solomon, H., Slater,
E. & Tosteson, D.C. (1982) Red cell lithium-sodium
countertransport and sodium-potassium cotransport
in patients with essential hypertension. Hypertension,
4,795-804.
16. Canessa, M.L., Spulvins, A., Adragna, N.C. & Falkner, B. (1984) Red cell sodium countertransport
and cotransport in normotensive and hypertensive
blacks. Hypertension, 6,344-351.
17. Wiley, J.S., Clarke, D.A., Bonacquisto, L.A., Scarlett,
J.D., Harrap, S.B. & Doyle, A.E. (1984) Erythrocyte
cation transport and countertransport in essential
hypertension. Hypertension, 6,360-368.
18. Levy, R., Paran, E., Keynan, A. & Livne, A. (1983)
Essential hypertension: improved differentiation by
the temperature dependence of Li efflux in erythrocytes. Hypertension, 5,821-827.
19. Brugnara, C., Corrocher, R., Foroni, L., Steinmayr,
M., Bonfanti, F. & De Sandre, G. (1983)
Lithium-sodium countertransport in erythrocytes of
normal and hypertensive subjects. Relationship with
age and plasma renin activity. Hypertension, 5 ,
529-534.
20. Williams, R.R., Hunt, S.C., Kurda, H., Smith, J.B. &
Ash, K.O. (1983) Sodium-lithium countertransport
in erythrocytes of hypertension prone families in
Utah. Journal of Epidemiology, 118,338-344.
21. Cooper, R., Trevisan, M., Ostrow, D., Sempos, C. &
Stamler, J. (1984) Blood pressure and sodiumlithium countertransport: findings in populationbased surveys. Journal of Hypertension, 2,467-471.
22. Beutler, E., Kulhl, W. & Sacks, P. (1983) Sodiumpotassium ATPase activity is influenced by ethnic
origin and not by obesity. New England Journal of
Medicine, 309,756-760.
23. Duhm, J. & Becker, B.F. (1977) Studies on the
lithium transport across the red cell membrane. IV.
Interindividual variations in the Na dependent Li
countertransport system of human erythrocytes.
Pjliigers Archiv, 370,211-219.
24. Swales, J.D. (1983) Abnormal ion transport studies
in hypertension: methods, myths and hypotheses.
Journal of Hypertension, 1 (Suppl. 2), 391-394.
25. Brand, S.C. & Whittam, R. (1984) The effect of
furosemide on sodium movements in human red
cells. Journal of Physiology (London), 348,
301-306.
26. Postnov, Y.V. & Orlov, S.N. (1984) Cell membrane
alterations as a source of primary hypertension. Journal of Hypertension, 2, 1-6.
27. Blaustein, M.P. (1977) Sodium ions, calcium ions,
blood pressure regulation and hypertension: a reassessment and an hypothesis. American Journal of
Physiology, 232, C 165-C173.
28. Haddv, F.J. & Overbeck, H.W. (1976) The role of
229
humoral agents in volume expanded hypertension.
Life Sciences, 19, 935-947.
29. De Wardener, H.E. & MacGregor, G.A. (1982) The
natriuretic hormone and essential hypertension.
Lancet, i, 1450-1454.
30. Brading, A.F. & Latagan, T.W. (1985) Na-Ca
exchange in vascular smooth muscle. Journal of
Hypertension, 3, 109-1 16.
31. Riozzi, A., Heagerty, A.M., Bing, R.F., Thurston, H.
& Swales, J.D. (1984) Noradrenaline: a circulating
inhibitor of sodium transport. British Medical Journal, 289,1025-1027.
32. Goldstein, D.S. (1983) Plasma catecholamines and
essential hypertension: an analytical review. Hypertension, 5 , 86-99.
33. Swales, J.D., Bing, R.F., Bradlaugh, R., El-Ashry, A.,
Godfrey, N., Heagerty, A.M. & Thurston, H. (1984)
Cell membrane handling of sodium, sodium balance
and blood pressure. Journal of Cardiovascular
Pharmacology, 6 (Suppl. l),S42-S48.
34. Cooper, R.A., Trevisan, M., Horn, L.V., Larbi, E.,
Liu, K., Nanas, S., Ueshima, H., Sempos, C., Ostow,
D. & Stamler, J. (1984) Effect of dietary sodium restriction on red blood cell sodium concentration and
sodium-lithium counter-transport. Hypertension, 6,
731-735.
35. Post, R.L., Albright, C.D. & Dayani, K. (1967) Resolution of pump and leak components of sodium and
potassium ion transport in human erythrocytes. Journalof GeneralPhysiology, 50,1201-1212.
36. Roth, J. & Grunfeld, C. (1981) Endocrine systems;
mechanisms of disease, target cells and receptors. In:
Textbook of Endocrinology, pp. 57-58. Ed.
Williams, R.H. W.B. Saunders, Philadelphia.
37. Kimmelberg, H.K. (1975) Alterations in phospholipid dependent (Na-K)ATPase activity due to lipid
fluidity. Biochimica et Biophysica Acta, 413,
143-1 56.
38. Cooper, R.A. (1977)Abnormalities of cell membrane
fluidity in the pathogenesis of disease. New England
Journal of Medicine, 297,371-377.
39. Grisham, C.M. & Barnett, R.E. (1973)The effects of
long-chain alcohols on membrane lipids and the
(Na-K)ATPase. Biochimica et Biophysica Acta, 31 1,
417-422.
40. Jackson, P.A. & Morgan, D.B. (1982) The relation
between membrane cholesterol and phospholipid
and sodium efflux in erythrocytes from healthy subjects and patients with chronic cholestasis. Clinical
Science, 62,101-107.
41. Wiley, J.S. & Cooper, R.A. (1975) Inhibition of
cation cotransport by cholesterol enrichment of
human red cell membranes. Biochimica et Biophysics Acta, 4 13,425-43 1.
42. Neyses, L., Stimpel, M., Locher, R., Streuli, R.,
Kuffer, B. & Vetter, W. (1984) Cholesterol and its
oxidised derivatives modulate the calcium channel in
human red blood cells. Journal of. Hypertension, 2
(SUPPI.3), 489-492.
43. Heaeertv. A.M.. Ollerenshaw, J.D., El-Ashry, A.,
B i n i RYF., Thurston, H. & Swales, J.D. (1985) Influence of dietary linoleic acid on sodium efflux and
blood pressure. Clinical Science, 169 (Suppl. 12),53P.
44. Adragna, N.C., Chang, J.L., Morley, M.C. &
Williams, R.S. (1985) Effect of exercise on cation
transport in human red cells. Hypertension, 7 ,
132-139.
45. Hunt, S.C., Williams, R.R., Smith, J.B. & Ash, K.O.
(1986) Associations of three erythrocyte cation
transport systems with plasma lipids in UTAH subjects. Hypertension, 8, 30-36.
__
230
R. F. Bing et al.
46. Funder, J. & Wieth, J.O. (1967) Effects of some
monovalent anions on fluxes of Na and K, and on
glucose metabolism of ouabain treated human red
cells. Acta Physiologica Scandinavica, 71, 168-195.
47. Brand, S.C. & Whittam, R. (1985) The change from
symmetry to asymmetry of a sodium transport system
in red cell membranes. Proceedings of the Royal
Society London, Series B, 223,449-457.
48. Orlov, S.N. & Postnov, Y.V. ( 1 982) Calcium binding
and membrane fluidity in essential and renal hypertension. CIinicalScience, 63.28 1-284.
49. Devynck, A.-M., Pernollet, M.G., Nunez, F.V.,
Montenay-Carestier, T,, Helene, C. & Meyer, P.
(1982) Diffuse structural alterations in cell membranes of soontaneouslv hvoertensive rats. IJroceedings of the k a t i o n a l A c i d / i y of Sciences U.S.A., 79,
5057-5060.
50. Reznikova, M.B., Adler, R.M. & Postnov, Y.V. (1984)
Erythrocyte membrane sialic acids in primary and
secondary hypertension in man and the rat.
European Journal of Clinical Investigation, 14,
87-89.
51. Heagerty, A.M., Ollerenshaw, J.D., Bing, R.F.,
Thurston, H. & Swales, J.D. (1985) Changes in membrane fatty acid composition in hypertension: studies
in human and rat erythrocytes. Clinical Science, 67
(Suppl. l l ) , 11-12.
52. Oster, P., Arab, L., Schellenberg, B., Heuck, C.C.,
Mordasini, R. & Schlierf, G. (1929) Blood pressure
and adipose tissue linoleic acid. Research in ExperimentalMedicine, 175,287-291.
53. Wood, D.A., Butler, S., Riemersma, R.A., Thomson,
M., Oliver, M.F., Fulton, M.,, Birtwhistle, A. & Elton,
R. ( 1 984) Adipose tissue and platelet fatty acids and
coronary heart disease. Lancet, ii, 117-121.
54. Bolton, T.B. (1979) Mechanisms of action of transmitters and other substances on smooth muscle.
Physiological Reviews, 59,606-718.
55. Hander, D.R. & Hermsmeyer, K. ( 1 983) Membrane
mechanisms in arterial hypertension. Hypertension,
5,404-408.
56. Jones, A.W. ( 1 974) Altered ion transport in large and
small arteries from spontaneously hypertensive rats
and the influence of calcium. Circulation Resenrch,
34 (SUPPI.l ) , 117-122.
57. Forstner, J. & Manery, J.F. (1971) Calcium binding
by human erythrocyte membranes. Biochemical
Journal, 124,563-571.
58. Allan, D. & Mitchell, R.H. (1978) A calcium activated polyphosphoinositide phosphodiesterase in the
plasma membrane of human and rabbit erythrocytes.
Biochimica et Biophysica Acta, 508, 277-286.
59. Schatzmann, H.J. (1984) The plasma membrane
calcium pump of erythrocytes and other animal cells.
In: Membrane Transport of Calcium, pp. 41-108.
Ed. Carafoli, E. Academic Press, London.
60. Berridge, M.J. & Irvine, R.F. (1984) Inositol triphosphate, a novel second messenger in the cellular
signal transduction. Nature (London), 312,
315-321.
61. Marche, P., Koutouzov, S., Girard, A,, Elghozi, J.-P.,
Meyer, P. & Ben-Ishay, D. (1985) Phosphoinositide
turnover in erythrocyte membranes in human and
experimental hypertension. Journal of Hypertension,
3.25-30.
62. Postnov, Y.V., Orlov, S.N. & Pokudin, N.I. (1979)
Decrease of calcium binding by the red blood cell
membrane in spontaneously hypertensive rats and in
essential hypertension. PflCgers Archiv, 379,
191-1 95.
63. Godfraind de Becker, A. & Godfraind, T. ( 1980) Calcium transport systems: a comparative study in different cells. Internntional Review of Cytology, 67,
141-170.
64. Postnov, Y.V., Orlov, S.N., Pokudin, N.I., Reznikova,
M.B. & Ryazsky, G.G. (1982) Calcium transport and
calmodulin distribution in erythrocytes in primary
hypertension. Cardiology(Moscow), 22,63-66.
65. Zidek, W., Vetter, H., Dorst, K.-G., Zumkey, H. &
Losse, H. ( 1 982) Intracellular Na and Ca activities in
essential hypertension. Clinical Science, 6 3 (Suppl.
8), 4 1-43.
66. Erne, P., Burgisser, E., Bolli, P., BoaHua, J. & Buhler,
F.R. (1984) Free calcium concentration in platelets
closely relates to blood pressure in normal and essential hypertensive subjects. Hypertension, 6 (Suppl. I ) ,
166-169.
67. Shore, A.C., Beynon, G.W., Jones, J.C., Markandu,
N.D., Sagnella, G.A. & MacGregor, G.A. (1985)
Mononuclear leucocyte intracellular free calcium does it correlate with blood pressure? Journal of
Hypertension, 3, 183-187.
68. Bing, R.F., Heagerty, A.M., Jackson, J.A., Swales,
J.D. & Thruston, H. (1986) Leucocyte ionised calcium, sodium content and blood pressure in man.
Hypertension (In press).
69. Bohr, D.E. (1981)What makes the pressure go up? A
hypothesis. Hypertension, 3 (Suppl. 2), 160-165.
70. Kwan, C.Y. (1985) Calcium-handling defects and
smooth muscle pathophysiology. In: Calcium and
Contractility, pp. 299-325. Ed. Grover, A.K. &
Daniel, E.E. Humana Press, New Jersey.
71. Rouse, I.L. & Beilin, L.J. (1984) Vegetarian diet and
blood pressure. Journal of Hypertension, 2,
231-240.
72. Puska, P., Iacono, J.M., Nissinen, A,, Korhonen, H.J.,
Vartiainen, E., Pietinen, P., Dougherty, R., Leino, U.,
Mutanen, M., Moisio, S. & Huttimen, J. ( 1 983) Controlled randomised trial of the effects of dietary fat on
blood pressure. Lancet, i, 1-5.
73. Rao, R.H., Rao, U.B. & Srikantia, S.G. (1981) Effect
of polyunsaturate-rich vegetable oils on blood pressure in essential hypertension. Clinical and Experimental Hypertension, 3, 27-38.
74. Iacono, J.M., Puska, P., Dougherty, R.M., Pietinen, P.,
Vartiainen, E., Leino, U., Mutanen, M. & Moisio, S.
(1983) Effect of dietary fat on blood pressure in a
rural Finnish population. American Journal of Clinical Nutrition, 38,860-869.
75. Editorial (1984) Diet and hypertension. Lancet, ii,
671-673.
76. Hoffman, P. & Forster, W. (1981) Influence of dietary
linoleic acid content on blood pressure regulation in
salt loaded rats. Advances in Lipid Research, 18,
203-227.
77. Schoene, N.W. & Fiore, D. (1981) Effect of a diet
containing fish oil on blood pressure in spontaneously hypertensive rats. Progress in Lipid
Research, 20,568-572.
78. Margetts, B.M., Beilin, L.J., Armstrong, B.K., Rouse,
I.L., Vandongen, R., Croft, K.D. & McMurchie, E.J.
(1985) Blood pressure and dietary polyunsaturated
and saturated fats: a controlled trial. Clinical Science,
69,165-175.
79. Aalkjaer, C., Heagerty, A.M., Parvin, S.D., Bell,
P.R.F., Bing, R.F. & Swales, J.D. (1986) Cell membrane sodium transport: a correlation between
human resistance vessels and leucocytes. Lancet (In
press).