Cells, Ions, and Blood-pressureERYTHROCYTES and leucocytes from hypertensive
patients show abnormalities in the handling of sodiumand potassium. When we last commented upon thislthe picture was confused by the multiplicity of defectswhich had been demonstrated. No single hypothesiscould embrace all the observations although it wasdifficult to escape from the belief that abnormalities in
physiological processes so fundamental as those whichcontrol intracellular electrolytes must in some way berelated to the development of high blood-pressure.Regrettably, it also seemed likely that some of thereported observations were flawed. These problemshave not been resolved in the past two years but in somerespects the picture is becoming clearer.The original stimulus to present-day work in this
area was provided by TOBIAN’s2 suggestion that theretention of sodium and fluid in the blood-vessel wallnarrowed the lumen and increased the resistance toblood flow in hypertensive patients. The preciseanatomical site of such sodium retention remained
obscure, and the changes in arterial electrolytecomposition are probably in most cases a consequencerather than a cause of hypertension. This work did,however, lead to the search for a global membranedefect which might be demonstrated in more accessibletissues. The original report that erythrocyte sodium isincreased in essential hypertension 3 has beenconfirmed by some groups4,5 but not by others.6,7
1 Editorial. Essential hypertension: another defect? Lancet 1980; i: 1227-29.2. Tobian L. The electrolytes of arterial wall in experimental hypertension. Circ Res 1956;
4: 671-75.3 Losse H, Wehmeyer H, Wessels F. Wasser-und Elektrolytgehalt von Erythrozyten bei
arterieller Hypertonie. Klin Wschr 1960; 38: 393-95.4. Fadeke Aderounmu A, Salako LA Abnormal cation composition and transport in
erythrocytes from hypertensive patients. Eur J Clin Invest 1979; 9: 379-75.5. Clegg G, Morgan DB, Davidson C. The heterogeneity of essential hypertension.
relation between lithium efflux and sodium content of erythrocytes and a familyhistory of hypertension. Lancet 1982; ii: 891-94.
6 Canessa M, Adragna N, Solomon HS, Connolly TM, Tosteson DC. Increased sodium-lithium countertransport in red cells of patients with essential hypertension. N EnglJ Med 1980; 302: 772-76.
7 Walter U, Distler A. Abnormal sodium efflux in erythrocytes of patients with essentialhypertension. Hypertension 1982; 4: 205-10.
Measuring absolute electrolyte content of the cells maynot be the most sensitive method of demonstratingabnormality since living cells have excellent
compensatory mechanisms for restoring compositionto normal. On first principles, therefore, it seemed thatdynamic measurements of movements of electrolytesacross the cell membrane would be more likely to reveala primary disturbance of membrane function. At thispoint Pandora’s box was opened. Our difficulty indeciding what precisely is happening is largely due tolimited understanding of the complex physiologicalprocesses involved. The cell membrane is not
completely impermeable to sodium and potassium:there is normally a steady leak of sodium into the celland of potassium out. This is opposed by the energy-requiring sodium/potassium pump which transportspotassium into the cell and sodium out and which isinhibited by ouabain. Whilst some groups have shownincreased red cell permeability in hypertension8,9 andincreased sodium pump activity,9,10 others have not.7EDMONDSON et al.11 reported subnormal ouabain-sensitive sodium pumping in white cells from
hypertensives. Ions can move across the cell membranein other ways, transported by a carrier protein, and twoof these systems have shown impressive abnormalitiesin hypertensive subjects. One such system exchangesan external sodium molecule for an intracellularsodium molecule (measured as lithium-sodium countertransport): this process was strikingly increased in agroup of American hypertensive subjects6 but noabnormality could be demonstrated in a more recentstudy of German hypertensives. 12 Frusemide-sensitivesodium/potassium co-transport is another system.Earlier reports suggested that the ratio of sodium topotassium extrusion from sodium-loaded cells by thispathway was reduced in essential hypertension but notin renovascular hypertension.13 This abnormality,however, was not found in South African hyper-tensives. 14 Whilst a collaborative study confirmed thereduction in co-transport in French hypertensives, itdemonstrated increased co-transport in American
hypertensives. 15 Therefore the abnormalities are
unlikely to be directly involved in the processes whichgive rise to hypertension. It seems equally improbablethat they are simply the result of a genetic linkage since
8. Wessels F, Junge-Hulsing G, Losse M. Untersuchunger zur Natriumpermeabilitat derErythrocyten bei Hypertonikern und Normotonike mit familiarer
Hochdruckbelastung. Z Kreislaufforsch 1967; 56: 374.9. Postnov Y, Ovlov S, Shevchenko A, Adler A. Altered sodium permeability, calcium
binding and Na+, K+-ATPase activity in the red blood cell membrane in essentialhypertension. Pflugers Arch 1977; 371: 263-69.
10. Woods KL, Beevers DG, West MJ. Racial differences in red cell cation transport andtheir relationship to essential hypertension. Clin Exp Hypertension 1981; 3: 655-62.
11. Edmondson RPS, Thomas RD, Jilton PJ, Patrick J, Jones NF. Abnormal leucocytecomposition and sodium transport in essential hypertension. Lancet 1975; i:1003-05.
12. Duhm J, Gobel BO, Lorenz R, Weber PC. Sodium-lithium exchange and sodium-potassium cotransport in human erythrocytes. Hypertension 1982; 4: 477-82.
13. Garay RP, Elghozi JL, Dagher G, Meyer P. Laboratory distinction between essentialand secondary hypertension by measurement of erythrocyte cation fluxes. N Engl JMed 1980; 302: 769-71.
14. Davidson JS, Opie LH, Keding B. Sodium-potassium cotransport activity as a geneticmarker in essential hypertension. Br Med J 1982; 284: 539-41.
15. Canessa M, Bize I, Soloman H, Adragna N, Tosteson DC, Dagher G, Garay R, MayerP. Na countertransport and cotransport in human red cell function, dysfunction andgenes in essential hypertension. Clin Exp Hypertension 1981; 3: 783-95.
sodium and potassium transport are fundamental to thebehaviour of excitable tissues such as vascular smoothmuscle. Another regrettable but real possibility is thatat least some of these observations are invalid. Not allthe studies had carefully matched control andhypertensive patients. Few reports record patients’weight, although untreated hypertensive patients areusually heavier than normotensive controls and obesityis associated with a decrease in red cell sodium pumpsites.16 Persistent effects of antihypertensive treatment(which may have been discontinued for a short periodonly) also tend to be ignored. We are therefore in theposition of the man who knows that half of what he saysis true but does not know which half. We are, however,better off in another respect. We can study geneticstrains of rat in which the extraneous influences whichobscure the clinical picture do not operate. In additionthere is a major bonus in that we have access to therelevant membranes-i. e., those of the vascular smoothmuscle. Several studies of the Okamoto strain of
spontaneously hypertensive rat have shown that, inboth the red cell and the smooth muscle cell of thearterial wall, permeability to sodium and potassium isincreased, resulting in enhanced turnover of theseions. 17- 19 There is indirect evidence that this stimulatesa compensatory increase in sodium pumping by thevascular smooth muscle cell. 20 Similar changes havebeen described in the vascular smooth muscle of thesalt-sensitive Dahl strain of rat which on a high saltintake acquires fixed hypertension.21 The abnormalityin cell permeability in spontaneously hypertensive ratsand in hypertensive human beings is associated with achange in the viscosity of the phospholipids of the cellmembrane.22,23 How can these abnormalities beassociated with the development of hypertension? TheBLAUSTEIN hypothesis gives a central role to an
increase in free intracellular calcium stimulatingsmooth muscle contraction.24 BLAUSTEIN further
postulates that this is mediated by inhibition of apostulated mechanism which exchanges sodium forcalcium across the cell membrane by increasedintracellular sodium which is in turn the result ofdecreased sodium pumping. The latter changes areconsistent with previously described observations on
16. De Luise M, Blackburn GL, Flier JS. Reduced activity of the red-cell sodium-potassium pump m human obesity. N Engl J Med 1980; 303: 1017-22.
17. Postnov Y, Orlov S, Gulak P, Shevchenko A. Altered permeability of the erythrocytemembrane for sodium and potassium ions in spontaneously hypertensive rats.Pfluger’s Arch 1976; 365: 257-63.
18. Friedman SM, Nakashima M, McIndoe RA, Friedman CL. Increased erythrocytepermeability to Li and Na in spontaneously hypertensive rats. Experientia 1976; 32:476.
19 Jones AW. Altered ion transport in large and small arteries from spontaneouslyhypertensive rats and the influence of calcium. Circ Res 1974; suppl 1: 117-22.
20 Webb RC, Bohr DF. Potassium relaxation of vascular smooth muscle from
spontaneously hypertensive rats. Blood Vessels 1979; 16: 71-79.21. Overbeck HW, Ku DD, Rapp JP. Sodium pump activity in arteries of Dahl-sensitive
rats. Hypertension 1981; 3: 306-12.22 Orlov SN, Gulak PV, Litninov IS, Postnov Yu V. Evidence of altered structure of the
erythrocyte membrane in spontaneously hypertensive rats. Clin Sci 1982; 63:43-45.
23. Orlov SN, Postnov YV. Ca++ binding and membrane fluidity in essential and renalhypertension. Clin Sci 1982; 63: 281-84
hypertension: a reassessment and a hypothesis. Am J Physiol 1977; 232:C165-C173.
the human leucocyte and also with experiments insome models of experimental hypertension in whichsodium loading occurs.25 However, this hypothesisdoes not explain the majority of observations upon thered cells from hypertensive patients and upon genetichypertension in the rat, where other mechanisms areapparently involved. In these situations there seems tobe an intrinsic genetic membrane defect affectingseveral functions.The calcium ion may still provide the link between
this defect and the development of hypertension.Increased permeability to sodium and potassium in thesmooth muscle cell membrane could reflect loss ofcalcium. It has long been known that calcium has astabilising effect upon such membranes. 26 Thus,removal of external calcium from vascular smoothmuscle reproduces the increased turnover of potassiumions, and spontaneously hypertensive rats are moresusceptible to the removal of calcium in this respect."Several groups have reported that cell membrane
affinity for calcium is reduced in hypertension .21,21,21 If,as has been suggested, this gives rise to an increase inthe pool of free exchangeable calcium within the cell/9perhaps by inhibition of the calcium extrusion
mechanism, the association between hypertension andsome of the described abnormalities would be
explained.This still leaves a question: Why should the sodium
pump be inhibited in the white cell in essential
hypertension and in the aorta when hypertension isassociated with volume expansion? This could reflectthe presence of a circulating ouabain-like inhibitor."Even so, the relevance of such an inhibitor to
hypertension is doubtful. Thus, prolongedadministration of ouabain, sufficient to cause
considerable retention of sodium and water in thevascular wall, is not associated with hypertension.3’ Analternative view is that, at least in the human white cell,sodium pumping is impaired as a result of the globalmembrane abnormality, but the change in sodiumpumping is not responsible for the change in blood-pressure. This seems particularly likely in the case ofsodium/sodium countertransport, where the observed
abnormality could not influence intracellular
electrolytes if the transport system operated in thismode. Two recent papers support such an "innocent
bystander" explanation for abnormalities of cellmembrane sodium handling. CLEGG et al. reported25. Pamnani MB, Clough DL, Huot SJ, Haddy FJ. Vascular sodium-potassium activity in
various models of experimental hypertension Clin Sci 1980, 59: suppl 6:179s-181s.
26. Rothstein A. Membrane phenomena. Annu Rev Physiol 1968; 30: 15-7227. Wei JW, Jams RA, Daniel EE. Calcium accumulation and enzymatic activities of
subcellular fractions from aortas and ventricles of genetically hypertensive rats CircRes 1976; 39: 133-40.
28. Devynck MA, Pernollet MG, Nunez AM, Meyer P. Analysis of calcium handling inerythrocyte membranes of genetically hypertensive rats. Hypertension 1981; 3:397-403.
29. Postnov YV, Orlov SN, Pokudin NI. Alteration of intracellular calcium distribution mthe adipose tissue of human patients with essential hypertension. Pflugers Arch1980; 388: 89-91.
30. de Wardener HE, MacGregor GA. The natriuretic hormone and essential
hypertension. Lancet 1982; i. 1459-5431. Overbeck HW, Pamnani MB, Ku DD. Arterial wall ’waterlogging’ accompanying
chronic digoxin treatment in dogs. Proc Soc Exp Biol Med 1980; 164: 401-04.
increased lithium/sodium countertransport and redcell sodium in patients with essential hypertension. 5However, further analysis indicated that each of thesevariables was increased only in patients with a familyhistory of hypertension, implying that theabnormalities were either serving as a marker for aninherited membrane defect or alternatively that theywere responsible for hypertension in a subgroup ofpatients only. The former explanation seems morelikely in the light of other observations on leucocytesodium transport. HEAGERTY et al. 32 studied thesodium efflux rate constant in hypertensive subjectsand confirmed that it was subnormal. However, anequal reduction was observed in normotensive relativesof hypertensive patients. The two studies thereforeindicate in quite different ways that hypertension canbe dissociated from the abnormality of sodium
transport and argue against a direct role for this
abnormality in the genesis of raised blood-pressure. Itis possible that the changes which have beendemonstrated in the blood cells of hypertensivesubjects do reflect an underlying abnormality which isresponsible for raised blood-pressure and therefore forone of the major causes of serious ill-health in Westerncivilisation. The link may be more indirect than wasoriginally thought when "waterlogging" of bloodvessels was first postulated, but such a link probablydoes exist.
REGULATORY PEPTIDES—WHAT DO THEYREGULATE?
IN the past decade, gastrointestinal endocrinology hasbecome bewildering even for the experts. After a slow startbetween 1902 (the discovery of gastrin) and 1964 (thestructure of gastrin), the big four of secretin, gastrin,cholecystokinin, and pancreozymin became a triumvirate,when cholecystokinin and pancreozymin proved to have thesame chemical structure. The idyll was ended by thediscovery of an additional 20 - 30 gastrointestinal peptideswith "hormone-like" and "neurotransmitter-like" effects.This diverse group of extremely potent substances, with
characteristic individual distribution and complex mutualinteractions, has turned into a veritable "endocrine cuckoo inthe digestive nest, which requires ever-increasingcommitment of effort without commensurate returns in
conceptual enlightenment". Some of these peptides werefirst isolated from the brain and, conversely, most of thegastrointestinal peptides were subsequently found in thebrain. This led to the coining of the mysterious term "brain-gut" peptides and to the revival of the interest in neuro-endocrine links. The brain-gut concept is, however,misleading, since these peptides are also present in theendocrine glands, salivary glands, pancreas, placenta,respiratory tract, urogenital tract, peripheral nervous system,
32. Heageny AM, Milner M, Bing RF, Thurston H, Swales JD. Leucocyte membranesodium transport in normotensive populations: dissociation of abnormalities ofsodium efflux from raised blood-pressure. Lancet 1982; ii: 894-96.
1. Wingate D. The eupeptide system: A general theory of gastrointestinal hormones.Lancet 1976; i: 529-32.
frog skin, and elsewhere. Their non-neural distributioncorresponds closely to the diffuse endocrine system of
Feyrter.2 2The contributors to the September issue of the British
Medical Bulletit; which is devoted to various aspects of the"regulatory peptides of gut and brain", are themselvesoverwhelmed with the amount of information put at their
disposal, and the editor (R. A. Gregory), whose experiencebridges the prestructural and modern eras of gastrointestinalendocrinology, wisely suggests that "our most importantproblems are to decide what are the best questions to ask, andhow best to ask them."3 The first question which comes tomind is: what do these regulatory peptides regulate when thesame peptides occur in invertebrates and man alike? Whilethis may show nature’s parsimony in the use of biologicallyactive molecules, why then is the parsimony contravened bythe presence of different analogues of the same peptide in thebrain and in the gut of the same species? Why should severalstructurally different peptides have an identical action, whileone peptide may have several different actions? How many ofthese effects are pharmacological curiosities, and which are ofphysiological importance?
The wide distribution, the extreme pharmacologicalpotency, and the diversity of effects of these peptides frustratethe search for the physiological function. Take, for example,neurotensin, which was discovered only ten years ago.Although originally isolated from the brain, it has been foundin plasma and synovial fluid, in endocrine cells of the
intestine, in the peripheral nervous system, in the thymus, inovarian and lung tumours, and in bacteria. Among othereffects, neurotensin excites retinal ganglion cells, inhibitslocus coeruleus neurons, induces hypothermia, releases
hypothalamic and pituitary hormones, has an antinociceptiveeffect, acts as a dopamine antagonist, stimulatesnoradrenaline release, increases acetylcholine turnover,induces peripheral vasodilatation and hypotension, contractsand relaxes smooth muscles of the gut, increases pancreaticbicarbonate and hormone release, and raises blood glucoseand cholesterol. How are we to reconcile these curiousexperimental findings, which have no apparent commondenominator, with the clinical observation that "althoughlevels 100 times the postprandial concentration are found, noparticular clinical symptoms have been described to be aconsequence of this high plasma neurotensinconcentration"5?One possible answer to this dilemma has been suggested by
Creutzfeldt.6 Since the function of regulatory peptidesdepends on a complex interaction of other agonist andantagonist regulatory peptides and agonist and antagonistnerves (which may also contain regulatory peptides), excessor deficit of any particular peptide, such as neurotensin, maybe clinically undetectable owing to a shift in the equilibriumof other peptides and the neural control. Moreover, since theregulatory peptides are presumed to have a paracrineeffect-i.e., to act locally on adjacent cells-their plasmalevels do not reflect their physiological effects, but are merelyan overspill of unused material.Thus the function of the regulatory peptides may be that
they are regulatory at a level of fine tuning, involving a high
2. Powell D, Skrabanek P. Brain and gut. Clins Endocrinol Metab 1979; 8: 299-312.3. Gregory RA. Introduction. Br Med Bull 1982; 38: 219-20.4. Brown DR, Miller RJ. Neurotensin. Br Med Bull 1982; 38: 239-45.5. Bloom SR, Polak JM. Clinical aspects of gut hormones and neuropeptides. Br Med Bull
1982; 38: 233 - 38.6. Creutzfeldt W. Gastrointestinal peptides-role in pathophysiology and disease. Scand