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NATRIURETIC HORMONE AND ESSENTIAL HYPERTENSION
553 NATRIURETIC HORMONE AND ESSENTIAL HYPERTENSION
SIR,-Professor de Wardener and Dr MacGregor (June 26, p. 1450) have certainly sustained their controversial hypothesis about the role of a circulating sodium transport inhibitor in essential
hypertension, but what is now needed is more evidence and more awkward questions. I was puzzled when I first read that a natriuretic factor has to be produced to offset the difficulty that the kidneys of the patient with essential hypertension have in excreting answers to
load.The hypothesis
combines the observations of an inhibitor of Na/K ATPase for white cells, smooth muscle, and kidneys in volume expanded hypertension with Dahl’s suggestion that induction of hypertension by salt loading is due to the kidneys’ inability to excrete sodium. The idea is critically dependent on transplantation and parabiosis experiments in rats. After reading the current hypothesis I still feel that more information and explanations are required. (1) Although the existence of a natriuretic factor is widely accepted, its relevance to essential hypertension is doubtful. This factor cannot be assayed directly, it has not been adequately characterised, it is not available in pure form, and its actions on the biochemistry of smooth muscle have not been elucidated. In the one paper3 on which de Wardener and MacGregor place their trust the evidence hinges on the effects on normal leucocytes of eight sera from people with hypertension. No details are given about these patients. In studies of Na/K ATPase values in controls and patients tend to overlap, and the normal range is very wide, the enzyme being influenced by several factors. (2) Inhibition ofNa/K ATPase was reported to be accompanied by stimulation of glucose -6-phosphate dehydrogenase. This seems curious: if the cell is not utilising so much ATP, presumably production will be curtailed, and why is the pentose-phosphate shunt stimulated? The technique was evolved because measurement of Na/K ATPase is laborious, but measuring the binding of 3H-ouabain is not. (3) If so many cell systems are affected by natriuretic factor, why not the neurones? Patients with uraemic and hepatic coma, whose sera contain other Na/K ATPase inhibitors, may have sick neurones, and abnormal numbers of sodium pumps occur on the red cells, platelets, and neurones of people with familial mood changes.4 (4) Many factors influence Na/K ATPase activity. Do we assume that natriuretic factor has an overriding effect? Factors which increase the rigidity of cell membranes reduce Na/K ATPase activity and result in an increased influx of calcium ions and increased vascular reactivity of smooth muscle. Such factors include an increase of the membrane cholesterol, an increase of membrane saturated fatty acids, extra availability of insulin, and lipid peroxidation, and explain why Na/K ATPase activity varies in normal people. (5) Whenever the Na/K ATPase pump of a nucleated cell is inhibited new pump sites appear, to compensate.5This will surely apply to smooth muscle. (6) Why does essential hypertension only develop after a lag of 20-30 years and then show increasing prevalence with age? Surely this means that the difficulty which the kidneys have in excreting salt is a secondary acquisition, for which there are other a
sodium
Haddy2
on
explanations. 6,7
Omvik et al. showed that persons with a raised diastolic pressure have a diminished excretion of salt for the level of arterial pressure that they inhibit and this is best explained by their degree of volume 1. Marx JL. Natriuretic hormone linked to hypertension. Science 1981; 212: 1255-57 2. Haddy JF, Overbeck HW. The role of humoral agents in volume expanded hyper-
Life Sci 1976; 19: 935-48. Poston L, Sewell RB, Wilkinson SP et al. Evidence for a circulating transport inhibitor in essential hypertension. Bri Med J 1981; 282: 847-49. Naylor GJ, Smith AHW. Defective genetic control of sodium pump density in manic depressive psychosis. Psychol med 1981, 11: 257-63. Vaughan GL, Cook JS. Regeneration of cation transport capacity in Hela cell membranes after specific blockade by ouabain. Proc Nat Acad Sci USA 1972, 69: tension
3 4 5
2627-31. Hall JE, Lohmeier TE, Jackson TE, Kastner PR. Blood pressure Basic concepts. Fed Proc 1981; 40: 2252-56. 7. Omvik P, Tarazi RC, Bravo EL. Regulation of sodium balance in hypertension. Hypertension 1980, 2: 515-23.
6. Guyton AC, regulation
contraction. So far there have been no studies of natriuretic factor at different ages of persons predisposed to essential hypertension. (7) Only one-quarter of patients with essential hypertension have low renin values. Patients with this feature are often Blacks, but the one study on leucocyte Na/K ATPase in Blacks8 showed increased enzyme activities. (8) The de Wardener paper emphasises that patients with hypertension show accelerated natriuresis and while those with essential hypertension have an inability to excrete sodium that can supposedlv be opposed by natriuretic factor. There are haemodynamic explanations for accelerated natriuresis.9 Moveover sympathetic nervous stimulation will account for retention of sodium by the kidneys. This explanation will apply to those younger patients with essential hypertension who show increased adrenergic activity that is often accompanied by high plasma renin values (at least 25%). Indeed there is much evidence for increased sympathetic nervous outflow in subjects with essential hypertension,1O even though current opinion holds that this activity cannot be assessed adequately by plasma catecholamine levels. (9) The rat experiments could be misleading? Bianchi et al. and Dahl showed that a normal rat becomes hypertensive when it receives a kidney from a rat with genetic hypertension. Is it not likely that the vasculature of a hypertensive rat is already damaged, or just possible that there is an intrinsic cell membrane
phospholipid abnormality? (10) Should one ignore the evidence that spontaneous hypertensive rats are akin to patients with essential hypertension, and that such hypertension is central in origin and mediated by over-activity of the sympathetic nervous system. Such animals are apparently sensitive to noise (stress) and have increased erythrocyte and smooth muscle Na/K ATPase activities that are secondary to a passive permeability of the cell membranes to sodium. This mechanism can quite readily account for hypertension and may either reflect an inherited cell membrane phospholipid anomaly12 or be a consequence of the action of noradrenaline in increasing membrane permeability to sodium. 13
Hollenberg14 has gone to much trouble to demonstrate increased sympathetic tone to the renal vasculature in essential hypertension. Undoubtedly many feel that this is sufficient explanation for the observed effects on sodium handling and for the pathogenesis of the
syndrome. Now it seems that various biochemical markers of the genetic anomaly are almost to hand. The de Wardener hypothesis may
turn out to
33 Hawthorn
be
a
digression.
Gardens,
Kenton,
E. N. WARDLE
Newcastle upon Tyne NE3 3DE
SiR,—We would be grateful if we could begin by a brief historical recapitulation of the order of events in this subject in order to rectify a false impression, inadvertently contained in our survey, that we were the first to suggest that essential hypertension might be due to a circulating sodium transport inhibitor. The proposal that plasma contains a natriuretic substance which controls urinary sodium excretion stemmed from some animal experiments described by de Wardener et al. in 1961.1 Dahl and colleagues’2work in 1969 in rats
TE, Alleyne G. Sodium, potassium and rate constants for sodium efflux in leucocytes from hypertensive Jamaicans. Br Med J1981; 283: 5-7 9 Dal Canton A, Conte G, Fuiano G, Guasco R, Andreucci UE Exaggerated natriuresis in hypertensive man: clinical evidence for intrarenal haemodynamic heterogeneity. Nephron 1981; 27: 122-26. 10. Dickinson CJ Neurogenic hypertension re-visited. Clin Sci 1981, 60: 471-77. 11 Bianchi G, Fox V, DiFrancesco GF, Giovanetti AM, Pagetti D. Blood pressure changes produced by transplantation between spontaneously hypertensive and 8. Forrester
Clin Sci 1974; 47: 435-48. SN, Gulak PV, Litvinov IS, Postnov YV. Evidence of altered
normotensive rats
12. Orlov
erythrocyte
membrane
in
spontaneously hypertensive
rats.
structure of the Clin Sci 1982; 63:
43-45. K. Electrogenesis of increased nor-epinephrine sensitivity of arterial vascular smooth muscle in hypertension. Circ Res 1976; 38: 362-67 14. Hollenberg NK. Control of renal blood flow in essential hypertension Adv Nephrol 1981, 10: 89-109. 1. de Wardener HE, Mills IH, Clapham WF, Hayter CJ. Studies on the efferent mechanism of the sodium diuresis which follows the administration of intravenous saline in the dog. Clin Sci 1961; 21: 249-58. 2. Dahl LK, Knudsen KD, Iwai J. Humoral transmission of hypertension: Evidence from
13. Hermsmeyer
parabiosis. Circ Res 1969; i (suppl. 24, 25):
21-33.
554 led him to propose that the arterial pressure might be raised by a circulating natriuretic substance. In 1976, Haddy and Overbeck’s3 observations on some experimental forms of hypertension associated with an initial period of sodium retention led them to suggest that in such experiments the blood pressure might be raised by a circulating Na+ -K+ -ATPase inhibitor. Blaustein’s4 studies on sodium calcium exchange across the membrane of vascular smooth muscle demonstrated how a Na+-K+-ATPase inhibitor might cause a rise in peripheral resistance, and he was the first5 to suggest, in 1977, that such an inhibitor might be responsible for a rise in
arterial pressure in essential hypertension. The role of the kidney in both experimental forms of hypertension with sodium retention and the inherited forms of hypertension in the rat, and our observations in man and on the relation between sodium intake and the plasma’s capacity to inhibit Na+ -K+ -ATPase, led to our suggestion in 19806 that the increase in the sodium transport inhibitor in essential hypertension might be due to an inherited defect in the kidney’s ability to excrete sodium. In 1981 we showed that the plasma of normal man is able to inhibit Na+ -K+ -ATPase and that the extent of the inhibition is controlled by sodium intake,? and we also showed that the plasma of hypertensive patients has an increased ability to inhibit Na+ -K+ -ATPase,8,9 which is the reason why we would support the proposition that essential hypertension may be due to an increase in such an inhibitor. Dr Wardle is dubious about the relation between a circulating sodium transport inhibitor and essential hypertension. The purpose of a hypothesis, however, is not to convert but to stimulate further work. Wardle is also less than totally enthusiastic about the information so far available. Part of this indifference may stem from his tendency to ignore what information there is. For instance, he does not comment on the evidence that plasma of patients with essential hypertension or of rats with inherited hypertension has increased vasoconstricting properties. Though we would agree that -the explanation of the inverse relation between Na+ -K+ -ATPase activity and G6PD activity is incomplete, we do not think this is a sufficient reason to dismiss our use of a validated assay which measures the plasma’s capacity to stimulate G6PD as an index of its ability to inhibit Na+ -K+ -ATPase. His intimation, therefore, that the only evidence that we ourselves have acquired for the existence of an excess circulating Na+ -K+ -ATPase inhibitor in essential hypertension is that obtained with leucocytes, is not correct. It is also sweeping for Wardle to state that in the leucocyte experiments we gave no information about the patients, for we gave their ages, sex, race, arterial pressure, and state of therapy. Wardle’s enquiries about the role of the circulating sodium transport inhibitor on neurons was touched upon in our survey when we pointed out that by analogy with the action of ouabain on neurons, the circulating sodium transport inhibitor might be responsible for the increased sympathetic activity sometimes demonstrated in essential hypertension. His comments on sodium pumps were also alluded to in that we suggested that in the in-vitro increase in Na+ -K+ ATPase activity in isolated vessels of ’the spontaneously hypertensive rat might be due to a compensatory increase in the numbers of sodium pumps caused by the raised concentration of the inhibitor in vivo. Nevertheless, it must be pointed out that in experimental forms of hypertension this compensatory increase in the number of pumps is not sufficient to prevent a rise in the intracellular sodium of the vessels. 3. Haddy FJ, Overbeck HW. The role of humoral agents in volume expanded hypertension. Life Sci 1976; 19: 935-48 4. Blaustein MP Sodium ions, calcium ions, blood pressure regulation and hypertension: a reassessment and a hypothesis. Am J Physiol 1977, 232: C165-73. 5. Blaustein MP. The role ofNa-Ca exchange in the regulation oftone in vascular smooth muscle. In Castees R, et al., eds. Excitation contraction coupling in smooth muscle. Amsterdam: Elsevier/North Holland Biomedical Press, 1977 101-07. 6. de Wardener HE, MacGregor GA. Dahl’s hypothesis that a saluretic substance may be responsible for a sustained rise in arterial pressure: Its possible role in essential hypertension. Kidney Int 1980, 18: 1-9. HE, MacGregor GA, Clarkson EM, Alaghband-Zadeh J, Bitensky L, Chayen J. Effect of sodium intake on ability of human plasma to inhibit renal Na+Ka+-adenosine triphosphatase in vitro. Lancet 1981; i 411-12. Poston L, Sewell RB, Wilkinson SP, et al. Evidence for a circulating sodium transport inhibitor in essential hypertension. Br Med J 1981; 282: 847-49. MacGregor GA, Fenton S, Alaghband-Zadeh J, Markandu N, Roulston JE, de Wardener HE. Evidence for a raised concentration of a circulating sodium transport inhibitor in essential hypertension. Br Med J 1981, 283: 1355-57.
7. de Wardener
8. 9.
We cannot explain why the hypertension takes so long to become established. But there is increasing evidence that the arterial pressure begins to rise before the age of 10.10 Furthermore, the abnormalities in hypertensive patients of sodium excretion following intravenous saline loads can also be demonstrated in the normotensive children of such patients. This observation, which was mentioned in our survey, indicates that the abnormalities of sodium excretion are not secondary to the hypertension. In this context we also have to point out that, in contrast to early observations, an exaggerated natriuresis can be produced in rats and man without any associated observable haemodynamic
explanation.ll,12 Wardle mis-quotes the paper on Blacks. Forrester and Alleyne did show that these patients’ leucocytes had an increased enzyme activity. On the contrary, their evidence suggests a decrease in activity in that the leucocyte sodium content was significantly raised and the mean sodium-efflux rate constant was low, but not significantly different from the controls. This failure of the reduction in sodium efflux to achieve significance is discussed by Jones and Hilton. 13 In relation to the cross-transplantation experiments, Wardle seems to mislead himself in choosing to ignore the fact that a kidney transplanted from a genetically normotensive rat prevents the rise in blood pressure in a genetically hypertensive rat. He only comments on the part of the experiment where a kidney transplanted from a genetically hypertensive rat causes a rise in blood pressure in a genetically normotensive rat. The only conclusion that can be drawn from these elegant studies is that in Dahl, Bianchi, and Okamoto rats, the fundamental abnormality causing the rise in blood pressure resides in the kidney. Hence, our proposal that in essential hypertension, there is an inherited abnormality of the kidney.6 This is a proposal which is in line with Wardle’s exhortation that one should not "ignore the evidence that spontaneously hypertensive rats are akin to patients with essential hypertension ...". Unfortunately, by leaning on the evidence that demonstrates an increased sympathetic activity as the basic cause of the hypertension in the inherited forms of hypertension in the rat and ignoring the renal transplantation experiments, Wardle fails to heed his own advice. We would agree that in the spontaneously hypertensive rat and in essential hypertension there may be evidence of an increased sympathetic activity which probably contributes to the rise in pressure, and we would suggest that this increase is related to the demonstrated rise in the concentration of the circulating inhibitor of Na+ -K+ -ATPase. The merit of our hypothesis is that it forms a link between several facets of essential hypertension which are otherwise difficult to explain, including the effect of dietary sodium, an inherited abnormality of the kidney, generalised abnormalities of sodium transport, low plasma renin, increased sympathetic activity, the beneficial effects of increased dietary potassium and calcium antagonists, and the plasma’s increased vasoconstrictive properties and ability to inhibit sodium transport. not
Research Laboratories, Charing Cross Hospital, London W6 8RF
H. E. DE WARDENER
Blood Pressure Unit,
Department of Medicine, Charing Cross Hospital Medical School, London W6 8RF
G. A. MACGREGOR
TRACE ELEMENTS IN HAIR
SiR,—Regarding the survey by Mr Laker (July 31, p. 260) I should to bring to your attention another caveat. We have recently reported a case of lead poisoning from ingestion of hair spray. In the course of this study we observed that some hair sprays may like
10. Onesti
G, Kwan EK, eds. Hypertension in the young and old. New York: Grune & Stratton, 1981 11. DiBona G, Rios LL Mechanism of exaggerated diuresis in spontaneously hypertensive rat Am J Physiol 1978; 235: F409-16. 12. Willassen Y, Ofsted J. Renal sodium excretion and the petitubular capillary physical factors in essential hypertension. Hypertension 1980; 2: 771-79. 13. Jones NF, Hilton PJ. Sodium, potassium and sodium efflux in leucocytes from hypertensive Jamaicans. Br Med J1981; 283: 309-10. 1. Raasch FO, Rosenberg JH, Abraham JL. Lead poisoning from hair spray ingestion. Am JForens Med Pathol (in press).
SIR,-Professor de Wardener and Dr MacGregor (June 26, p. 1450) have certainly sustained their controversial hypothesis about the role of a circulating sodium transport inhibitor in essential
hypertension, but what is now needed is more evidence and more awkward questions. I was puzzled when I first read that a natriuretic factor has to be produced to offset the difficulty that the kidneys of the patient with essential hypertension have in excreting answers to
load.The hypothesis
combines the observations of an inhibitor of Na/K ATPase for white cells, smooth muscle, and kidneys in volume expanded hypertension with Dahl’s suggestion that induction of hypertension by salt loading is due to the kidneys’ inability to excrete sodium. The idea is critically dependent on transplantation and parabiosis experiments in rats. After reading the current hypothesis I still feel that more information and explanations are required. (1) Although the existence of a natriuretic factor is widely accepted, its relevance to essential hypertension is doubtful. This factor cannot be assayed directly, it has not been adequately characterised, it is not available in pure form, and its actions on the biochemistry of smooth muscle have not been elucidated. In the one paper3 on which de Wardener and MacGregor place their trust the evidence hinges on the effects on normal leucocytes of eight sera from people with hypertension. No details are given about these patients. In studies of Na/K ATPase values in controls and patients tend to overlap, and the normal range is very wide, the enzyme being influenced by several factors. (2) Inhibition ofNa/K ATPase was reported to be accompanied by stimulation of glucose -6-phosphate dehydrogenase. This seems curious: if the cell is not utilising so much ATP, presumably production will be curtailed, and why is the pentose-phosphate shunt stimulated? The technique was evolved because measurement of Na/K ATPase is laborious, but measuring the binding of 3H-ouabain is not. (3) If so many cell systems are affected by natriuretic factor, why not the neurones? Patients with uraemic and hepatic coma, whose sera contain other Na/K ATPase inhibitors, may have sick neurones, and abnormal numbers of sodium pumps occur on the red cells, platelets, and neurones of people with familial mood changes.4 (4) Many factors influence Na/K ATPase activity. Do we assume that natriuretic factor has an overriding effect? Factors which increase the rigidity of cell membranes reduce Na/K ATPase activity and result in an increased influx of calcium ions and increased vascular reactivity of smooth muscle. Such factors include an increase of the membrane cholesterol, an increase of membrane saturated fatty acids, extra availability of insulin, and lipid peroxidation, and explain why Na/K ATPase activity varies in normal people. (5) Whenever the Na/K ATPase pump of a nucleated cell is inhibited new pump sites appear, to compensate.5This will surely apply to smooth muscle. (6) Why does essential hypertension only develop after a lag of 20-30 years and then show increasing prevalence with age? Surely this means that the difficulty which the kidneys have in excreting salt is a secondary acquisition, for which there are other a
sodium
Haddy2
on
explanations. 6,7
Omvik et al. showed that persons with a raised diastolic pressure have a diminished excretion of salt for the level of arterial pressure that they inhibit and this is best explained by their degree of volume 1. Marx JL. Natriuretic hormone linked to hypertension. Science 1981; 212: 1255-57 2. Haddy JF, Overbeck HW. The role of humoral agents in volume expanded hyper-
Life Sci 1976; 19: 935-48. Poston L, Sewell RB, Wilkinson SP et al. Evidence for a circulating transport inhibitor in essential hypertension. Bri Med J 1981; 282: 847-49. Naylor GJ, Smith AHW. Defective genetic control of sodium pump density in manic depressive psychosis. Psychol med 1981, 11: 257-63. Vaughan GL, Cook JS. Regeneration of cation transport capacity in Hela cell membranes after specific blockade by ouabain. Proc Nat Acad Sci USA 1972, 69: tension
3 4 5
2627-31. Hall JE, Lohmeier TE, Jackson TE, Kastner PR. Blood pressure Basic concepts. Fed Proc 1981; 40: 2252-56. 7. Omvik P, Tarazi RC, Bravo EL. Regulation of sodium balance in hypertension. Hypertension 1980, 2: 515-23.
6. Guyton AC, regulation
contraction. So far there have been no studies of natriuretic factor at different ages of persons predisposed to essential hypertension. (7) Only one-quarter of patients with essential hypertension have low renin values. Patients with this feature are often Blacks, but the one study on leucocyte Na/K ATPase in Blacks8 showed increased enzyme activities. (8) The de Wardener paper emphasises that patients with hypertension show accelerated natriuresis and while those with essential hypertension have an inability to excrete sodium that can supposedlv be opposed by natriuretic factor. There are haemodynamic explanations for accelerated natriuresis.9 Moveover sympathetic nervous stimulation will account for retention of sodium by the kidneys. This explanation will apply to those younger patients with essential hypertension who show increased adrenergic activity that is often accompanied by high plasma renin values (at least 25%). Indeed there is much evidence for increased sympathetic nervous outflow in subjects with essential hypertension,1O even though current opinion holds that this activity cannot be assessed adequately by plasma catecholamine levels. (9) The rat experiments could be misleading? Bianchi et al. and Dahl showed that a normal rat becomes hypertensive when it receives a kidney from a rat with genetic hypertension. Is it not likely that the vasculature of a hypertensive rat is already damaged, or just possible that there is an intrinsic cell membrane
phospholipid abnormality? (10) Should one ignore the evidence that spontaneous hypertensive rats are akin to patients with essential hypertension, and that such hypertension is central in origin and mediated by over-activity of the sympathetic nervous system. Such animals are apparently sensitive to noise (stress) and have increased erythrocyte and smooth muscle Na/K ATPase activities that are secondary to a passive permeability of the cell membranes to sodium. This mechanism can quite readily account for hypertension and may either reflect an inherited cell membrane phospholipid anomaly12 or be a consequence of the action of noradrenaline in increasing membrane permeability to sodium. 13
Hollenberg14 has gone to much trouble to demonstrate increased sympathetic tone to the renal vasculature in essential hypertension. Undoubtedly many feel that this is sufficient explanation for the observed effects on sodium handling and for the pathogenesis of the
syndrome. Now it seems that various biochemical markers of the genetic anomaly are almost to hand. The de Wardener hypothesis may
turn out to
33 Hawthorn
be
a
digression.
Gardens,
Kenton,
E. N. WARDLE
Newcastle upon Tyne NE3 3DE
SiR,—We would be grateful if we could begin by a brief historical recapitulation of the order of events in this subject in order to rectify a false impression, inadvertently contained in our survey, that we were the first to suggest that essential hypertension might be due to a circulating sodium transport inhibitor. The proposal that plasma contains a natriuretic substance which controls urinary sodium excretion stemmed from some animal experiments described by de Wardener et al. in 1961.1 Dahl and colleagues’2work in 1969 in rats
TE, Alleyne G. Sodium, potassium and rate constants for sodium efflux in leucocytes from hypertensive Jamaicans. Br Med J1981; 283: 5-7 9 Dal Canton A, Conte G, Fuiano G, Guasco R, Andreucci UE Exaggerated natriuresis in hypertensive man: clinical evidence for intrarenal haemodynamic heterogeneity. Nephron 1981; 27: 122-26. 10. Dickinson CJ Neurogenic hypertension re-visited. Clin Sci 1981, 60: 471-77. 11 Bianchi G, Fox V, DiFrancesco GF, Giovanetti AM, Pagetti D. Blood pressure changes produced by transplantation between spontaneously hypertensive and 8. Forrester
Clin Sci 1974; 47: 435-48. SN, Gulak PV, Litvinov IS, Postnov YV. Evidence of altered
normotensive rats
12. Orlov
erythrocyte
membrane
in
spontaneously hypertensive
rats.
structure of the Clin Sci 1982; 63:
43-45. K. Electrogenesis of increased nor-epinephrine sensitivity of arterial vascular smooth muscle in hypertension. Circ Res 1976; 38: 362-67 14. Hollenberg NK. Control of renal blood flow in essential hypertension Adv Nephrol 1981, 10: 89-109. 1. de Wardener HE, Mills IH, Clapham WF, Hayter CJ. Studies on the efferent mechanism of the sodium diuresis which follows the administration of intravenous saline in the dog. Clin Sci 1961; 21: 249-58. 2. Dahl LK, Knudsen KD, Iwai J. Humoral transmission of hypertension: Evidence from
13. Hermsmeyer
parabiosis. Circ Res 1969; i (suppl. 24, 25):
21-33.
554 led him to propose that the arterial pressure might be raised by a circulating natriuretic substance. In 1976, Haddy and Overbeck’s3 observations on some experimental forms of hypertension associated with an initial period of sodium retention led them to suggest that in such experiments the blood pressure might be raised by a circulating Na+ -K+ -ATPase inhibitor. Blaustein’s4 studies on sodium calcium exchange across the membrane of vascular smooth muscle demonstrated how a Na+-K+-ATPase inhibitor might cause a rise in peripheral resistance, and he was the first5 to suggest, in 1977, that such an inhibitor might be responsible for a rise in
arterial pressure in essential hypertension. The role of the kidney in both experimental forms of hypertension with sodium retention and the inherited forms of hypertension in the rat, and our observations in man and on the relation between sodium intake and the plasma’s capacity to inhibit Na+ -K+ -ATPase, led to our suggestion in 19806 that the increase in the sodium transport inhibitor in essential hypertension might be due to an inherited defect in the kidney’s ability to excrete sodium. In 1981 we showed that the plasma of normal man is able to inhibit Na+ -K+ -ATPase and that the extent of the inhibition is controlled by sodium intake,? and we also showed that the plasma of hypertensive patients has an increased ability to inhibit Na+ -K+ -ATPase,8,9 which is the reason why we would support the proposition that essential hypertension may be due to an increase in such an inhibitor. Dr Wardle is dubious about the relation between a circulating sodium transport inhibitor and essential hypertension. The purpose of a hypothesis, however, is not to convert but to stimulate further work. Wardle is also less than totally enthusiastic about the information so far available. Part of this indifference may stem from his tendency to ignore what information there is. For instance, he does not comment on the evidence that plasma of patients with essential hypertension or of rats with inherited hypertension has increased vasoconstricting properties. Though we would agree that -the explanation of the inverse relation between Na+ -K+ -ATPase activity and G6PD activity is incomplete, we do not think this is a sufficient reason to dismiss our use of a validated assay which measures the plasma’s capacity to stimulate G6PD as an index of its ability to inhibit Na+ -K+ -ATPase. His intimation, therefore, that the only evidence that we ourselves have acquired for the existence of an excess circulating Na+ -K+ -ATPase inhibitor in essential hypertension is that obtained with leucocytes, is not correct. It is also sweeping for Wardle to state that in the leucocyte experiments we gave no information about the patients, for we gave their ages, sex, race, arterial pressure, and state of therapy. Wardle’s enquiries about the role of the circulating sodium transport inhibitor on neurons was touched upon in our survey when we pointed out that by analogy with the action of ouabain on neurons, the circulating sodium transport inhibitor might be responsible for the increased sympathetic activity sometimes demonstrated in essential hypertension. His comments on sodium pumps were also alluded to in that we suggested that in the in-vitro increase in Na+ -K+ ATPase activity in isolated vessels of ’the spontaneously hypertensive rat might be due to a compensatory increase in the numbers of sodium pumps caused by the raised concentration of the inhibitor in vivo. Nevertheless, it must be pointed out that in experimental forms of hypertension this compensatory increase in the number of pumps is not sufficient to prevent a rise in the intracellular sodium of the vessels. 3. Haddy FJ, Overbeck HW. The role of humoral agents in volume expanded hypertension. Life Sci 1976; 19: 935-48 4. Blaustein MP Sodium ions, calcium ions, blood pressure regulation and hypertension: a reassessment and a hypothesis. Am J Physiol 1977, 232: C165-73. 5. Blaustein MP. The role ofNa-Ca exchange in the regulation oftone in vascular smooth muscle. In Castees R, et al., eds. Excitation contraction coupling in smooth muscle. Amsterdam: Elsevier/North Holland Biomedical Press, 1977 101-07. 6. de Wardener HE, MacGregor GA. Dahl’s hypothesis that a saluretic substance may be responsible for a sustained rise in arterial pressure: Its possible role in essential hypertension. Kidney Int 1980, 18: 1-9. HE, MacGregor GA, Clarkson EM, Alaghband-Zadeh J, Bitensky L, Chayen J. Effect of sodium intake on ability of human plasma to inhibit renal Na+Ka+-adenosine triphosphatase in vitro. Lancet 1981; i 411-12. Poston L, Sewell RB, Wilkinson SP, et al. Evidence for a circulating sodium transport inhibitor in essential hypertension. Br Med J 1981; 282: 847-49. MacGregor GA, Fenton S, Alaghband-Zadeh J, Markandu N, Roulston JE, de Wardener HE. Evidence for a raised concentration of a circulating sodium transport inhibitor in essential hypertension. Br Med J 1981, 283: 1355-57.
7. de Wardener
8. 9.
We cannot explain why the hypertension takes so long to become established. But there is increasing evidence that the arterial pressure begins to rise before the age of 10.10 Furthermore, the abnormalities in hypertensive patients of sodium excretion following intravenous saline loads can also be demonstrated in the normotensive children of such patients. This observation, which was mentioned in our survey, indicates that the abnormalities of sodium excretion are not secondary to the hypertension. In this context we also have to point out that, in contrast to early observations, an exaggerated natriuresis can be produced in rats and man without any associated observable haemodynamic
explanation.ll,12 Wardle mis-quotes the paper on Blacks. Forrester and Alleyne did show that these patients’ leucocytes had an increased enzyme activity. On the contrary, their evidence suggests a decrease in activity in that the leucocyte sodium content was significantly raised and the mean sodium-efflux rate constant was low, but not significantly different from the controls. This failure of the reduction in sodium efflux to achieve significance is discussed by Jones and Hilton. 13 In relation to the cross-transplantation experiments, Wardle seems to mislead himself in choosing to ignore the fact that a kidney transplanted from a genetically normotensive rat prevents the rise in blood pressure in a genetically hypertensive rat. He only comments on the part of the experiment where a kidney transplanted from a genetically hypertensive rat causes a rise in blood pressure in a genetically normotensive rat. The only conclusion that can be drawn from these elegant studies is that in Dahl, Bianchi, and Okamoto rats, the fundamental abnormality causing the rise in blood pressure resides in the kidney. Hence, our proposal that in essential hypertension, there is an inherited abnormality of the kidney.6 This is a proposal which is in line with Wardle’s exhortation that one should not "ignore the evidence that spontaneously hypertensive rats are akin to patients with essential hypertension ...". Unfortunately, by leaning on the evidence that demonstrates an increased sympathetic activity as the basic cause of the hypertension in the inherited forms of hypertension in the rat and ignoring the renal transplantation experiments, Wardle fails to heed his own advice. We would agree that in the spontaneously hypertensive rat and in essential hypertension there may be evidence of an increased sympathetic activity which probably contributes to the rise in pressure, and we would suggest that this increase is related to the demonstrated rise in the concentration of the circulating inhibitor of Na+ -K+ -ATPase. The merit of our hypothesis is that it forms a link between several facets of essential hypertension which are otherwise difficult to explain, including the effect of dietary sodium, an inherited abnormality of the kidney, generalised abnormalities of sodium transport, low plasma renin, increased sympathetic activity, the beneficial effects of increased dietary potassium and calcium antagonists, and the plasma’s increased vasoconstrictive properties and ability to inhibit sodium transport. not
Research Laboratories, Charing Cross Hospital, London W6 8RF
H. E. DE WARDENER
Blood Pressure Unit,
Department of Medicine, Charing Cross Hospital Medical School, London W6 8RF
G. A. MACGREGOR
TRACE ELEMENTS IN HAIR
SiR,—Regarding the survey by Mr Laker (July 31, p. 260) I should to bring to your attention another caveat. We have recently reported a case of lead poisoning from ingestion of hair spray. In the course of this study we observed that some hair sprays may like
10. Onesti
G, Kwan EK, eds. Hypertension in the young and old. New York: Grune & Stratton, 1981 11. DiBona G, Rios LL Mechanism of exaggerated diuresis in spontaneously hypertensive rat Am J Physiol 1978; 235: F409-16. 12. Willassen Y, Ofsted J. Renal sodium excretion and the petitubular capillary physical factors in essential hypertension. Hypertension 1980; 2: 771-79. 13. Jones NF, Hilton PJ. Sodium, potassium and sodium efflux in leucocytes from hypertensive Jamaicans. Br Med J1981; 283: 309-10. 1. Raasch FO, Rosenberg JH, Abraham JL. Lead poisoning from hair spray ingestion. Am JForens Med Pathol (in press).