- Email: [email protected]
HEREDITY IN HYPERTENSION
1269
follow-up care. Modern surgery is such that the techniques and aseptic precautions are usually beyond him. Another thing that stands out in this country is that, in many of the hospitals that have general-practice sections, there are really only one or two general practitioners in the true sense of the word. When they come into a hospital department, the practitioners’ specialist work has to be restricted, and they end up by practising what is essentially internal medicine. But they do this without having trained for internal medicine by taking their American Board specialisation certificate. In the United States family care is not confined to the general practitioner; and in many respects the trained internist is better qualified to do it. I send many of my newborn patients to internists because they do nice work and because I am convinced that a good internist from the cradle to the grave can eliminate the need for two or three other doctors. Westbury, Long Island,
hypertension in the general population, but I would welcome a full discussion with Dr. Parnell, and to save your columns from tedious argument perhaps we could submit
a
joint report later.
Royal Infirmary. Manchester.
ROBERT PLATT.
SIR,-The article by Dr. Ostfeld and Dr. Paul
(March 16) is of interest because of the mathematical form of the frequency distributions of blood-pressure. When the histograms of the frequency-distribution of bloodpressure are replotted with the logarithm of the bloodpressure as abscissa instead of the simple blood-pressure, all the distributions become symmetrical about the mean of the distribution. Moreover, the distribution of systolic and diastolic blood-pressure becomes Gaussian. Typical examples of these transformed distributions are two accompanying figures; in both, normal curves
shown in the
ROBERT S. MILLEN.
New York.
THE PROCRUSTEAN BED
SIR,-Ishould like to correct one impression that may be conveyed by Dr. Crombie’s admirable essay (June 1) on thymopathognosis (no apology-like Procrustes, I am merely cutting it down to size). He suggests that in hospital practice there will be fewer patients with illnesses having an emotional content than there are in general practice. With due allowance for differing criteria this is not so. If a figure of 10% is taken for general practice, the corresponding figure for general-hospital outpatients is 16%. This was found by Bruce Pearsonand by Priest2 and it emphasises not only the incidence of emotional disturbances but also the impressive nature of the somatic mask-a point which I think Dr. Crombie might like to drive home. IAN SKOTTOWE. Oxford. HEREDITY IN HYPERTENSION
SIR,-Dr. Parnell’s interesting letter of June 1 lists three characteristics of the distribution curves of sibs of hypertensives, but only the first two are claimed as evidence against multifactorial inheritance. There is, however, another very important piece of evidence, perhaps not sufficiently stressed in my paper (April 27) -namely, that all frequency distribution curves of bloodpressure in normal populations aged above 40 are nonGaussian in shape (e.g., those of Bøe quoted in my paper) Thus the even though compiled from large numbers. sibs show in exaggerated form a feature clearly discernible in the unselected general population. It has always seemed to me that this has been ignored by the exponents of the multifactorial theory, but the hypothesis which I put forward would neatly explain the facts. Dr. Parnell shows that curves similar to those shown by my sibs might be consistent with multifactorial inheritance if we start with a parent who is at the high end of the curve. Unfortunately his work on the height of undergraduates does not include their sibs, and work on hypertension is never adequate for parents. His results could mean, I suppose, that the multifactorial inheritance of height is not quite so multi- as we have thought! At present I do not see how multifactorial inheritance can account for the non-Gaussian distribution curves of 1. 2.
R. S. B. Lancet, 1938, i, 451. Priest, W. M. ibid. 1962, ii, 1043.
Pearson,
Fig. 1-Probability of diastolic blood-pressure for positive family history of hypertension.
men
with
a
have been fitted to the data, using only the sample mean and standard deviation. The original distributions of diastolic blood-pressure for men, classified according to their family history, are seen to be of the log-normal type differing only in the value of the mode (88-2 mm. Hg for men with a positive family history, and 85-6 mm. Hg for men with a negative history of hypertension). Similarly, the original systolic distributions also were found to become Gaussian when the distributions were replotted with
Fig. 2-Probability of diastolic blood-pressure for negative family history of hypertension.
men
with
a
logarithm of the blood-pressure as abscissa instead of the simple blood-pressure. But these two curves differed both in the value of the mode (135 mm. Hg for men with a positive family history and 129 mm. Hg for men with a negative family history) and in the spread of the log-normal distribution. The main conclusion, judged by these samples, is that the systolic and diastolic blood-pressure of men of these two
the
1270
supposed genotypes is the result of the product, rather than the sum of a number of either potentiating or nullifying influences. In other words, if there were two typical potentiating characters (each of which caused on the average a certain value of bloodpressure) the possession of both by a particular individual would tend to result in a blood-pressure greater than the simple sum of the two effects. This observation may suggest some mechanisms of the hypertensive syndrome to medical workers. All the distributions I looked at in the article were remarkably symmetrical when plotted in the way described, and they seemed to be Gaussian in their transformed state. United Kingdom Atomic Energy Authority, Authority Health and Safety Branch, Radiological Protection Division, S. A. BEACH. Harwell, Didcot, Berkshire.
HYPERTENSION EXPLAINED BY STARLING’S THEORY OF CIRCULATORY HOMŒOSTASIS
SIR,-Professor Borst and Mevr. Borst-de Geus’s explanation (March 30) of many types of hypertension as the consequence of an increase in cardiac performance initiated by the retention of salt and water1 is a very stimulating attempt to rationalise the rather vague feeling of many investigators that the adrenal cortex and Na ions are definitely related in some way to the regulation of "
"
"
blood pressure ".1 The validity of the Borsts’ hypothesis rests, however, on the demonstration of a definitely lowered " willingness " of the kidneys to excrete sodium and water, at least in the initial stages of hypertension. No such depression of renal sodium excretion has, to my knowledge, been demonstrated in human " essential " hypertension. In established cases the " willingness of the kidneys to excrete sodium, tested as the renal response to an acute sodium and water load, has consistently been found to be increased rather than decreased..2-4 Similarly the kidneys of hypertensive patients have been shown to respond by an increased excretion of sodium and water to a stimulus (infusion of angiotensin) which causes retention of sodium in normal subjects.5-9 The argument that normal levels of the sodium excretion might still reflect a depressed " willingness " to excrete sodium, because " a normal kidney excretes tremendous amounts of sodium if the arterial pressure rises to the level found in hypertension ", may " very well prove fallacious, since the phenomenon of pressure 10-12 diuresis " referred to by this statement has been proved to occur only in acute experiments under very particular conditions, but evidently not in human or experimental chronic hypertension. It would probably not apply to human renal hypertension where impaired renal sodium excretion, if present, may often be referred to a decrease in glomerular-filtration rate. On the other hand, the type of kidney disease causing the most pronounced sodium retention with little depression of glomerular-filtration rate-i.e., the more or less " pure nephrotic syndrome-does not usually induce hypertension. If an increase in cardiac performance, and eventually cardiac hypertrophy, were the ultimate causes of hypertension, an increase in cardiac output should be demonstrable more often than it actually is.13 The assumption that an increase in cardiac " " output is prevented by autoregulation in major parts of the vascular system in normal man is in contradiction with the fairly frequent observation of increased cardiac output in other "
-
1. 2. 3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Perera, G. A. Bull. N.Y. Acad. Med. 1950, 26, 75. Brodsky, W. A., Graubarth, H. N. J. Lab. clin. Med. 1959, 41, 43. Green, D. M., Wedell, H. G., Wald, M. H., Learned, B. Circulation, 1952, 6, 919. Thompson, D. E., Silva, T. E., Kinsey, D., Smithwick, R. ibid. 1959, 10, 912. Peart, W. S. Brit. med. J. 1959, ii, 1421. Peart, W. S., Brown, J. J. Lancet, 1961, i, 28. Del Greco, F. Proc. Soc. exp. Biol., N. Y. 1961, 107, 943. Biron, P., Chrétien, M., Koiw, E. Brit. med. J. 1962, i, 1569. Brown, G. G., Peart, W. S. Clin. Sci. 1962, 22, 1. Goll, F. Z. rat. Med. N.F. 1854, 6, 86. Selkurt, E. E. Circulation, 1951, 4, 541. Thurau, K., Deetjen, P. Arch. ges. Physiol. 1962, 274, 567. Fishberg, A. M. Hypertension and Nephritis; p. 292. Philadelphia, 1954.
diseases. Furthermore, the increased " cardiac in patients with hypertension should induce a tremendous rise in cardiac output when vascular " autoregulation " is abolished by drugs. Again, neither drugs which are known to lower blood-pressure of hypertensive patients (such as ganglion-blocking agents or guanethidine) nor papaverine, which is said to abolish " autoregulation " of the renal circulation, have, to our knowledge, yet been shown to induce a large increase in cardiac output. If cardiac hypertrophy as a result of transitory retention of sodium and water, and an equally transitory increase in central venous pressure, were responsible for chronic hypertension, blood-pressure should remain elevated in hypertension caused by salt-retaining steroids when the drugs are discontinued. In most cases, as in the Borsts’ patient on liquorice, blood-pressure does, however, fall to normal a very short time after discontinuing the drug responsible for hypertension. Similarly, in experimental hypertension in rats induced by desoxycorticosterone + salt, or by aldosterone + salt, hypertension often when the treatment is stopped.l4-18 " Metadisappears cortioid " hypertension is notoriously difficult to induce, and, at best, occurs in less than half of the experimental animals (unpublished observations). Hypertension induced in rats by the administration of excessive amounts of salt always vanishes when the salt intake is reduced to normal levels. Renal hypertension induced by narrowing one renal artery in the rat is accompanied by an increase in the concentration of renin in the " clamped " kidney. There is, however, no cause to effect relationship between this increase and the occurrence of hypertension.17 Furthermore, total renal sodium excretion in this type of renal hypertension may, under particular circumstances, be accelerated,18 but never is depressed.19 Also, an increase in the angiotensin concentration in blood as a 20 would be consequence of an increase in circulating renin expected to increase rather than to decrease renal sodium excretion. 21 Renal hypertension does, however, occur in the absence of an increase in renal or blood renin concentration,17 20 in unilaterally nephrectomised rats bearing a clamp on the artery of the remaining kidney. Furthermore, renal hypertension of this type consistently disappears within one to two hours when the " clamped " kidney is removed; this fall in blood-pressure occurs also in the absence of a contralateral kidney-i.e., when there cannot be any additional excretion of sodium (unpublished observations). conditions
or
performance "
Nevertheless, the fact remains that some types of experimental hypertension are induced by changes which are known to cause a transitory positive sodium balance. This applies to hypertension induced by D.O.C.A., by aldosterone, or by adding NaCl to the drinking water in rats, but apparently does not apply to experimental renal hypertension.22 Also, some measures known to be therapeutically effective in human hypertension are equally known to induce a transitory, though sometimes very short-lasting, negative sodium balance. Examples would be the institution of dietary sodium deprivation, or the administration of thiazide diuretics. 23 Professor Borst and Mevr. Borst-de Geus’s hypothesis may thus provide a clue for future research, though it does not account for many facts known at the present time. Biological
Research Laboratories, Ciba Limited, Basle, Switzerland.
14. 15.
16. 17. 18.
19. 20. 21. 22. 23.
G. PETERS.
Gross, F. Arch. int. Pharmacodyn. 1950, 81, 211. Gross, F., Loustalot, P., Sulser, F. Arch. exp. Path. Pharm. 1956, 229, 381. Gross, F., Loustalot, P., Meier, R. Acta endocr. 1957, 26, 417. Regoli, D., Hess, R., Brunner, H., Peters, G., Gross, F. Arch. int. Pharmacodyn. 1962, 160, 416. Brunner, H., Desaulles, P. A., Regoli, D., Gross, F. Amer. J. Physiol. 1962, 202, 795. Peters, G., Brunner, H. Proc. int. Union Physiol. Sci. 1962, 2, 244 (abstract). Schaechtelin, G., Regoli, D., Gross, F. Amer. J. Physiol. (in the press). Peters, G. Proc. Soc. exp. Biol., N.Y. 1963, 112, 771. Gross, F. in Essential Hypertension; p. 92. Berlin, 1960. Conway, J., Lauwers, P. Circulation, 1960, 21, 21.
follow-up care. Modern surgery is such that the techniques and aseptic precautions are usually beyond him. Another thing that stands out in this country is that, in many of the hospitals that have general-practice sections, there are really only one or two general practitioners in the true sense of the word. When they come into a hospital department, the practitioners’ specialist work has to be restricted, and they end up by practising what is essentially internal medicine. But they do this without having trained for internal medicine by taking their American Board specialisation certificate. In the United States family care is not confined to the general practitioner; and in many respects the trained internist is better qualified to do it. I send many of my newborn patients to internists because they do nice work and because I am convinced that a good internist from the cradle to the grave can eliminate the need for two or three other doctors. Westbury, Long Island,
hypertension in the general population, but I would welcome a full discussion with Dr. Parnell, and to save your columns from tedious argument perhaps we could submit
a
joint report later.
Royal Infirmary. Manchester.
ROBERT PLATT.
SIR,-The article by Dr. Ostfeld and Dr. Paul
(March 16) is of interest because of the mathematical form of the frequency distributions of blood-pressure. When the histograms of the frequency-distribution of bloodpressure are replotted with the logarithm of the bloodpressure as abscissa instead of the simple blood-pressure, all the distributions become symmetrical about the mean of the distribution. Moreover, the distribution of systolic and diastolic blood-pressure becomes Gaussian. Typical examples of these transformed distributions are two accompanying figures; in both, normal curves
shown in the
ROBERT S. MILLEN.
New York.
THE PROCRUSTEAN BED
SIR,-Ishould like to correct one impression that may be conveyed by Dr. Crombie’s admirable essay (June 1) on thymopathognosis (no apology-like Procrustes, I am merely cutting it down to size). He suggests that in hospital practice there will be fewer patients with illnesses having an emotional content than there are in general practice. With due allowance for differing criteria this is not so. If a figure of 10% is taken for general practice, the corresponding figure for general-hospital outpatients is 16%. This was found by Bruce Pearsonand by Priest2 and it emphasises not only the incidence of emotional disturbances but also the impressive nature of the somatic mask-a point which I think Dr. Crombie might like to drive home. IAN SKOTTOWE. Oxford. HEREDITY IN HYPERTENSION
SIR,-Dr. Parnell’s interesting letter of June 1 lists three characteristics of the distribution curves of sibs of hypertensives, but only the first two are claimed as evidence against multifactorial inheritance. There is, however, another very important piece of evidence, perhaps not sufficiently stressed in my paper (April 27) -namely, that all frequency distribution curves of bloodpressure in normal populations aged above 40 are nonGaussian in shape (e.g., those of Bøe quoted in my paper) Thus the even though compiled from large numbers. sibs show in exaggerated form a feature clearly discernible in the unselected general population. It has always seemed to me that this has been ignored by the exponents of the multifactorial theory, but the hypothesis which I put forward would neatly explain the facts. Dr. Parnell shows that curves similar to those shown by my sibs might be consistent with multifactorial inheritance if we start with a parent who is at the high end of the curve. Unfortunately his work on the height of undergraduates does not include their sibs, and work on hypertension is never adequate for parents. His results could mean, I suppose, that the multifactorial inheritance of height is not quite so multi- as we have thought! At present I do not see how multifactorial inheritance can account for the non-Gaussian distribution curves of 1. 2.
R. S. B. Lancet, 1938, i, 451. Priest, W. M. ibid. 1962, ii, 1043.
Pearson,
Fig. 1-Probability of diastolic blood-pressure for positive family history of hypertension.
men
with
a
have been fitted to the data, using only the sample mean and standard deviation. The original distributions of diastolic blood-pressure for men, classified according to their family history, are seen to be of the log-normal type differing only in the value of the mode (88-2 mm. Hg for men with a positive family history, and 85-6 mm. Hg for men with a negative history of hypertension). Similarly, the original systolic distributions also were found to become Gaussian when the distributions were replotted with
Fig. 2-Probability of diastolic blood-pressure for negative family history of hypertension.
men
with
a
logarithm of the blood-pressure as abscissa instead of the simple blood-pressure. But these two curves differed both in the value of the mode (135 mm. Hg for men with a positive family history and 129 mm. Hg for men with a negative family history) and in the spread of the log-normal distribution. The main conclusion, judged by these samples, is that the systolic and diastolic blood-pressure of men of these two
the
1270
supposed genotypes is the result of the product, rather than the sum of a number of either potentiating or nullifying influences. In other words, if there were two typical potentiating characters (each of which caused on the average a certain value of bloodpressure) the possession of both by a particular individual would tend to result in a blood-pressure greater than the simple sum of the two effects. This observation may suggest some mechanisms of the hypertensive syndrome to medical workers. All the distributions I looked at in the article were remarkably symmetrical when plotted in the way described, and they seemed to be Gaussian in their transformed state. United Kingdom Atomic Energy Authority, Authority Health and Safety Branch, Radiological Protection Division, S. A. BEACH. Harwell, Didcot, Berkshire.
HYPERTENSION EXPLAINED BY STARLING’S THEORY OF CIRCULATORY HOMŒOSTASIS
SIR,-Professor Borst and Mevr. Borst-de Geus’s explanation (March 30) of many types of hypertension as the consequence of an increase in cardiac performance initiated by the retention of salt and water1 is a very stimulating attempt to rationalise the rather vague feeling of many investigators that the adrenal cortex and Na ions are definitely related in some way to the regulation of "
"
"
blood pressure ".1 The validity of the Borsts’ hypothesis rests, however, on the demonstration of a definitely lowered " willingness " of the kidneys to excrete sodium and water, at least in the initial stages of hypertension. No such depression of renal sodium excretion has, to my knowledge, been demonstrated in human " essential " hypertension. In established cases the " willingness of the kidneys to excrete sodium, tested as the renal response to an acute sodium and water load, has consistently been found to be increased rather than decreased..2-4 Similarly the kidneys of hypertensive patients have been shown to respond by an increased excretion of sodium and water to a stimulus (infusion of angiotensin) which causes retention of sodium in normal subjects.5-9 The argument that normal levels of the sodium excretion might still reflect a depressed " willingness " to excrete sodium, because " a normal kidney excretes tremendous amounts of sodium if the arterial pressure rises to the level found in hypertension ", may " very well prove fallacious, since the phenomenon of pressure 10-12 diuresis " referred to by this statement has been proved to occur only in acute experiments under very particular conditions, but evidently not in human or experimental chronic hypertension. It would probably not apply to human renal hypertension where impaired renal sodium excretion, if present, may often be referred to a decrease in glomerular-filtration rate. On the other hand, the type of kidney disease causing the most pronounced sodium retention with little depression of glomerular-filtration rate-i.e., the more or less " pure nephrotic syndrome-does not usually induce hypertension. If an increase in cardiac performance, and eventually cardiac hypertrophy, were the ultimate causes of hypertension, an increase in cardiac output should be demonstrable more often than it actually is.13 The assumption that an increase in cardiac " " output is prevented by autoregulation in major parts of the vascular system in normal man is in contradiction with the fairly frequent observation of increased cardiac output in other "
-
1. 2. 3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Perera, G. A. Bull. N.Y. Acad. Med. 1950, 26, 75. Brodsky, W. A., Graubarth, H. N. J. Lab. clin. Med. 1959, 41, 43. Green, D. M., Wedell, H. G., Wald, M. H., Learned, B. Circulation, 1952, 6, 919. Thompson, D. E., Silva, T. E., Kinsey, D., Smithwick, R. ibid. 1959, 10, 912. Peart, W. S. Brit. med. J. 1959, ii, 1421. Peart, W. S., Brown, J. J. Lancet, 1961, i, 28. Del Greco, F. Proc. Soc. exp. Biol., N. Y. 1961, 107, 943. Biron, P., Chrétien, M., Koiw, E. Brit. med. J. 1962, i, 1569. Brown, G. G., Peart, W. S. Clin. Sci. 1962, 22, 1. Goll, F. Z. rat. Med. N.F. 1854, 6, 86. Selkurt, E. E. Circulation, 1951, 4, 541. Thurau, K., Deetjen, P. Arch. ges. Physiol. 1962, 274, 567. Fishberg, A. M. Hypertension and Nephritis; p. 292. Philadelphia, 1954.
diseases. Furthermore, the increased " cardiac in patients with hypertension should induce a tremendous rise in cardiac output when vascular " autoregulation " is abolished by drugs. Again, neither drugs which are known to lower blood-pressure of hypertensive patients (such as ganglion-blocking agents or guanethidine) nor papaverine, which is said to abolish " autoregulation " of the renal circulation, have, to our knowledge, yet been shown to induce a large increase in cardiac output. If cardiac hypertrophy as a result of transitory retention of sodium and water, and an equally transitory increase in central venous pressure, were responsible for chronic hypertension, blood-pressure should remain elevated in hypertension caused by salt-retaining steroids when the drugs are discontinued. In most cases, as in the Borsts’ patient on liquorice, blood-pressure does, however, fall to normal a very short time after discontinuing the drug responsible for hypertension. Similarly, in experimental hypertension in rats induced by desoxycorticosterone + salt, or by aldosterone + salt, hypertension often when the treatment is stopped.l4-18 " Metadisappears cortioid " hypertension is notoriously difficult to induce, and, at best, occurs in less than half of the experimental animals (unpublished observations). Hypertension induced in rats by the administration of excessive amounts of salt always vanishes when the salt intake is reduced to normal levels. Renal hypertension induced by narrowing one renal artery in the rat is accompanied by an increase in the concentration of renin in the " clamped " kidney. There is, however, no cause to effect relationship between this increase and the occurrence of hypertension.17 Furthermore, total renal sodium excretion in this type of renal hypertension may, under particular circumstances, be accelerated,18 but never is depressed.19 Also, an increase in the angiotensin concentration in blood as a 20 would be consequence of an increase in circulating renin expected to increase rather than to decrease renal sodium excretion. 21 Renal hypertension does, however, occur in the absence of an increase in renal or blood renin concentration,17 20 in unilaterally nephrectomised rats bearing a clamp on the artery of the remaining kidney. Furthermore, renal hypertension of this type consistently disappears within one to two hours when the " clamped " kidney is removed; this fall in blood-pressure occurs also in the absence of a contralateral kidney-i.e., when there cannot be any additional excretion of sodium (unpublished observations). conditions
or
performance "
Nevertheless, the fact remains that some types of experimental hypertension are induced by changes which are known to cause a transitory positive sodium balance. This applies to hypertension induced by D.O.C.A., by aldosterone, or by adding NaCl to the drinking water in rats, but apparently does not apply to experimental renal hypertension.22 Also, some measures known to be therapeutically effective in human hypertension are equally known to induce a transitory, though sometimes very short-lasting, negative sodium balance. Examples would be the institution of dietary sodium deprivation, or the administration of thiazide diuretics. 23 Professor Borst and Mevr. Borst-de Geus’s hypothesis may thus provide a clue for future research, though it does not account for many facts known at the present time. Biological
Research Laboratories, Ciba Limited, Basle, Switzerland.
14. 15.
16. 17. 18.
19. 20. 21. 22. 23.
G. PETERS.
Gross, F. Arch. int. Pharmacodyn. 1950, 81, 211. Gross, F., Loustalot, P., Sulser, F. Arch. exp. Path. Pharm. 1956, 229, 381. Gross, F., Loustalot, P., Meier, R. Acta endocr. 1957, 26, 417. Regoli, D., Hess, R., Brunner, H., Peters, G., Gross, F. Arch. int. Pharmacodyn. 1962, 160, 416. Brunner, H., Desaulles, P. A., Regoli, D., Gross, F. Amer. J. Physiol. 1962, 202, 795. Peters, G., Brunner, H. Proc. int. Union Physiol. Sci. 1962, 2, 244 (abstract). Schaechtelin, G., Regoli, D., Gross, F. Amer. J. Physiol. (in the press). Peters, G. Proc. Soc. exp. Biol., N.Y. 1963, 112, 771. Gross, F. in Essential Hypertension; p. 92. Berlin, 1960. Conway, J., Lauwers, P. Circulation, 1960, 21, 21.