IS ADRENALINE THE CAUSE OF ESSENTIAL HYPERTENSION?

1079 We thank Mrs Ulrike Michels for the

phototechnical

part of this

investigation and for preparing the figures.

Requests for reprints should be addressed to I. A-L., Institut flir Ultrastrukturfbrschung der Haut, Hautklinik der Ruprecht-Karls-Umversitat Heidelberg, Voss-Str. 2, 6900 Heidelberg 1, West Germany. REFERENCES

Jr, Anton-Lamprecht I. Epidermolysis bullosa. In: Emery AEH, Rimoin DL, eds. The principles and practice in medical genetics. Edinburgh: Churchill Livingstone (in press). 2 Bauer EA, Gedde-Dahl T Jr, Eisen AZ. The role of human skin collagenase in 1. Gedde-Dahl T

epidermolysis bullosa. J Invest Dermatol 1977; 68: 119-24. dystrophic epidermolysis bullosa. Evidence for an altered collagenase in fibroblast cultures. Proc Nat Acad Sci USA 1977; 74: 4646-50. Pearson RW. Studies on the pathogenesis of epidermolysis bullosa. J Invest Dermatol

3 Bauer EA. Recessive 4

1962; 39: 551-75. I, Schnyder UW, Anton-Lamprecht I, Gedde-Dahl T Jr, Ward S.

5 Hashimoto

6. 7.

8. 9

10.

Ultrastructural studies in epidermolysis bullosa hereditaria. III. Recessive dystrophic types with dermolytic blistering (Hallopeau-Siemens type and inverse type). Arch Dermatol Res 1976; 256: 137-50. Anton-Lamprecht I. Electron microscopy in the early diagnosis of genetic disorders of the skin. Dermatologica 1978, 157: 65-85. Rauskolb R. Fetoskopie. Eine klinische Methode zur pränatalen Diagnostik. Stuttgart: Thieme, 1980. Peracchia C, Mittler BS. Fixation by means of glutaraldehyde-hydrogen peroxide reaction products. J Cell Biol 1972, 53: 234-38. Anton-Lamprecht I. Prenatal diagnosis of genetic disorders of the skin by means of electron microscopy. Hum Genet (in press). Rodeck CH, Eady RAJ, Gosden CM. Prenatal diagnosis of epidermolysis bullosa letalis. Lancet 1980; i: 949-52.

Hypothesis IS ADRENALINE THE CAUSE OF ESSENTIAL HYPERTENSION? M. J. BROWN

I. MACQUIN

Department of Clinical Pharmacology, Royal Postgraduate Medical School, Ducane Road, London W12 0HS

Summary

Intermittent raised secretion of adrenaline

(AD) by the adrenal medulla increases the AD concentration in sympathetic nerve endings. This facilitates subsequent noradrenaline release from these nerves, leading to a sustained increase in stimulation of alphaadrenergic receptors and development of hypertension. The increase in AD secretion postulated for subjects likely to develop hypertension may be confirmed by 24 h urine the role of raised AD secretion in the the hypertension may be assessed by which reduce AD synthesis by the adrenal gland.

estimations, and development of treatments

INTRODUCTION

DESPITE the increasingly sophisticated analytical techniques for measuring the low plasma concentrations of endogenous pressor substances, the past decade has not seen any convincing progress towards elucidation of the pathogenesis of essential hypertension. Although this lack of

progress may be due to the existence of an as yet undiscovered substance, it seems more likely that the solution rests in devising a satisfactory model from data that are already largely available. Since essential hypertension is a statistical description of the skewed part of the distribution of blood pressure in the population and is considered a disease only by virtue of its sequelae, no qualitative abnormality is likely to be found.’ Increased sympathetic nervous activity has long been considered a possible cause of essential hypertension, and many investigators have found evidence of higher levels of noradrenaline (NA) release in essential hypertension.2-6 There are, however, major obstacles to accepting that these results help in understanding the pathogenesis of essential pressor

not only is the apparent increase in NA release small, but its very existence is far from universally accepted .7- 10 This dissension arises partly from argument about the data, but there are also doubts about the ability of any of the current biochemical indices of NA release to provide valid estimates of sympathetic nervous activity, especially in comparisons between individuals and groups.i’-i4 Second, the apparent mean increase in NA release in essential hypertension is smaller than the considerable variation in NA release found in the control, normotensive population, and yet no correlation exists in the latter between blood pressure and NA release.10,15 In contrast, blood-pressure elevations known to be caused by NA (e.g., in phaechromocytoma patients, during NA infusion, or during endogenous NA release by tyramine or stress) are associated with a marked increase in the plasma NA concentration.16-19 Thirdly, the sympathetic nervous system is considered to be a mechanism for regulating short-term changes in blood pressure; one would expect excessive stimulation to be limited by the baroreflex arc and possibly by negative feedback through the presynaptic alpha-receptor on sympathetic nerve endings.20 Invoking increased sympathetic nervous activity as a cause of essential hypertension seems at best only to throw the burden of explanation back one stage-why should increased sympathetic nervous activity occur, and how is it maintained? Our hypothesis aims to solve this dilemma, drawing on recent evidence that NA release from sympathetic nerves is controlled not only by the nervous impulses but also by local feedback circuits through presynaptic receptors. The hypothesis also attempts to meet a difficulty common to all hypotheses of pathogenesis of essential hypertension-the ability to be tested. The tests should include a demonstration of prevention of essential hypertension, which is difficult in a disorder that develops over many years or decades and is possibly irreversible by the time it is declared.

hypertension. First,

THE HYPOTHESIS

The primary "abnormality" in essential hypertension is increased release of adrenaline (AD) from the adrenal medulla. The AD does not itself cause hypertension but facilitates NA release from the sympathetic nerve endings. The NA release results in a sustained elevation of sympathetic activity, which leads to the development of

hypertension. Three strands of evidence require evaluation: (i) that AD promote increased release ofNA; (ii) that AD secretion by the adrenal medulla is raised during the development of that a sustained, mild essential hypertension; and elevation of sympathetic nervous activity leads to the development of irreversible hypertension. can

(iii)

Effect of Adrenaline on Noradrenaline Release For several years it has been known that release ofNA is

partly controlled by feedback mechanisms operating through presynaptic alpha and beta receptors on adrenergic nerves. The alpha-receptors mediate negative feedback and the betareceptors positive feedback loops.2o-22 In several isolated tissues, at low frequencies of sympathetic nerve stimulation, beta-agonists such as isoprenaline or AD increase the amount ofNA released from the nerve ending,23-26 but, until recently, in-vivo demonstration of these feedback circuits has proved difficult, leading to doubts about their physiological importance.27 Now, however, it has been shown28 that in

1080

healthy volunteers infusion of AD causes persistent tachycardia after the infusion, although the plasma AD concentration falls rapidly to basal levels. For several hours after the infusion both systolic and diastolic pressures are raised, whereas diastolic pressure and mean blood pressure are reduced during the infusion. These effects can be

prevented by pretreatment with either desmethylimipramine, which inhibits uptake of the AD into sympathetic nerve endings during the infusion, or a-methylp-tyrosine, which depletes the nerve endings of NA. The persistent tachycardia and hypertension depend, therefore, on both AD uptake into the nerves and the presence of endogenous NA stores. It was concluded from these studies and from measurements of cardiac levels of NA and AD in parallel animal studies that transient elevation of circulating AD levels increases AD concentration in the sympathetic nerve endings; its subsequent release from the nerve endings by sympathetic nerve stimulation leads to enhanced NA release.29 In the same animal studies we showed that cardiac AD content was also increased by stress-induced release of endogenous AD; this suggests a mechanism by which intermittent surges of AD release from the adrenal medulla may influence subsequent NA release from sympathetic nerve endings. The inferred AD-induced rise in NA release was not always associated with an increase in the plasma NA concentration,29 which may explain why plasma-NA has been of limited use as a marker of sympathetic nervous

activity. Adrenaline Secretion in Essential Hypertension Elevated plasma AD concentrations in patients with essential hypertension have been reported. 30 Assessment of adrenal medullary discharge by plasma measurements is, however, more difficult even than estimation of sympathetic nervous activity by plasma NA measurements, because it is difficult both to measure the very low physiological concentrations of plasma AD and to assure truly basal values of plasma AD.31,32 24 h urine AD excretion is not only easier to measure accurately than plasma AD concentrations but is also more pertinent to the hypothesis. To date, little attention has been paid to the role of AD in essential hypertension, because infusion ofAD to achieve a small elevation of plasmaAD causes a fall in diastolic and mean blood pressure. 33,34 What was not noticed until our study28,29 was the elevated diastolic pressure and mean blood pressure which occur after such infusions. The most likely reason for raised secretion of AD by the adrenal medulla in essential is intermittent increased stimulation by such factors as stress and anxiety. Some epidemiological studies have suggested that these factors are responsible for the tendency of blood pressure to rise with age, of which essential hypertension may be an

hypertension

exaggerated expression.35 Alternatively, it is possible

that in essential hypertension medulla secretes a "normal" amount of catecholamines, but a higher proportion than usual of the catecholamines is AD rather than NA. We recently reported that in 8 patients with essential hypertension from whom adrenal vein samples were obtained the adrenal secretion of AD was 10 times that ofNA.12,31 This difference is slightly higher than previous estimates in unselected subjects, but a prospective comparative study of the finding is necessary. The enzyme that converts NA to AD, phenylethanolamineN-methyltransferase (PNMT), is inducible and may, the adrenal

therefore, provide an explanation of the genetic component of essential hypertension.36

Sympathetic Nervous Activity and Hypertension A slight increase in sympathetic nervous activity sustained over a long period-perhaps several decades-may lead to secondary changes in the arterioles which result in a chronic increase in peripheral resistance. These changes may be the obvious structural abnormalities of hypertension (smooth or more subtle changes in muscle hypertrophy, &C.)37 receptor populations giving increased sensitivity to various endogenous pressor agents.15,38 Undoubtedly a sustained small increase in release or administration of pressor agents can have such effects. The best example is angiotensin II; there is a pronounced increase in blood pressure after administration of low doses of angiotensin II over long periods, although the plasma angiotensin concentration remains within the physiological range.39 It is difficult to test whether similar administration of NA causes such changes because exogenous NA and NA released from sympathetic nerves have different effects; moreover, the increased sympathetic activity that we postulate as being caused by overstimulation of the presynaptic beta-receptor may be selective for certain tissues (probably those with narrow synaptic clefts).4O If the increased sympathetic activity is selective for certain tissues, the best way to test the hypothesis would be an attempt to cause a sustained increase in sympathetic nervous activity by increasing tissue AD concentration over a long period. Majewski et a1.41 have reported the development of sustained hypertension in the rat after the long-term administration of low doses of AD which did not raise plasma AD concentrations above the

physiological range. Increased sympathetic nervous activity causes hypertrophy of cardiac muscle and other tissues with sympathetic innervation in animals.42,43 The hypertrophy may be mediated by an increase in RNA and protein synthesis.44 The effect of increased sympathetic activity in the heart may also be directly relevant to the development of essential hypertension, if the evidence for an initial increase in cardiac

confirmed;45 indeed, one attraction of the is hypothesis that it explains how elevated cardiac output and peripheral vascular resistance could occur together, rather than a rise in one being compensated by a fall in the other. output is

DISCUSSION

We believe that the failure to explain essential hypertension has resulted partly from the search for a qualitative abnormality, whether this is a circulating pressor agent, a circulating natriuretic factor,46 a faulty sodium pump,4 or a renal barrier to sodium excretion45 and partly from the lack of success in incriminating known pressor systems, such as the sympathetic nervous system or the renin-angiotensin axis, because the differences between hypertensives and normotensives appear either slight or non-existent. Since blood pressure in the population is not bimodally distributed, it is unlikely that any qualitative abnormality could cause essential hypertension, and any major difference between hypertensives and norinotensives is likely to be secondary rather than primary. The distribution of blood pressure within the population and its normal tendency to rise with age suggest that the cause of essential hypertension should be sought within the framework of the normal control of blood pressure, of which-despite its complexity-physiologists

1081

claim to have a good understanding. For a hypothesis based within this framework, however, the postulated differences between normotension and hypertension may be beyond detection by even the most sensitive analytical techniques, but the hypothesis-to be meaningful-must be testable. The discovery of presynaptic receptors was one of the major advances of the past decade in neurophysiology and pharmacology, but clinical research has been singularly unsuccessful in demonstrating that they have any role in man-or indeed any intact animal. Our adrenaline infusion studies29 have enabled a tenable hypothesis of essential hypertension to be centred on the role of presynaptic receptors in blood-pressure control. Since presynaptic receptors are important in controlling NA release only into narrow synaptic clefts (from which little NA escapes into the circulation), it is not surprising that the plasma NA concentration has proved an insensitive marker in previous attempts to identify presynaptic receptor stimulation in vivo. How can the hypothesis be tested? The requisite demonstration of reproducibility in an animal has already been performed.41 The next requirement will be to measure AD secretion during the pathogenesis of essential hypertension, probably by 24 h urine estimations in the young offspring of hypertensive parents. The hypothesis does not relate blood pressure to the plasma concentration of AD; rather, it emphasises the relevance of the tissue concentration of AD and its dependence on total AD output over a period of time by the adrenal medulla. The improved analytical methods now available for AD estimation should be applied, therefore, to integrated 24 h urine estimations rather than random plasma measurements. We would expect small differences between offspring of normotensive and hypertensive parents and a large overlap, since not all offspring of hypertensive parents become hypertensive. A long-term prospective study of the predictive value of 24 h urine AD excretion for subsequent development of essential hypertension may be required. The third and major test of the hypothesis, the demonstration that essential hypertension can be prevented by appropriate means, is more difficult, but it is conceptually possible. It has been suggested that beta-blocking drugs owe their antihypertensive effect to blockade of the presynaptic beta-receptor,48 but this does not help to test our hypothesis, since treatment is different from prevention and there are several other mechanisms by which beta-blocking drugs might work. To test the hypothesis we need a drug which inhibits PNMT, the enzyme in the adrenal medulla that synthesises AD; the drug (a) should be selective (i.e., should have no other effect interfering with the interpretation of results); (b) should not cross the blood-brain barrier, since PNMT is present in some brain nuclei; and (c) should be without known toxicity, so that it could be administered safely over several years to patients at risk of essential hypertension. A drug with properties (a) and (b) has already been developed,49 and PNMT inhibitors have been successfully used in animal models of hypertension.50 A PNMT inhibitor would have no side-effects related to its pharmocological action since adrenaline is not an essential hormone; many patients undergo adrenalectomy for various z causes and do not need subsequent adrenaline replacement. 51 There would, however, be little advantage in discovering the cause of essential hypertension if the prevention required more years of tablet-taking than does treatment of the established disorder. The current revolution in monoclonal may

now

antibodies is likely to make the irreversible destruction of cells with a unique enzyme a simple and safe procedure; an antibody targeted on the PNMT-containing cells of the adrenal medulla, with access to the enzyme, could be an ideal application of such technology. Requests for reprints

should be addressed

to

M.

J. B.

REFERENCES G. Hypertension: causes, consequences and management. Edinburgh: Churchill Livingstone, 1974: 34-36. 2. De Quattro V, Chan S. Raised plasma catecholamines in some patients with essential hypertension. Lancet 1972; i: 806-07. 3. Engelman K, Portnoy B, Sjoerdsma A. Plasma catecholamine concentrations in patients with essential hypertension. Circ Res 1970; 27 (Suppl. 1): 141-45. 4. Esler M, Julius S, Zweifler A, et al. Mild high-renin essential hypertension: neurogenic human hypertension? N Engl J Med 1977; 296: 405-11. 5. Henquet JW, Kho T, Schols M, Thijssen H, Rahn KH. The sympathetic nervous system and the renin-angiotensin system in borderline hypertension. Clin Sci 1981; 60: 25-31. 6. Pedersen EB, Christensen WWJ. Catecholamines in plasma and urine in patients with essential hypertension determined by double isotope derivative techniques. Acta Med Scand 1975; 198: 373-77. 7. Lake CR, Ziegler MG, Coleman MD, Dopin IJ. Age-adjusted plasma norepinephrine levels are similar in normotensive and hypertensive subjects. N Engl J Med 1977; 296: 208-09. 8. Sever PS, Osikowska B, Birch M, Tunbridge RDG. Plasma noradrenaline in essential hyptertension. Lancet 1977; i: 1078-81. 9. Taylor AA, Pool JL, Lake CR, et al. Plasma norepinephrine concentrations-no differences among normal volunteers and low, high or normal renin hypertensive patients. Life Sci 1978; 22: 1499-1510. 10. Jones DH, Hamilton CA, Reid JL. Choice of control groups in the appraisal of sympathetic nervous activity in essential hypertension. Clin Sci 1979; 57: 339-44. 11. Avakian EV, Horvath SM. Plasma catecholamine responses to tyrosine hydroxylase inhibition and cold exposure. Life Sci 1980; 26: 1691-96. 12. Brown MJ, Jenner DA, Allison DJ, Dollery CT. Variations in individual organ release of noradrenaline: limitations of peripheral venous measurements in the estimation of sympathetic nervous activity. Clin Sci 1981; 61: 585-90. 13. Brown MJ, Causon R. "NA" or "Na" in hypertension? Lancet 1981; i: 721-22. 14. Brown MJ, Lhoste FJM, Zamboulis C, Ind PW, Jenner DA, Dollery CT. Problems with estimation of sympathetic activity in essential hypertension. Clin Pharmacol Ther (in press). 15. Kiowski W, Buhler FR, van Brummelen P, Amann FW. Plasma noradrenaline concentration and alpha-adrenoceptor-mediated vasoconstriction in normotensive and hypertensive man. Clin Sci 1981; 60: 483-89. 16. Manger WM, Gifford RW. Phaeochromocytoma. New York: Springer-Verlag, 1978. 17. Silverberg AB, Shah SD, Haymond MW, Cryer PE. Norepmephrine: hormone and neurotransmitter in man. Am J Physiol 1978; 243: E252-56. 18. Scriven AJI, Dollery CT, Brown MJ, et al. Changes in blood pressure and plasma noradrenaline during infusions of tyramine and noradrenaline in normal subjects. Br J Clin Pharmacol (in press). 19. Lake CR, Ziegler MG, Kopin IJ Use of plasma norepinephrine in the evaluation of sympathetic neuronal function in man. Life Sci 1976; 18: 1315-26. 20. Langer SZ. Presynaptic regulation of catecholamine release. Biochem Pharmacol 1974; 23: 1793-1800. 21. Rand MJ, McCulloch MW, Story DF. Pre-junctional modulation of noradrenergic transmission by noradrenaline, dopamine and acetylcholine In: Davies DS, Reid JL, eds. Central Action of Drugs in Blood Pressure Regulation. London: Pitman Medical 1975:94-132. 22. Starke K. Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol 1977; 77: 1-124. 23 Stjarne L, Brundm J. Beta2-adrenoceptors facilitating noradrenaline secretion from human vasoconstrictor nerves. Acta Physiol Scand 1976; 97: 88-93 24. Adler-Graschinsky E, Langer SZ. Possible role of abeta-adrenoceptor in the regulation of noradrenaline release by nerve stimulation through a positive feedback 1.

25.

Pickering

mechanism Br J Pharmacol 1975; 53: 43-50. Majewski H, Rand MJ, Tung L-H. Activation of prejunctional beta-adrenoceptors in rat atria by adrenaline applied exogenously or released as a co-transmitter. Br J

Pharmacol 1981, 73: 669-79. de Champlain J, Nadeau RA. Regulation of norepinephrine release from cardiac sympathetic fibres in the dog by presynaptic alpha and beta receptors. Circ Res 1977; 41: 108-17. 27. Fitzgerald GA, Watkins J, Dollery CT Regulation of norepinephrine release by peripheral alpha2 receptor stimulation. Clin Pharmacol Ther 1981; 29: 160-67. 28. Macquin I, Brown MJ, Causon R, et al. Is adrenaline a cardiac neurotransmitter in man? Br J Clin Pharmacol (in press). 29. Brown MJ, Macqum I. Catecholamme neurotransmitters in the heart. Acta Med Scand 26.

Yamaguchi N,

(in press). R, Elghozi JL, Joly E, di Giuho S, Meyer P. Increased plasma benign essential hypertension. Br Med J 1977, ii: 1251-54. Brown MJ, Allison DJ, Jenner DA, Lewis PJ, Dollery CT Increased sensitivity and accuracy of phaeochromocytoma diagnosis achieved by use of plasma adrenaline estimations and a pentolinium suppression test. Lancet 1981; i: 174-77 Brown MJ, Jenner DA A novel double-isotope technique for the enzymatic assay of plasma catecholamines, permitting high precision, sensitivity and sample capacity. Clin Sci 1981; 61: 591-98

30. Franco-Morselli

adrenaline

31.

32.

in

1082

Reviews of Books Nuclear Magnetic Resonance

Imaging in Medicine

Edited by Leon Kaufman, Lawrence E. Crooks, and Alexander R. Margulis, University of California, San Francisco. New York and Tokyo:

Igaku Shoin. 1981. Pp. 242.$29.50 IMAGES of lemons, wrists, chests, and now brains can all be produced by a plethora of new imaging techniques which are clamouring for our attention. The newest technique, which uses the magnetic properties of water (and called regrettably "zeugmatography" by a man with great vision but less Greek), probably deserves a closer look by the medical investigator and by clinicians well beyond the usual interested parties, the radiologists. This is because, in principle and now in practice too, the technique of observing the radio signals emitted by certain atoms within a powerful magnetic field allows body chemistry to be studied in a non-invasive manner. Zeugmatography, or NMR imaging, creates familiar anatomical photographs by the recording of the relative distribution of the most abundant atom, hydrogen in water. If that was all, NMR might be a minor branch of CT scanning or ultrasonography. However, the differences between magnetic properties of the water in tumours, abscesses, kidney cortex versus medulla, and many other tissues are large enough to be easily measured. The full significance of these differences is not clear. The most -exciting by far-their possible usefulness in the diagnosis of cancer, as promoted originally by the American prophet, R. Damadian-is one of the topics dealt with in this book. Although physicists can refine and perfect the NMR method, clinicians and medical investigators of all walks are required to establish its place in medicine. To do so requires a brushing up on quantum mechanics, molecular theory, physics,- electronics, and biochemistry. It is to the credit of the predominantly physicist contributors and to the editors of this book that difficult concepts are simplified, and the whole volume could be read at a sitting. The book deals succinctly with the principles of nuclear magnetic resonance in one of the best accounts for the non-physicist that I have read, and it gives an account of the esoteric methods required to produce a spatial image and record T 1. Excellent photographs whet the appetite for what this technique can tell of human physiology and pathology; there follows a diversion into an area in which NMR is less likely to displace existing methods, the measurement of blood flow. Perhaps the most exciting section deals somewhat speculatively with elements other than hydrogen-notably phosphorus, which already makes non-invasive investigation of body chemistry by NMR a clinical reality, and carbon, for which injection of an isotope (13C) will be needed and clinical use is that much more

remote.

33. Clutter WE, Bier DM, Shah SD, Cryer PE. Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and haemodynamic actions in man. J

Clin Invest 1980; 66: 94-101. 34.

Fitzgerald GA, Barnes PJ, Hamilton CA, Dollery CT. Circulating adrenaline and blood pressure: the metabolic effects of infused adrenaline in man. Eur J Clin Invest

1980; 10: 401-06. 35. Editorial. Why does blood-pressure rise with age? Lancet 1981; ii: 289-90. 36. Pohorecky LA, Wurtman RJ. Adrenocortical control of epinephrine synthesis. Pharmacol Rev 1971; 23: 1-35. 37. Folkow B. The haemodynamic consequences of adaptative changes of the resistance vessels in hypertension. Clin Sci 1971; 41: 1-12. 38. Philipp T, Distler A, Cordes U. Sympathetic nervous system and blood pressure control in essential hypertension. Lancet 1978; ii: 959-63. 39. Bean BL, Brown JJ, Casals-Stenzel J, et al. The relation of arterial pressure and plasma angiotensin II concentration. A change produced by prolonged infusion of angiotensin II in the conscious dog. Circ Res 1979; 44: 452-58. 40. Langer SZ. Presynaptic receptors and their role in the regulation of transmitter release. Br J Pharmacol 1977, 60: 481-97. 41. Majewski H, Tung L-H, Rand MJ. Adrenaline-induced hypertension in rats. J Cardiovasc Pharmacol 1981; 3: 179-85. 42. Ostman-Smith I. Cardiac sympathetic nerves as the final common pathway in the induction of adaptive cardiac hypertrophy. Clin Sci 1981; 61: 265-72.

This book is the first of its kind. It is written in somewhat technocratic English, but is well worth a place on the bedside table. Inevitably, it is out of date; the subject is galloping on, but not as fast as did roentgenography, on which 1044 publications appeared during its first year. Which reminds me, since it will soon be on everyone’s lips, could not the term zeugmatography be bettered before it is too late? Nuffield Department of Medicine, University of Oxford

B. D. Ross

Management of Anaerobic Infections: Prevention and Treatment Antimicrobial Chemotherapy Research Studies Series. A. T. Willis, P. H. Jones, and S. Reilly, Luton and Dunstable Hospital. Chichester: Research Studies Press (Wiley). 1981. Pp. 97. :&9.50.

THIS very concise and comprehensive account of the prevention and management of anaerobic infections is the first of a new series and, as might be expected from the reputation of the authors, the text is authoritative and fully referenced and sets a high standard for the remainder of the series. In the first chapter, which briefly describes the various infections caused by anaerobic bacteria, the only surprising feature is the inclusion, without any explanation, of enteritis due to Campylobacter coli and Campylobacter jejuni. A clue to why these microaerophilic bacteria have been included is perhaps provided by the later discussion of their susceptibility to metronidazole. However, it is unlikely that many microbiologists will be convinced by this reasoning, since the MICs for these organisms are higher than those for anaerobes, some strains are resistant, and their inhibition by metronidazole differs from that of oxygen-tolerant anaerobes in that it occurs in the presence of air. In the second chapter in which the anti-anaerobe activity of all the major antibiotics is discussed, the many references given will be extremely useful to the microbiologist with an interest in bacterial susceptibility to antibiotics. The clinician will find his needs fully provided for by metronidazole, with occasional recourse to chloramphenicol, clindamycin, penicillin, and vancomycin. The authors have found the currently available cephalosporins (or cephamycins) disappointing and do not recommend them. The rest of the book covers the prevention and management of tetanus, gas gangrene, and gastrointestinal diseases, and the treatment of and prevention of non-clostridial anaerobic infections. It is of the last chapter that criticism must be made. The authors rightly emphasise the importance of anaerobic bacteria in sepsis occurring after colonic surgery but dismiss aerobic infection as unimportant, a view which many surgeons would challenge. They also dismiss short-term prophylaxis without any discussion of the experimental data on which it is based or of the results of several successful clinical trials of single-dose prophylaxis. They also regard the argument that long courses of antibiotics may increase the prevalence of resistant

43. Laks MM, Morady F, Swan HJC. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest 1973; 64: 75-78. 44. Caldarera CM, Giorgi PP, Casti A. The effect of noradrenaline on polyamine and RNA synthesis in the chick embryo. J Endocrinol 1970; 46: 115-16. 45. Guyton AC, Coleman TG, Cowley AW, Manning RD, Norman RA. Arterial pressure regulation: Overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med 1972; 52: 584-94. 46. Poston L, Sewell RB, Wilkinson SP, et al. Evidence for a circulating sodium transport inhibitor in essential hypertension. Br Med J 1981; i: 847-49. 47. Cannessa M, Adragna N, Solomon HS, Connolly TIM, Tosteson DE. Increased sodium-lithium countertransport in red cells of patients with essential hypertension. N Engl Med 1979; 302: 772-76. J 48. Rand MJ, Law M, Story DF, McCulloch MW. Effect of beta-adrenoceptor blocking drugs on adrenergic transmission. Drugs 1976; 11 (Suppl. 1,): 134-43. 49. Pendleton RG, McCafferty JP, Roesler JM. The effects of PNMT inhibitors upon cardiovascular changes induced by hemorrhage in the rat. Eur J Pharmacol 1980; 66:1-10. 50. Saavedra JM, Axelrod J. Adrenaline forming enzyme in brain stem: elevation in genetic and experimental hypertension. Science 1975; 191: 483-84. 51. Engelman K. The adrenal medulla and sympathetic nervous system. In: Beeson P, McDermott W, eds. Textbook of Medicine. Philadelphia: WB Saunders & Co, 1975.