NORADRENALINE IN THE HEART OF THE SPONTANEOUSLY HYPERTENSIVE RAT

1013

symmetrical peripheral neuropathy in both, are of particular interest. Although mononeuritis multiplex and symmetrical peripheral neuropathy have been frequently described in polyarteritis nodosa (Miller and Daley 1946, Bleehen et al. 1963) they must be rare in giant-cell arteritis. and the

the first to describe mononeuritis multiplex in association with giant-cell arteritis. One of his patients had a progressive painful median-nerve lesion perhaps due to increasing ischxmia of the nerve caused by narrowing of its nutrient artery; the other had a painless lateral-popliteal-nerve palsy causing sudden foot-drop, probably due to sudden thrombotic occlusion of the nutrient vessel. Case 1 demonstrated both these patterns of onset. His median-nerve lesion was slowly progressive and was associated with transient painful parsesthesiae in its cutaneous distribution. The radial-nerve palsy was, in contrast, painless and caused sudden wrist and finger drop. Symmetrical peripheral neuropathy has not been previously described in association with giant-cell arteritis. In case 1 the clinical evidence for peripheral neuropathy was sensory loss in the extremities, distal muscular weakness in the upper limbs, distinct from that associated with the right median and radial nerve palsies, and decreased or absent tendon-reflexes in the lower limbs. There was electromyographic evidence of neuropathy. In case 2 there was generalised muscle wasting and weakness, sensory loss over the fingers and toes, and symmetrical reduction of the There was also electromyographic tendon-reflexes. evidence of neuropathy. Both patients had serum-folate values which were low by some standards (case 1, 4-4 m[Lg. per ml.; case 2, 4-5 m[Lg. per ml.). Peripheral neuropathy and other neurological abnormalities have been described in patients with serum-folate levels in the range 1-8-4-3 m[Lg. per ml. (Grant et al. 1965). But those patients whose neurological features responded to folic-acid therapy had serum-folates in the lower range of 1-8-3-7 m[Lg. per ml. There is no evidence that patients with serum-folates of the order shown by these two patients are necessarily folic-aciddeficient. Recent studies have yielded values in normals of 3-6±1-5 m[Lg. per ml. (Carney 1967). Case 1 was given folic acid before this problem was appreciated; but in case 2 the striking improvement in the peripheral neuropathy followed prednisone treatment alone, while his profound anaemia responded to iron after prednisone had been started. Generalised myalgia, muscle wasting, and weakness have long been associated with the acute phase of giant-cell arteritis, and more recently the occurrence of a chronic form has been stressed by Russell (1959, 1962). Its relationship to anarthritic rheumatoid disease (Bagratuni 1956) and polymyalgia rheumatica (Barber 1957) has caused much interest (Hamrin 1964). In case 1 there was clinical, histological, and electromyographic evidence of myopathy. There was no muscle tenderness, and no nodules were palpable. The distribution was proximal, as described by others (Russell 1962). In Russell’s case there was giant-cell arteritis of the medium-sized muscular arteries in deltoid and quadriceps

Russell (1959)

was

biopsy specimens. No arteries were biopsy specimens taken from case 1.

seen

in the

triceps

These two cases emphasise the need for careful palpation of the temporal and occipital arteries in all elderly patients who present with a high sedimentation-rate, peripheral neuropathy and myopathy, and anorexia and

generalised wasting-features usually more suggestive of malignant disease. Giant-cell arteritis may exist despite the absence of headaches, visual disturbances, and other features expected from the classical descriptions of this condition. The importance of making the diagnosis of giant-cell arteritis is that prompt corticosteroid therapy may dramatically improve symptoms and will prevent irreversible visual impairment. We are grateful to Dr. C. M. Fletcher and Dr. E. J. M. Campbell for allowing us to describe their patients, and to Dr. C. Pallis and Dr. Elaine Allen for helpful advice. Requests for reprints should be addressed to D. A. W., Royal Postgraduate Medical School, Ducane Road, London W.12. REFERENCES

Andrews, J. M. (1966) Neurology, Minneap. 16, 963. Bagratuni, L. (1956) Lancet, ii, 694. Balmforth, G. V. (1964) Archs intern. Med. 113, 230. Barber, H. S. (1957) Ann. rheum. Dis. 12, 98. Bleehen, S. S., Lovelace, R. E., Cotton, R. E. (1963) Q. Jl Med. 32, 193. Carney, M. W. P. (1967) Br. med. J. ii, 512. Cooke, W. T., Cloake, P. C. P., Govan, A. D. T., Colbeck, J. C. (1946) Q. Jl Med. 15, 47. Crompton, M. R. (1959) Brain, 82, 377. Frangenheim, H. (1951) Zentbl. allg. Path. path. Anat. 88, 81. Gilmour, J. R. (1941) J. Path. Bact. 53, 263. Grant, H. C., Hoffbrand, A. V., Wells, D. G. (1965) Lancet, ii, 763. Hamrin, B., Jonsson, N., Landberg, T. (1964) ibid. i, 397. Harrison, C. V. (1948) J. clin. Path. 1, 197. Heptinstall, R. A., Porter, K. A., Barkley, H. (1954) J. Path. Bact. 67, 507. Horton, B. T., Magath, T. B., Brown, G. E. (1934) Archs intern. Med. 53, 400. Miller, H. G., Daley, R. (1946) Q. Jl Med. 15, 255. Russell, R. W. R. (1959) ibid. 28, 471. — (1962) Ann. rheum. Dis. 21, 171.

Preliminary Communication NORADRENALINE IN THE HEART OF THE SPONTANEOUSLY HYPERTENSIVE RAT Studies of the fate of intravenously administered [3H]-noradrenaline in normal and spontaneously hypertensive (S.H.) rats revealed an increased 24-hour accumulation in the heart of the S.H. animal. This increased accumulation was associated with a normal 5-minute uptake of [3H]-noradrenaline and normal endogenous levels of cardiac noradrenaline. It is suggested that the increased accumulation reflects a reduced rate of noradrenaline release. These changes in noradrenaline metabolism do not explain the hypertension but rather appear to be secondary to the hypertension.

Summary

INTRODUCTION

THE elevated blood-pressure in phaeochromocytoma is clearly associated with increased blood-levels of catecholamines, but attempts to discover a disturbance in catecholamine metabolism in other forms of hypertension have failed or have proved equivocal.I-3 The difficulties have included both an inability to investigate the turnover noradrenaline in tissues, so that reliance has had to be placed on urinary excretion of metabolites as an index of catecholamine metabolism, and the lack of an adequate experimental model for essential hypertension. In 1963 Okamoto and Aokireported that they had 1. 2. 3.

4.

Sjoerdsma, A. Circulation Res. 1960, 9, 734. Brunjes, S. New Engl. J. Med. 1964, 271, 120. Crout, J. R. in Hormones and Hypertension (edited by W. M. Mayer); P. 3, Springfield, Illinois, 1966. Okamoto, K., Aoki, K. Jap. Circulation J. 1963, 27, 282.

1014

produced, by selective inbreeding, a strain of Wistar rats in which the incidence of spontaneous " hypertension was 100%. They have named these rats " spontaneously hypertensive rats " or s.H. rats. The hyper"

CARDIAC

WEIGHT, NORADRENALINE CONTENT, AND METABOLISM OF

[3H]-NORADRENALINE

THE

IN

HEART

OF

NORMOTENSIVE

AND

HYPERTENSIVE RATS

tension in these animals in some respects resembles essential hypertension in man. It is not due to any of the of

secondary hypertension; the bloodpressure increases progressively with age, and is associated, in a considerable percentage of adult rats, with cardiac, renal, and vascular complications.5 There is also in these animals, as in human hypertension, an increased vascular responsiveness to noradrenaline.6

recognised

causes

We describe here studies of catecholamine metabolism in the heart of S.H. rats. METHODS

Experiments were carried out in male s.H. and normotensive Wistar rats weighing 150-250 g. Each S.H. rat was carefully matched for age and weight with its normotensive control. Blood-pressure was measured weekly and on the day before each experiment in unanaesthetised animals using the tail water plethysmographic method.7 Unanaesthetised animals had blood-pressure levels within 5 mm. Hg of the plethysmographic technique when their blood-pressure was determined directly by cannulating the aorta via the tail artery. Rats were given 0-5 ml. isotonic saline solution containing 20 C of 7-[3H]-DL-noradrenaline (New England Nuclear

All values tested.

are

means ±

S.E.M.

Figures in parentheses show no. of animals

of age the s.H. animals show little difference in bodyweight from their control counterparts, animals in both groups weighing 200-250 g. From this age on, the s.H. rats grow at a somewhat slower rate than controls. Similarly, cardiomegaly (see table) and renal damage are not apparent in animals that weigh less than 250 g. These results are similar to those previously reported by Okamoto et a1.5 The table summarises the results of experiments carried out in animals given tracer doses of tritiated noradrenaline. The 5-minute accumulation, which is a measure of uptake of noradrenaline, was slightly but not significantly greater in the S.H. rats than in the Wistar controls (P=0-2). The 24-hour accumulation of [3H]noradrenaline was much greater in the s.H. animal than the Wistar control whether this was expressed as nC per g. heart (P < 0-001) or as % of the initial uptake (p < 0-01) (table). This increased 24-hour accumulation is consistent with a diminished rate of release of endogenous noradrenaline from sympathetic nerve-endings. Despite this apparent diminished rate of release of [3H]-noradrenaline the endogenous levels of cardiac noradrenaline were the same in the S.H. and Wistar rats (P=0.4). DISCUSSION

increased 24-hour accumulation finding of (decreased release) [3H]-noradrenaline and normal levels of noradrenaline in the heart of the endogenous The

blood-pressure with age in normotensive and spontaneously hypertensive rats. Each point represents a mean S.E.M. of results in 10 different animals.

Rise in systolic

7-2 C per mmole) intravenously via a tail vein and killed either 5 minutes or 24 hours later. Hearts were rapidly removed, frozen in dry ice, weighed, and analysed for -noradrenaline and endogenous noradrenaline using the methods described by de Champlain et al.8

Corporation

RESULTS

The

figure illustrates the progressive rise in bloodpressure which occurs with age in all S.H. rats compared with normotensive controls. At all ages the systolic blood-pressure of the s.H. rats is significantly higher (P< 0-001) than that of the controls. Until 10-15 weeks Okamoto, K., Aoki, K., Nosaka, S., Fukishima, M. ibid. 1964, 28, 943. Okamoto, K. et al. ibid. 1966, 30, 987. Williams, J. R., Harrison, T. R., Grollman, A. J. clin. Invest. 1939, 18, 373. 8. de Champlain, J., Krakoff, L., Axelrod, J. Circulation Res. 1967, 20, 5. 6. 7.

136.

of

an

animal is in contrast to the observations of de Champlain et al.89 in rats from which one kidney had been removed and which had been made hypertensive with desoxycorticosterone and sodium choride. These workers reported decreased endogenous levels of noradrenaline and diminished [3H]-noradrenaline accumulation in the heart and other organs of such rats. They presumed that excessive leakage of noradrenaline from sympathetic neurones on to receptors might produce the hypertension. It is difficult, however, to apply these findings to human essential hypertension for desoxycorticosterone/salt hypertension is acute in onset and associated with the rapid development of renal damage, fibrinoid change, necrotising vasculitis, and cardiac hypertrophy.10-12 It is conceivable that the results of de Champlain et al. 8and pathological alterations are somehow interrelated since the greatest abnormalities in noradrenaline metabolism were observed in the heart, S.H.

9. 10. 11. 12.

Krakoff, L. R., de Champlain, J., Axelrod, J. ibid. 1967, 21, 583. Gardner, D. L. Br. J. exp. Path. 1960, 41, 60. Gardner, D. L. Q. Jl exp. Physiol. 1963, 48, 156. Hill, G. S., Hepinstall, R. H. Am. J. Path. 1968, 52, 1.

1015

gut, and

kidney which are also the areas

in which vascular

damage is greatest.810-12 By contrast the hypertension in the

s.H.

rat

more

closely resembles human essential hypertension. The aetiology is uncertain; the hypertension is not dependent on high salt intake, is gradual in onset, progressive, and not associated with cardiac, renal, or vascular complications until well into the adult life of the animal.45 In a proportion of older rats with systolic blood-pressures greater than 200 mm. Hg the hypertension enters a malignant phase associated with fibrinoid necrosis.5 Our results show that if these s.H. rats are studied before the development of any complications the rate of release of [3H]-noradrenaline, which is considered to be a measure of the turnover of endogenous noradrenaline,99 is diminished. Since this happened in the presence of normal endogenous levels of noradrenaline it seems likely that the synthesis of noradrenaline has also been reduced. If these alterations happen throughout the cardiovascular system, they would tend to diminish the vasoconstrictor effects of endogenous noradrenaline. Whether these alterations are centrally or reflexly mediated, or whether the unknown factor producing the hypertension leads to an increased receptor sensitivity to noradrenaline which in turn produces a feedback inhibition of noradrenaline synthesis and release remains to be determined. In addition to the apparent decreased release of sympathetic neurotransmitter substance the circulating renin

Reviews of Books Sarcoidosis

J. G. SCADDING, M.D., F.R.C.P., professor of medicine in the University of London at the Institute of Diseases of the Chest. London: Eyre & Spottiswoode. New York: Barnes & Noble. 1967. Pp. 542. E7 7s. THIS monograph provides an authoritative account of a multi-system chameleon which continues to tease and bewilder doctors of many different disciplines throughout the world. Professor Scadding covers clinical manifestations, setiological hypotheses, and problems of diagnosis and treatment with the clarity of thought and expression which marks his many other writings. Obviously he has enjoyed every moment he has devoted to the painstaking compilation of this volume, based on thirty years’ experience. His pleasure will now be shared by many readers. This publication is also important in that it marks the end of an era in which recognition of sarcoidosis has evolved from that of a rare dermatological curiosity to a commonplace disorder involving most systems. It was always important to remain alert to the possibility of syphilis in the pre-penicillin era, and the same may now be said of sarcoidosis. Its relative infrequency in the tropics may be due to obscuring tuberculosis or to lack of awareness, or to

both factors.

Henceforth we must assess how much of an in any community and how to distinguish it from unrelated sarcoid-tissue reactions, and try to unravel its complex immunology. These roads may lead to the final goal -namely, its aetiology.

iceberg sarcoidosis is

Performances in Aphasia A Neurodynamical Diagnostic

and Psychological Study. A. KREINDLER and A. FRADis, Institute of Neurology of the Academy of the Socialist Republic of Rumania. Paris: GauthierVillars. 1968. Pp. 261. Fr.44.

THIS monograph from the Institute of Neurology of the

Rumanian Academy of Sciences is a useful contribution to published work on aphasia. Its value is not so much in

also low.13 14 Thus, it would seem spontaneously hypertensive rat, before the development of vascular, cardiac, and renal complications, homoeostatic mechanisms come into play which diminish the production and activity of some naturally occurring pressor hormones notably noradrenaline and angiotensin. It is possible that, as in desoxycorticosterone/salt hypertension, once fibrinoid change and arteritis develop in the s.H. rat, these mechanisms may be damaged and noradrenaline now leaks on to the

levels in the that in the

s.H. rat are

receptor and contributes

the arteriolar necrosis and which are characteristic of

to

accelerating hypertension both malignant and desoxycorticosterone/salt hypertension. We thank Dr. J. de Champlain, National Institute of Mental Health, for his advice and assistance. W. J. L. is on an overseas research fellowship from the National Heart Foundation of Australia and

acknowledges with thanks its support. Requests for reprints should be addressed W. J. L. W. J. LOUIS M.D. Melb., M.R.A.C.P. S. SPECTOR PH.D. Jefferson R. TABEI M.D. Kyoto

Experimental Therapeutics Branch, National Heart Institute, Bethesda, Maryland 13. Sokabe, H. 14. Sokabe, H.

A.

SJOERDSMA

M.D., PH.D.

Nature, Lond. 1965, 205, Jap. J. Physiol. 1966, 16,

Chicago

90. 380.

facts to light as in considering established facts The authors give special attention to aspects which are often mentioned only indirectly or aphasia inadequately. Thus the importance of attention, of memory disorder, and of facilitation in overcoming aphasic disability, and the involvement of general " intelligence " when aphasia occurs, are all considered. The linguistic aspect of the defect and changes in phoneme usage are also discussed. Some attempt is made to interpret the neurological defects in terms of Pavlovian physiology, and a rather unconvincing analogy is drawn between aphasic disturbances and the breakdown of digital computer performance. Nevertheless the traditional aspects of dysphasia are well covered and often presented in a fresh light; and there is a comprehensive and up-to-date bibliography. The book will be a valuable source of reference. The meaning is occasionally obscure, which is a pity for so potentially useful a book.

bringing in of

new

new

ways.

The Management of Trauma By Members of the Staff of the Johns Hopkins University School of Medicine and the Johns Hopkins Hospital. Editors : WALTER F. BALLINGER, II, M.D., formerly associate professor of surgery, the Johns Hopkins University School of Medicine, Baltimore, Bixby professor and chairman, department of surgery, Washington University School of Medicine, St. Louis; ROBERT B. RUTHERFORD, M.D., assistant professor of surgery, the Johns Hopkins University School of Medicine; GEORGE D. ZUIDEMA, M.D., professor and director, department of surgery, the Johns Hopkins University School of Medicine. London, Philadelphia, and Toronto: W. B. Saunders. 1968. Pp. 815. E10 12s. 6d.; $25;$27 (Canada). TEN years ago there were only a few books dealing with in a general way. Now a new one appears almost month, and any addition to a long list ought to justify

trauma

every

itself. The present volume can do so, because it discusses in detail many conditions which are dismissed briefly in other works. Thus, the chapter on ordinary burns is followed by one on those due to electricity, and another on the pathological effects of cold. Radiation injuries are allocated fifteen pages, and the important place of tracheostomy in modern accident