Annotatiom 420

38. Beraldo, W. T.: Substance U: a depressor and smooth-muscle stimulating principle present in urine, Am. J. Physiol. 171:371, 1952

39. Braun-Men&dez, E., and Paladini, A. C.: I’ressor polypeptides formed in vivo and in vitro as mediators of renal hypertension, Cir- culation 17:668, 1958.

40. Smeby, R. R., and Rumpus, F. M.: Biochemis- try of pressor polypeptides (especially angio- tensin). In Milton Mendlowitz, editor: Hyper- tension, New York, 1961, Grune & Stratton, IllC.

41. Guttmann, S., and Boissonnas, R. A.: Syn- th&e d’analogues structuraux de la brady- kinine, Helvet. chim. acta 44:1713, 1961.

42. \:ogler, K., Studer, R. O., and Lergier, W.:

Synthese von dab’-dabg-bradykinin, Helvet. chim. acta 44:1495, 1961.

43. Woolley, D. W., and Merrifeld, R. B.: Speci ficity of peptides, Science 128:238, 1958.

44. Tritsch, G. L., and Woolley, D. W.: Bradykinin activity of some synthetic peptides with only slight structural resemblance to natural brady- kinin, Nature 186:76, 1960.

45. Boissonnas, R. A., and Guttmann, S.: Synthese d’analogues de I’oxytocine et de la lysine-vaso- pressine contenant de la phenylalanine ou de la tyrosine en positions 2 et 3, Helvet. chim. acta 43:190, 1960.

46. Huggins, C. G., and Walaszek, E. J.: Depressor polypeptides, AM. HEART J. 60:976, 1960.

Main cerebra’1 artery disease

as a cause of strokes

I-ntil fairly recently, cerebral infarction has been ascribed to arterial thrombosis, and cerebral hemor- rhage to arterial rupture. Despite early French observations in 1925l of the occurrence of cerebral infarction without thrombosis, this association was slow to achieve recognition. However, with the increasing use of cerebral angiography the concept of “cerebrovascular insufficiency”2 on a basis of “caroticovertebral stenosis”3 became widely ac- cepted. This led to the introduction of reconstructive surgery designed to improve the flow of blood through narrowed or occluded arterial segments in patients with recurrent cerebral ischemic episodes. These operations are also frequently performed prophylactically in those who have already suffered permanent brain damage, to prevent their getting further infarcts.

As always happens in new fields, opinion swings widely from one extreme to the other, and we are seeing at present a return to the old idea of cerebral thrombosis as a prime cause of infarction. Careful obser\atio& have shown a difference between old and recent infarcts. Although occlusion was de- monstrable in only a minority of patients with long- standinq cerebral infarcts, thrombus in the arteries of supply was found in 90 to 95 per cent of patients with acute brain softening. This raises the possi- bility that old infarcts may have been due to throm- bosis of arteries which have later recanalized.

Has the time come to discard altogether the con- cept of “cerebrovascular insufficiency,” with its emphasis on stenotic lesions of the larger vessels as a cause of cerebral infarction? It is unfortunate that most observations on the main cerebral arteries, particularly those in the neck, have been made in patients who died with strokes,6 and little is known of the incidence of stenotic lesions of the large cerebral arteries in people with normal brains. This omission has been rectified recently6 in an investi-

gation which has shown almost as high an incidence of severe arterial stenosis in people with normal brains as in those with cerebral infarction. The authors of this latter paper suggested that much of the relationship between cerebral infarction and carotid-vertebral stenosis might be accounted for by age alone, since older patients have narrower arteries and suffer more frequently from cerebral infarction. Perhaps an infarct not caused bv com- plete arterial occlusion needs for its production not only stenotic lesions of the arteries of supply, but also some other condition, such as heart disease, which causes a fall in blood pressure. Much evidence suggests that frank heart disease is present as often as not in cases of cerebral infarction.?

The relief of transient attacks of cerebral ischemia by reconstructive surgery cannot be taken to prove a pre-existing state of cerebrovascular insufficiency, because it is possible that operation removes a source of emboli. Some very interesting observations ha\-e recently been made of the retina in cases of internal carotid thrombosis, in which multiple small emboli were seen traveling along the retinal arteries.* Many of the attacks which formerly were considered to be due to spasm or to “cerebrovascular insufficiencv” can now be more convincingly reinterpreted ‘in terms of emboli passing to other parts of the in- ternal carotid territory.

Turning to cerebral hemorrhage, we have wit- nessed a whole spectrum of different opinions during the last 20 years. Miller Fisher9 supports the classic view that this condition is usually due to arterial rupture. However, many will remain unconvinced that simple spontaneous rupture is the whole es- planation, especially since it is so difficult to rupture cerebral arteries by high intraluminal pressure,‘” and because, when the bleeding vessels can be found, they are often small. Welch” showed long ago that experimental intestinal infarction could be made

430 Annotations

avascular or hemorrhagic at will, according to whether the arterial occlusion was complete or incomplete; and experimental embolic occlusion of a single leptomeningeal artery has been observed to produce hemorrhagic infarction in the gray matter.‘? It is interesting that massive cerebral hemorrhage has been produced in dogs simply bl the readmission of blood to a brain made totall) ischemic for a short time by increased intracranial pressure.13 The fact that cerebral hemorrhage can be produced in this way, without the stress of hyper- tension, suggests that cerebral hemorrhage in man could be due to the readmission of blood into an area of infarction. Bleeding into the brain may be different in nature from bleeding into other organs because of the ease with which brain tissue can be disrupted. Thus, damage due to a small infarct might spread far beyond the original lesion. This hypothesis, by no means new, can be neither proved nor disproved without more evidence, but three corollaries of it are worth examining.

First, if cerebral hemorrhage and cerebral in- farction share a common cause, the two conditions should often coexist. It is general knowledge that this is so; not only do we see areas of acute softening in cases of cerebral hemorrhage, but we also see long-standing cerebral cysts, presumably repre- senting previously infarcted areas. In a personal series of 20 cases of cerebral hemorrhage, I observed c,oesistent cysts five times.14

Secondly, if hemorrhage is usually due to bleeding into an infarcted area, we should expect to iind that the severity of stenotic vascular disease is as great in cerebral hemorrhage as in cerebral infarction. Yates and Hutchinson found a high incidence of stenotic disease of the large arteries in cases of cerebral hemorrhage, but it was still not so great as in cases of cerebral infarction. However, their assessment was made by eye, and, when using a simple perfusion method of gauging the approximate caliber of the arteries at necropsy, my colleague and I were not able to find a significant difference be- tween cases of cerebral hemorrhage and cases of cerebral infarction, although there was a clear-cut difference in the fluid-carrying capacity of these vessels in cases of strokes of all kinds, when com- pared with the vessels of people who died with normal brains.”

Thirdly, if cerebral hemorrhage is commonly due to bleeding into an area of previous infarction, we should not expect to find cerebral hemorrhage oc- curring in animals with experimental hypertension. Stamler’s has made the statement, which I have not seen refuted, that massive cerebral hemorrhage, so commonly associated with high blood pressure in man, does not occur in benign experimental hyper- tension in animals. This suggests strongly that some- thing more than high blood pressure is necessary for the production of rerebral hemorrhage.

Although arterial thrombosis clearly plays an important part in cerebral infarction, there is usually pre-existing stenotic vascular disease in addition. Possibly, the normally high blood pressure of nearly al! such patients protects them against stagnation of blood in the brain. It is perhaps relevant that most cerebral infarcts occur during sleep, when the blood pressure is low. It is becoming fashionable to

discount the significance of stenotic lesions of the main cerebral vessels in the neck. Certainly, col- lateral channels can be remarkably effective. ah was shown by a recent report in which the cerebral blood flow of 2 patients with bilateral obstruction of the internal carotid artery was found to be nor- mal.16 It is often observed that there may be ver) little drop in pressure across a greatly narrowed segment of carotid artery. However, under average waking conditions, and under anesthesia, the s!.s- temic arterial pressure is considerabl) higher than it needs to be to perfuse the brain adequateI\,. If \ve find a drop in pressure of, say, 2 mm. Hg across a narrow region of the carotid artery, this may Ix greater under different conditions, in which, at ;L lower blood pressure, the region itself is less dis- tended, and the other main cerebral arteries are also less distended. The possibility of greater ste- nosis higher up the course of the artery must also be borne in mind. In additon, it is now well estab- lished that the vertebral, and sometimes the carotid arteries also may be partly or completely occluded during certain movements of the neck.” The hemo- dynamic significance of small lesions could be mr1c.h increased 1n these circumstances.

There is a most urgent need to develop new tech- niques to study, during life, the resistance offered h> \-arious parts of the cerebral vascular tree under a variety of conditions. Irntil we have these nen techniques, future discussion in this field will be increasingly sterile.

C. J. Dickinson, D.X. Medical l’nit

REFERENCES

1. Foix, C., Chavany, J. ;\., and Bascourret: Foyers de ramollissement simultanes dans les deux h&nisphires. R6le des causes occasionelles et des oblit&ations incomplPtes dans la patho- genie du ramollissement cC&bral, Rev. neural. 32(pt. ii) :77, 1925.

2. Denny-Brown, D.: Symposium on specific meth- ods of treatment; treatment of recurrent cere- brovascular symptoms and question of “vaso- spasm,” M. Clin. North America 35:1457, 19.51.

3. Hutchinson, E. C.. and Yates, P. 0.: Carotiro- vertebral stenosis, Lancet 1:2, 1957.

4. Adams, R. D., and Fisher, C. M.: Pathology of cerebral arterial occlusion, in Fields, W. S.. editor: Pathogenesis and treatment of cerebra- vascular disease, Seventh Annual Scientific Meeting of the Houston Neurological Society, Texas Medical Center, Houston, Tex. Spring- field, Ill., 1961, Charles C Thomas, Publisher, pp. 126-142.

5. Yates, I’. O., and Hutchinson, F:. C.: Cerebral infarction: the role of stenosis of the extra- cranial cerebral arteries, M.R.C. Special Report Series, No. 300. London, 1961. Her Majesty’s Stationery Office.

6. Schwartz, C. J., and Mitchell, J. Ii. ,4.: Athe- roma of the carotid and vertebral arterial sys- tems, Brit. M. J. 2:10.57, 1961.

7. Gormsen, J.: Heart disease in 202 patients with

Annotations 431

acute cerebral infarction, Acta. psychiat. scan- diuav. Suppl. 150:106, 1960.

8. Russell, R. W. R.: Observations on the retinal blood vessels in monocular blindness, Lancet 2:1122. 1961.

9. Fisher, C. M.: In Fields, W. S.: Pathogen&s and treatment of cerebrovascular disease,’ pp. 320-32 1.

10. Lampert, H., a11d Miiller, W.: Bei welchem I)ruck kommt es zu einer Ruptur der Gehirnge- ftisse? (Durchsptilungsversuche an Leichenge- hirnen in situ), Frankfurt. Ztschr. Path. 33:471, 1925-26.

11. \Velch, W. H.: Haemorrhagic infarction, Tr. ;I. :Xm. Physicians 2:121, 1887.

12. I’enry. J. K., and Netsky, M. G.: Experimental embolic occlusion of a single leptomeningeal artery, A\.M.X. -Arch. Neurol. & Psychiat. 3:391, 1960.

13. M.ertheimer. P., Dechaume, J., and Fo11taine,

R. : Hemorragie &rebrale et hypertension art& rielle experimentales. Deductions therapeu- tiques, Lyon med. 152:677, 1933.

14. Dicki11son, C. J., and Thomson, A. D.: A post- mortem study of the main cerebral arteries, with special reference to the cause of strokes, Clin. SC. 20:131, 1961.

15. Stamler, J.: In Millikan, C. H.. editor: Cerebro- vascular diseases, New York, 19.58, Grtme & Stratton, Inc., p. 98 et seq.

16. Fazekas, J, F., Yuan, R. H., Callow, ~1. I)., Paul, R. E., Jr., and ,L\lman, R. \V.: Studies of cerebral hemodynamics in aortocranial disease, New England J. Med. 266:221, 1962.

17. Sheehan, S., Bauer, R. B., and Meyer, J. S.: \-ertebral artery compression in cervical span- dylosis. Arteriographic demonstration duri11g life of vertebral artery insufficiency due to rotz tion and extension of the neck, Neurolog!. 10:968, 1960.

Transfer of CdllSm

across the pericardium of dogs

The rates of transfer of radiocadmium, CdnSVfl, across the intact pericardium of dogs were meas- ured. This isotope was stt1died because of its many interesting features, and because it is an important and interesting trace element found in mammals, including ma1l.1-3 Cadmium is essential for certain enzyme functions.* Chronic cadmium-poisoning has been reported to produce cardiomegaly.5,fi However, cadmium is not a useful experimental tool for the production of cardiomegaly, as originally anticipated.7

Cdu5’” was instilled i11 the pericardial cavity in Ringer’s solution in a concentration of approxil mately 5.5 mg. per 50 ml. or 110 mg. per liter, which is far greater than the concentrations normally found in mammalian tissues3 This concentration did not change the electrocardiogram. By methods and mathematical analyses previously described*,9 the mean rate of transfer was 0.176 pg per square ce11timeter per minute; the range was 0.03 to 0.36 pg/cm.2/min. This represents a daily bidirectional rate of transfer of about 150 mg. across the peri- cardium of the dog. Of the ions studied in this laboratory by this technique (D,O, H3, Cl36, Na22, Mg28, Cd’=m), *,9 Cd116n1 had the slowest rate of transfer. This rate of disappearance of Cd116m from the pericardial test fluid probably represents not only loss by transfer through the pericardium but also Cdmm bound to protein and epithelial cells of the pericardium. Thus, like other serous mem- branes there is an extremely rapid transfer of many elements and complex substances across the peri- cardium. Because the pericardium is normally relatively dry in spite of the rapid and constant

exchanging of fluid and electrolytes, the accumula- tion of fluid and solutes in pericardial diseases remains a great mystery.

Tsunekaczl Takashina, M.D., Ph.D. Ralph Laczara, M.D.

James A. Cronoich, M.S. George E. Burch, M.D.

New Orleans, La.

REFERENCES

1. Margoshes, M., and Vallee, B. L.: A cadmium protein from equine kidney cortex, J. .4m. Chem. Sot. 79:4813, 1957.

2. Koch, H., Smith, E., Shimp, N., and Connor, J.: Analysis of trace elements in human tissues, Cancer 9:499, 1956.

3. Tietz, N. W., Hirsch, E. F., and Neyman, B.: Spectrographic study of trace elements in cancerous and noncancerous human tissues, J.A.M.A. 165:2187, 1957.

4. Simon, F. P., Potts, A. M., and Gerard, R. \V.: The action of cadmium and thiols on tissues and enzymes, Arch. Biochem. 12:283, 1947.

5. Stephens, G. A.: Cadmium poisoning, J. Indust. Hyg. 2:129, 1920.

6. Bonnell, J. A.: Emphysema and proteinuria in men casting copper cadmium alloys, Brit. J. Indust. Med. 11:181, 1954.

7. Walsh, J. J., and Burch, G. E.: The rate of disappearance from plastna and subsequent distribution of radiocadmium (Cdnsm) in nor- mal dogs, J. Lab. & Clin. Med. 54~59, 1959.

8. Burch, G. E., and Ray, C. T.: Studies of the