The difference in the size of the two hearts is at once apparent. Heart (A) is small, the heart muscle is pale, the slightest traction on the ligature around the bulb is sufficient to cause a temporary inhibition of the heart beat.

Heart of frog (B) is large, heart muscle has a high color, it beats forcibly and traction on the ligature or other manipulation does not interfere with the heart action.

Let us analyze the effect of pithing and that of the application of chloroform to the skin of the frog.

Pithing. Nussbaum (5) and later Huzinga (15) saw in the small arteries in the frog's web spontaneous, rhythmic contractions. The former also observed that pithing has for its immediate effect the cessation of these arterial contractions. Huzinga, who repeated and extended much of Nussbaum's work, explains the pithing effect as one of shock and found that its effect soon passed off. He went further and concluded that the real seat of these rhythmic contractions was in the intramuscular ganglia of the peripheral vessels or in the arterial muscle fibers themselves. This conception bears a resemblance to the myogenic theory of origin of the heart beat.

In frog (A) therefore, destruction of the spinal cord by pithing must have produced an inhibition of the vascular contractions the shock effect.

The application of chloroform to the skin resulted in a dilation of its capillaries. This was observed under the microscope. This together with the pithing effect greatly interferes with the functions of the small vessels. Thus, the vessels were affected through

their vasomotor nerves and locally through the direct action of chloroform on the vessel walls themselves.

In order to study more clearly the combined effect of vasomotor injury and vascular paralysis the following experiment was performed.

EXPERIMENT VIII

A frog was anaesthetized with ether. The sciatic nerve on the left side was cut and chloroform was applied to the web of the left foot. The right lower extremity was left entirely intact. Now the webs of both feet were separately fixed on two boards and viewed with two microscopes. By means of a "Comparison Ocular" the visual fields of the two microscopes were observed simultaneously.

The bulbus arteriosus was then

ligated and the circulation in both webs was observed.

In the right web (normal): The corpuscular after-flow lasted three and one-half minutes. This represents the vascular action in the normal extremity.

In the left web (sciatic section): The blood corpuscles stopped moving almost immediately after the aorta was ligated.

This experiment proves that when the vasomotor function is eliminated and capillaries are dilated, as in the left foot of the frog, aortic ligation is followed by immediate cessation of corpuscular flow in the vascular areas so affected.

Injury to the vasomotor system alone or the local application of vasodilators alone does not produce a very striking effect. The combination of the two procedures paralyses the peripheral vascular mechanism, and prevents the filling and enlargement of the heart after aortic ligation (see fig. 4, frog A).

This and the previous experiments have established for us, the following working hypothesis, that:

1. The size of the heart after ligation of the aorta is an index of the integrity and function of the peripheral vascular mechanism.

2. The peripheral vascular mechanism may be thrown out of function by the combined action of local vasodilator substance (chloroform, etc.) plus the destruction of vasomotor nerves (section or disease of vasomotors, pithing of the cord).

We conclude therefore, that when there occurs a severe injury to the blood vessels, no matter how produced, the heart will not enlarge when the aorta (bulbus arteriosus) is ligated. Since from our experiments, we know that aortic ligation calls forth a powerful vascular dynamic mechanism which drives blood into the heart, we infer that any procedure which is responsible for the absence of cardiac enlargement following aortic obstruction or ligation, must have inhibited the peripheral vascular dynamic mechanism. This indicates a severe injury to the peripheral blood vessels. The importance of this conception lies in the possibility of its applications to the experimental study of clinical problems dealing with circulatory failure and vascular diseases in general.

Our own experiments plus those referred to lead us to the following conclusions:

3. The tension within the vessels exerts a regulatory influence on the automatic vascular activity.

SUMMARY

The bulbus arteriosus of the frog was ligated. It produced a tremendous filling and dilatation of the heart. This was due to the active contractions of the peripheral vascular mechanism (arterioles, capillaries and venules).

That this was possible was proven by several different experiments:

1. The aorta of a cat was clamped and yet a capillary circulation persisted in the ear.

2. A frog's leg was ligated, nevertheless the capillary flow was still maintained in the foot. This occured even after the leg was amputated.

3. A subcutaneous artery in the frog's thigh was ligated. The corpuscular stream could be seen in the capillary branches for some time after.

4. A blood pressure cuff compressed the brachial artery in the human arm. The capillary circulation in the fingers continued for a while after this procedure.

Paralysis of this peripheral vascular mechanism (combined vasomotor and vascular injury) prevents cardiac enlargement after experimental aortic obstruction.

The absence of enlargement of the heart after aortic ligation is an indication of extensive and severe injury of the neuro-vascular mechanism. Activity of the latter may be elicited

2. It may be elicited by cutting off the blood supply (ligation of the aorta or arteries), or by the direct effect of acids or metabolic products on the blood vessels.

of acids or metabolites on the vessels. In conclusion, I wish to express my thanks to Dr. D. R. Hooker for his constructive criticism and for the privileges accorded me while working in his laboratory.

(1) DANZER AND HOOKER: Amer. Jour. Physiol., 1920, lii, vol. 1, 136.

(2) SCHIFF: Untersuch zur Physiol. des Nervensystems, 1855, Bd. II, 147.

(3) SOLOVEITCHIK: Petrograd

1917.

(4) BENJAMINS

Dissert.,

AND ROCHAT: Pflüger's Archiv., 1916, Bd. 164, 111.

(5) NUSSBAUM: Pflüger's Archiv., 1875, Bd. X, 375.

(6) TOFANOW AND TSCHALLUSSOW: Pflüger's Archiv., 1913, Bd. 151, 543. (7) Stepanov: Jour. Russe de Physiol., 1917-1918, 107-8.

(8) WEGENER: Archiv. f. Ophthalmologie, 1866, Bd. XII, Part II, 12.

(9) TSCHALLUSsow: Pflüger's 1913, Bd. 151, 523.

Archiv.,

(10) FRANCOIS, FRANK: Archiv. de Physiol. Norm. et Pathol., 1895, vii, 138. (11) ROBERTS: Eng. Jour. Physiol., 1922, lvi, 101.

(12) MEYER, O. B.: Zeitschr. f. Biol., 1913, lxi, 275.

(13) FULL: Zeitschr. f. Biol., 1913, lxi, 287. (14) GUNTHER: Zeitschr. f. Biol., 1915, xlviii, 280.

(15) HUZINGA: Pflüger's Archiv., 1875, xi, 207.

(16) HESS: Pflüger's Archiv., 1916, clxiii, 555.

(17) KARFUNKEL: Archiv. f. Anat. u. Physiol. (anat. Abteillung), 1905, 539. (18) LUCHSINGER: Pflüger's Archiv., 1881, xxvi, 445. (19) MERZBACHER: Pflüger's Archiv., 1903, Bd. C, 568.

(20) HENDERSON AND LOWI: Deut. Archiv. f. Exper. Patho. u. Pharmakol., 1905, liii, 48.

(21) NATUS: Virchow's Archiv., 1910, cxcix, 1.

(22) BAYLISS: Jour. Physiol., 1901, xxci, 32.

(23) SCHWARTZ AND LEMBERGER: Pflüger's Archiv., 1911, clxi, 149.

(24) DALE AND THACKER: Jour. Physiol., 1913, xlvii, 493.

(25) HURTHLE: Akand Archiv. f. Physiol., 1913, xxix, 100.

(26) TIGERSTEDT, C.: Skand Archiv. f. Physiol., 1912, xxviii, 433. (27) BLUMENFELDT: Pflüger's

1915, clxii, 390.

Archiv.,

(28) LEGROS AND ONIMUS: Jour. de L'Anat. et de la Physiol., 1865, 362, 469. (29) GRUTZNER: D. Archiv. f. klin. Med., 1906, Bd. 89, 132.

(30) LUCIANI: Human Physiology, 1905, i. (31) HASEBROEK: Über den Extrakardialen Kreislauf, Jena, 1914.

(32) KAUTSKY: Pflüger's Archiv., 1918, Bd. clxxi, 386.

(33) ROSENBACH: Berlin. klin. Wochen., 1903, Bd. 40, 1068.

(34) FRANKE: Wien. Klin. Wochen., 1910, Nr. 10, 317.

(35) STRAUB: Deutsche Archiv. f. klin. Med., 1914, cxv, 531.

(36) MALL: Archiv. Du Bois Reymond, 1892, 409.

(37) MARES: Quoted by Kautsky Pflüger's Archiv, 1918, Bd. clxxi, 386. (38) LOMBARD: Amer. Jour. Physiol., 1912, xxix, 335.

ANNALS OF CLINICAL MEDICINE, VOL. III, No. 8

ACQUIRED IMMUNITY OF RENAL EPI

THELIUM TO POISONS

THE

HE very fact that the kidneys as excretory organs must bear a very large share in the effects of poisons and toxins passing through them implies logically that they must have developed in the course of evolution more or less of a defense mechanism against such poisons. The renal epithelium in itself must be an agent in the detoxication and chemical transformation of such poisons. The modern pathological conceptions of the nature of parenchymatous nephritis have come more and more to be that this process is essentially a defense reaction on the part of the kidney to some poison. The more recent histopathological studies of kidneys showing parenchymatous nephritis in association with a definite clinical history of etiological factors have thrown much light upon the essentially defensive nature of Bright's disease, and upon the hitherto unsuspected regenerative and recuperative powers of the kidneys. Animal experimentation has added greatly to this knowledge and to its interpretation. We have learned that certain poisons produce parenchymatous lesions in the renal tubules, and indeed exercise a selective affinity for certain portions of the tubules. Chromium acts chiefly upon the first portion of the primary tubules, uranium upon the third portion, while mercuric chloride, cantharidin

That

and the poison of eclampsia affect the terminal transition portion. We know also that other substances formed within the body, such as bile-pigments, hemoglobin and hemosiderin, are excreted through the glomeruli and are resorbed and deposited in the proximal convoluted tubules, while glycogen is taken up by the cells of the loops and the straight transitional portion. Just why different substances are resorbed in different portions of the tubules we do not as yet know, but the solving of this problem will doubtedly throw light upon the question of the localization or the toxic effects of different substances. in addition to any intrinsic immunity the renal epithelium may possess the latter has also the power of developing an immunity or increased resistance to various poisons was shown as early as 1912 by Suzuki. He found that animals recovering after poisoning with uranium could later stand repeated injections of primarily lethal doses without apparent injury, and this was confirmed by histologic examination which showed the renal epithelium undamaged, although the first doses produced marked lesions in the tubal epithelium. This apparently could be interpreted only as an acquisition of local tolerance to uranium on the part of cells once injured by it. Suzuki's observations have been confirmed by others. Gil-y-Gil (Zeigler's Beiträge, 1924, Bd. LXXII) showed that animals surviving a

single injection of 0.01 gm. of uranium could by gradually increasing the dose be given subcutaneously a dose eighty times as large or ten times as large intravenously without the production of any toxic symptoms. Urinary examinations showed that the uranium was not retained in the body but was excreted through the kidneys without damaging the renal epithelium. Histologic examinations showed that the middle and distal portions of the convoluted tubules, which are damaged by the first injection of uranium, are not affected by the subsequent injections, although in some cases the proximal portions showed injury. In animals in which repeated injections of large doses were given the epithelium of the convoluted tubules was injured severely but the glomeruli escaped damage, so that the possibility of an acquired immunity on the part of the latter may be as

sumed. The acquired immunity or tolerance of the renal epithelium to poisons is like that of the intestinal epithelium in individuals habituated to the use of arsenic in poisonous doses, and is probably the essential factor in other forms of acquired tolerance affecting other tissue-cells. In the case of the renal epithelium the ability to develop such immunity to the action of excreted poisons throws much light upon the problems of parenchymatous nephritis. Taken into account with the more recent knowledge of the regenerative power of the tubal and glomerular epithelium our conceptions of renal injury and recovery must be greatly modified and certain clinical and pathologic stages of nephritis must be regarded as essentially reparative in character. Chronic parenchymatous nephritis, therefore, is revealed more clearly as a defensive process.