The reaction of various agents on the kidney is being studied widely today by using renal clearance tests and quite a number of new findings are being reported these days. At present we are examining how the medicines most widely used against pregnancy toxemia today work on the kidney.As a preliminary step, we have tried to ascertain how far renal function factors vary with the same individual subject. And with the purpose of establiching standards for future experiments, we have measured the renal function factors by using PAH and Thiosulfate for two hours straight on 19 different cases using the same normal non-pregnant woman and tried to find the limits where we are to renounce the findings.As a result we discovered that in conducting renal clearance tests by performing loading tests with various agents, we can say that the agents have significant effects on the kidney only when various clearance values obtained by such tests are fluctuating above the limits where they are to be renounced. [table] When the clearance values obtained after one hour fluctuate above the above-mentioned percentages as compared with the first clearance values, they are of significance.

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In the metabolism of cardiac muscle, carbohydrate metabolism is playing an important part and as an energy source of cardiac contraction in the normal condition, saccarides comes into the first consideration.Since Buedingen introduced the concept of "hypoglykaemische Kardiodystrophie" glucose has been used customary for the treatment of cardiac disorders, but its therapeutical effect has not been established yet. Some people recommend the use of fructose as it is more advantageous than glucose due to its special behavior in the intermediate metabolism, but many people do not agree with this idea as the perfusion experiments with isolated heart were showing negative results.The author admininistered glucose and fructose intravenously into the dog and studied their influences on the oxygen consumption and utilization of pyruvic acid lactic acid and glucose using the method of coronary sinus catheterization. At the same time, using Rotameter the influence of these manoeuvre on the coronary flow was studied.Results were as follows : 1) By the administration of glucose, coronary flow increased, glucose concentration of the coronary blood increased markedly but its utilization was not increased markedly. coronary arteriovenous difference of oxygen decreased and oxygen consumption showed the tendency to decrease. The metabolism seemed to decline anaerobically.2) By the administration of fructose, coronary flow increased and blood concentration of pyruvic acid and lactic acid increased markedly. The increased pyruvic acid is utilized cempletely by the myocardium but the utilization of lactic acid depended upon the concentration of pyruvic acid.3) Fructose itself was not utilized by the myocardium at all, and the change of pyruvic acid and lactic acid which are intermediate metabolite of fructose were observed as an alteration in the body.4) When fructose was administered, oxygen consumption did not increase markedly although the utilization of pyruvic acid by the myocardium increased remarkably.These results suggest that the utilization of pyruvic acid by the cardiac muscle is performed not only through Krebs cycle but also through some other process, such as the formation of acetoin.

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1. Using rabbits weighing about two kilograms, cerebral massive haemorrhages were produced by experimental renal hypertension with modified Goldblatt's method.2. Various sizes of U-shaped silver clamps were used in order to constrict the renal main artery. Cerebral massive haemorrhages were produced most frequently in the moderately constricted group. By this method, fifty per cent of the experimented animals showed cerebral massive haemorrhages.3. Alkaline phosphatase histochemically demonstrable in the renal tubules was decreased in variable degrees by ischemia resulted from the constriction of the renal main artery. And in the rabbits, which showed cerebral massive haemorrhages, the degree of its decrease was mostly severe in the right kidney (first operated side) and moderate or slight in the left (secondly operated side).4. There is no certain relationship between the incidence of hypertension and arteriolar fibrinoid necrosis in various organs of the experimented animals.5. Arteriolar fibrinoid necrosis was observed in all of the haemorrhagic brains, however, there were some which had no haemorrhage but did show arteriolar fibrinoid necrosis in the cerebral parenchym.6. Combination of hypertension and arteriolar fibrinoid necrosis in the brain would be an important factor to produce cerebral massive haemorranges in these experimented animals.7. Acid mucopolysaccharides were not demonstrated histochemically in the acute stage of necrotic arteriolar wall, but they could be seen in the subacute and chronic phases. Long survived animals in this experiment showed necrotic arterioles in various stages. This finding indicates the fact that arteriolar fibrinoid necrosis did not appear at a definite time but could appear successively, by some unknown agents, during the period of survival.8. In human autopsy cases with hypertensive cerebral haemorrhages, arterial or arteriolar fibrinoid necrosis was seen, not infrequently, in the brain as well as in other organs, and these cases had never showed any clinical signs of malignant hypertension.9. It is strongly suggested that human hypertensives might show, in some instances, cerebral haemorrhage, following the necrotizing process and consequent rupture of the cerebral arteries or arterioels.

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The production of experimental renal hypertension was first reported in 1934 by H. Goldblatt. According to recent study, if the renal arteries were moderately constricted by modified Goldblatt's method, the cerebral massive haemorrhage occurred in the experimental hypertensive rabbits. However, the haemorrhages were observed not only in the brain but also in the other organs. Arteriolar fibrinoid necrosis was one of the chief histological findings of the vascular lesions in these experiments. This vascular lesion resembled the arteriolar lesions in the malignant hypertension, but it was also similar to vascular lesions which were observed in the apoplectic brain.In this report, following two series of experiments were performed in order to study the relationship between the arteriosclerosis and the fibrinoid necrosis.In the first series, Goldblatt's operations were performed in the rabbits prepared by the arteriosclerosis-producing procedures, namely the daily subcutaneous injection of 0.2 cc of a adrenaline for 3 months or the cholesterol feeding for 3 months (0.5 gr daily). In these arteriosclerotic rabbits, the cerebral massive haemorrhage and the fibrinoid necrosis following the Goldblarr's operation were less frequent than in the group not prepared by the arteriosclerosis-producing procedures. (Table 1, 2, 3.)In the second series, experimental hypertensive rabbits were divided into two groups. One group consisted of the rabbits which died acutely within a week after the Goldblatt's operation and another group consisted of the hypertensive rabbits with long survival. The vascular lesions in both groups were compared by the histological study. (Table 4). In the acute cases, the fibrinoid necrosis was observed in the smaller arterioles and many of them were so severe to affect all layers of the blood vessel. Fibrosis of the vascular wall not observed in this group. In the chronic cases, the fibrinoid necrosis was observed in larger arterioles and severe lesion was less frequently observed than in the acute cases. In some cases, fibrinoid substance appeared only in subintimal portion of the blood vessels. Fibrosis was marked in many arteriolar walls, which resembled the arteriolosclerosis in the organs of aged people. Clinical experience shows that the malignant hypertension is most frequent in 30-50 years old and rare in the aged. Pickering suggested that the organic arterial changes might protect the arteriolar necrosis and Nishimori reported that the fibrinoid necrosis never occurred in the arteriosclerotic vessels with fibrous thickening. Above-mentioned experiments supported their opinions.I think the foregoing organic arterial changes can make the fibrinoid necrosis mild and the healing process of the fibrinoid necrosis may produce a type of the arteriolosclerosis.

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In the present patper, the effects of the stimulation of the peripheral end of the vagal nerve were reported, with consideration of the relationship between vasomotor and hemodynamic factors. Experimental methods were same as already described in the Part I of this study.Results were as follows : 1) Stimulations of the peripheral ends of the cut vagal nerves were performed, on the left side in 15 experiments on 11 dogs, on the right side in 4 experiments on 4 dogs. During the stimulation of the vagal nerve, the depression of the blood pressure and the bradycardia occurred in all experiments.2) Coronary blood flow decreased with the depression of the blood pressure, for example, as shown in Fig. 1. But, in about a half cases of all experiments, coronary blood flow increased initially for a short time, and then decreased with marked depression of the blood pressure, for example, as shown in Fig. 2 and 3. Experimental results of all cases in the initial increase and maximal decrease in coronary blood flow, were shown in Tab. I and II, respectively.3) Coronary vascular resistance decreased markedly during phases of the initial increase in coronary blood flow (white dots in Fig. 4). In addition, it decreased also during phases of the maximal decrease in coronary blood flow, in over a half cases of experiments (black dots in Fig. 4). Changes in coronary vascular resistance in the vagal nerve stimulation (Fig. 4) were quite different from that in the depressor response by the stimulation of the proximal end of the vagal nerve (Fig. 5) (already discussed in Part I of this study). It suggests coronary vasodilatory actions by the stimulation of the peripheral end of the vagal nerve.4) It seems likely that, the more decreases the heart rate, the more decreases the coronary vascular resistance, when the degree of the bradycardia is not over approximatery 40 %, but, in marked bradycardia, the coronary vascular resistance tended to increase, as shown in Fig. 6.The initial increase in coronary blood flow (white dots in Fig. 6), however, occurred with either very slight or marked bradycardia, in spite of depression of the blood pressure. It suggests the vagal active vasodilatation.5) From results reported in this paper, it may be concluded that ; the vagal nerve stimulation produces the coronary vosodilation and the initial increase in coronary blood flow ; but, the coronary blood flow decreases thereafter, or throughout during the stimulation from its beginning, because of the marked depression of the blood pressure ; the bradycardia itself may have some vasodilatatory effects on the coronary blood flow.

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In this study, the significance of mass survey for cardiovascular diseases was emphasized, and a tentative method for it was proposed. Discussion were made especially on the screening technique by 3-lead system electrocardiogram (Leads_aVF, V₁ and V₅).1) The tentative method of the authors for the cardiovascular mass survey consisted of two procedures. The first procedure was the screening test for all material ; it included the taking of personal and past history, and the examination of blood pressure, cardiac sound, chest X-ray minifilm and the 3-lead system electrocardiogram. The second procedure, which was carried out on the materials screened by the first procedure, included the investigation of personal and past history and subjective symptoms in detail, and re-examination of blood pressure, conventional 12-lead electrocardiogram, Master's two step test, ballistocardiogram, chest X-ray film, examination of the eye ground, kidney function test and so on.2) It was discussed whether or not the abnormality in electrocardiogram could be screened by the 3-lead system (Leads_aVF, V₁ and V₅). According to the reconstruction method of electrocardiogram by Toyoshima, the solid angle of areas on the epicardium was measured, and the potentials of nine lead points (conventional six precordial lead points and other three lead points which corresponded to those of Leads _aVR, _aVL and _aVF) were calculated. Therefore it was proved that all areas on the epicardium other than some parts of the lateral and posterior basal region could be reflected by one or more of Leads _aVF, V₁ and V₅. And the survey was made on electrocardiograms of two hundred out-patients, one hundred healthy materials and forty two patients with old myocardial infarction, by the aid of 3-lead system and conventional 12-lead system. 3-lead system did not exclude almostly any abnormal cases, even with small anterior infarction or high lateral infraction.The authors would stress that any abnormal cases could hardly escape detection by this 3-lead system screening.

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EXPERIMENTAL ENDOCRINE HYPERTENSION Among the endocrine glands, adrenal glands are considered to play a most important role in hypertension. Since Goldblatt observed for the first time that bilateral adrenalectomy interfered with the development or maintenance of experimental renal hypertension, the role of the adrenal cortex in hypertension has been discussed. Experimentally, since it is difficult to produce hypertension in dogs by administration of adrenal cortical hormones (DCA ets.), it was in this study attempted to produce a persistent hypertension by ligation of the adrenal veins in dogs. It was the purpose of this study to examine whether a surgical procedure on the adrenal in the natural state can cause hypertension.In this study, 13 trained dogs were used for the operation, which was performed on one side of adrenal glands and after 1-2 weeks on the other side. Blood pressure was measured directly on the femoral artery by mercury manometer. Effective renal plasma flow, glomerular filtration rate and filtration fraction were determined by renal clearance technique. At the same time, plasma Na and urine Na were measured.In some cases blood pressure was elevated after ligation of adrenal veins in one side, while the added operation on the other side showed a depressor effect. In others, the operation on both sides produced slight sustained hypertension. At that time RPF increased (10-70 %), GFR increased (25-90 %) and FF was unchanged, but the reabsorption of sodium in kidneys increased in most hypertensive animals. The histochemical study of adrenal cortex revealed signs of hyperfunction in zona glomerulosa.According to these results, the increase in amount of sodium reabsorption due to hyperfunction of zona glomerulosa is considered to play a great role in the pathogensis of hypertension.In conclusion, the above-mentioned results suggest that the patterns of Cushing's syndrome as well as Addison's disease may be produced artificially. It is assumed that the adrenal cortex is intimately concerned with sodium metabolism, where the retention of Na would be a factor in the pathogenesis of endocrine hypertension.EXPERIMENTAL NEUROGENIC HYPERTENSION In the opinions of many investigators, the nervous system occupies the domainant place in maintaining the elevated blood pressure during the chronic stage of hypertension, and humoral agents merely initiate the rise during the first few weeks of hypertension. The term "neurogenic" is used broadly, but usually "neurogenic" suggests the sympathetic component of the autonomic nervous system.Here, the participation of neurogenic factor in hypertension and its mechanism were studied by the section of buffer nerves and by using ganglionic blocking agents and adrenolytic agents.In pressoreceptor deneving hypertension, I attempted to study the elevation of blood pressure in its relation to the RPF, renal vascular resistance and GFR, and to study its mechanism. In this study, 10 trained dogs were used. Among them, 1 showed slight, 2 moderate and 4 marked hypertension. Percentage of success was 70 %. If the cases with transient elevation of blood pressure were included in the group of success, the percentage of success was 100 %.The elevated blood pressure reached a peak within one week after operation. The blood pressure fluctuated, but bacame sustained during weeks, and then decreased gradually. In some cases, the elevated blood pressure continued for over one year.Renal plasma flow increased along with the development of hypertension in all animals (7-43 %, average 22 %), but was not parallel with blood pressure and so renal vascular resistance increased.In conclusion, the hypertension due to section of buffer nerves may belong to the pheochromocytoma type, and its initiating mechanism is probably secretion of adrenalin and/or nor-adrenalin.

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Experimental renal hypertention was produced by the application of a Goldblatt clamp of 0.7 cm on the right renal artery and two weeks later placing a clamp of 0.9 cm on the left artery.Then tetrachloromethane was injected to this hypertensive rabbits, and experimental hepatic injury was produced. According to the time of injection, this hypertensive rabbits were divided into two groups.A-group. : Tetrachloromethane was injected between the operations on the right side and on the left side.B-group. : Tetrachloromethane was injected after the operation on both sides.Those rabbits received only Goldblatt operation served as control.The effect of hepatic injury on the blood pressure, vascular fibrinoid necrosis and cerebral hemorrhage by the experimental rabbits was observed.Results were as follows : 1) By the hepatic injury, rise of the blood pressure was inhibited in A-group, and the blood pressure decreased in B-group. A-group kept low blood pressure longer time than B-group.2) By the hepatic injury, the appearance of vascular fibrinoid necrosis was inhibted. In A- and B-group, the acute form of vascular fibrinoid necrosis was observed only in a few cases.3) By the hepatic injury, the occurrence of the cerebral hemorrhage was decreased. A location of the cerebral hemorrhage was more frequent in the cerebral meninx in A- and B-group.4) The stronger the hepatic injury, a rise of the blood pressure was more inhibited, and the appearance of vascular fibrinoid necrosis and cerebral hemorrhage was more decreased.

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The author performed the histologic and histochemical study of the adrenal cortex, determination of 17-ketosteroids in urine to investigate the relationship between experimental salt hypertension and adrenal cortex.Male rats divided into three groups were given NaCl by mouth and/or by injection for about 6-9 months, group 1, 1-1.5 % NaCl solution was given by mouth, the total NaCl being 200-300 mg per day, group 2 was divided into two subgroups : (a) 1-1.5 % NaCl solution by mouth and intraperitoneal injection of 2 % NaCl solution, the total NaCl being 200-300 mg per day, (b) intraperitoneal injection of 2 % NaCl solution, the total NaCl being 200-300 mg per day. For the first 72 days no differences were observed between subgroups (a) and (b). Since then 300-400 mg of NaCl daily has been given orally to both subgroups. Group 3, which was control, received 50 mg of NaCl per day. After 5 months NaCl-loading was withdrawn in some rats.In the course of experiments, the author performed the clinical examinations including the measurement of blood pressure, fluid intake, urinary volume, urinalysis, body weight, Cl in urine, and urinary 17-ketosteroids excretion. After the animals were sacrificed, the author performed the histologic and histochemical examination of the adrenal cortex.The summary and conclusion of this study are as follows : 1) The NaCl-loading could produce a marked hypertension which sustained at the level of about 200 mm Hg. The elevation of blood pressure at that time was proportional to the amount of loaded salt.2) Adrenal cortical changes occured in experimental salt hypertensive rats were a progressive disuse atrophy of zona glomerulosa in proportion to the amount of loaded salt, and they were reversible.On the contrary, there appeared an enlargement of zona fasciculatea, namely the sign of stress in this zona. The changes in zona fasciculata was almost proportionately to the amount of urinary 17-ketosteroids excretion, but no relation was found between 17-ketosteroids excretion and elevation of blood pressure.From the changes of zona glomerulosa, it is assumed that the adrenal cortex would not secrete mineralocorticoids in salt hypertension, and that zona glomerulosa would not be concerned with salt hypertension. The direct causative factor in salt hypertension would be the excessive retention of sudium.

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