The relationship between the changes in coronary sinus blood flow (CSF) and the anginal pain and ischemic ST depression has been studied in 16 cases of effort angina, in which the attack was induced by coronary sinus pacing, aiming at a target heart rate previously determined by the treadmill test. CSF was measured by the thermodilution method. Ischemic ST depression appeared in 11 cases, of which 7 cases were accompanied by anginal pain. The pacing period was divided into two stages: Stage I (period of 80% of the target heart rate) and Stage II (period of appearance of ischemic ST depression and/or anginal pain or attainment of target heart rate). At Stage I, CSF was significantly larger in cases with ST depression than in those without ST depression. CSF at Stage II decreased significantly more than at Stage I. On the contrary in all cases without ST depression, CSF increased at Stage significantly more than at Stage I. There was a significant correlation between CSF and the degree of ST depression. No significant difference in CSF was seen between anginal and nonanginal groups.
Myocardial lactate extraction ratio in the anginal group decreased significantly after pacing off, while no change was seen in the non-anginal group. No significant difference was observed in myocardial lactate extraction ratio between cases with and without ST depression.
At Stage II no significant change in left ventricular enddiastolic pressure (LVEDP) was seen, but it was significantly higher 2 or 3 heart beats after pacing off than at Stage II and 5min. after pacing in cases with ST depression, but such a difference was not seen in cases without ST depression.
There were no differences in LVSP, LV max dp/dt, and double product between cases with and without ST depression and between anginal and non-anginal groups.
Niludipine (a new Ca-antagonist) of 0.25mg was given intravenously in 9 cases. Significant increase in HR and CSF and significant decrease in LVSP were seen before pacing. At Stage II the degree of ST depression and decrease in LVSP and double product were observed to be suppressed. Increase in LVEDP immediately after pacing off was also suppressed. These findings indicate that niludipine partly shares pharmacological effect on effort angina with nitroglycerin and nifedipine.

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hereinafter referred to as AA, were investigated in consecutive decennial age groups of male and female healthy individuals with normal weights and obese persons, ranging from neonatal (cord blood) to eighties, as a basic study on the amino acid metabolism. The study has revealed remarkably characteristic findings in relation to age, sex and obesity.
(1) Cord serum AA showed higher concentrations in males than in females but there was no significant difference between sexes in the cord blood AA/maternal blood AA ratio, ranging between 1.0 and 2.0 in both sexes. Of individual amino acids and ninhydrin-positive substances in the cord serum, phosphoserine, serine, asparagine, glutamic acid, glutamine, citrulline, cystathionine, methionine, isoleucine, ethanolamine, 1-methylhistidine, 3-methylhistidine, anserine and carnosine were found to be at significantly higher levels in males.
(2) Male infants and children disclosed a significantly greater value for serum total AA concentration than females. Of the individual AAs, asparagine, proline, citrulline, α-aminon-butylic acid, cystathionine, tyrosine, ornithine, phenylalanine, ethanolamine, lysine, anserine, carnosine and arginine showed significantly higher values in the male.
(3) The serum total AA level increased progressively with advancing age from the teens to the forties, reaching a peak in the forties, both male and female. At all ages the obese exhibited greater values for serum total AA than the normal weight groups.
(4) Serum essential and non-essential AA levels varied significantly between sexes as well as with aging. Particularly, serum levels of branched AAs in males reached peaks at the thirties and declined thereafter till the eighties, whereas in females, they fluctuated with peaks at the twenties and showed the lowest values at the fifties.
(5) Ketogenic AAs in the serum of males increased to peaks at the forties with subsequent gradual decline. In the ferrale, they increased to peaks at the thirties and then decline to the lowest levels at the fifties, followed by a trend of gradual elevation. The serum ketogenic AA levels were significantly higher in males throughout life except the seventies and eighties.
(6) Glycogenic AAs showed the highest concentrations in cord serum and fell markedly during infancy and childhood, followed by a progressive rise to reach peaks at the thirties in both males and females. They declined thereafter. All these five types of AAs exhibited increased concentrations in the serum of obese subjects at all ages, regardless of sex.

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The mechanisms of the stimulating actions of ceruletide diethylamine (CDA), cholecystokininpancreozymin (CCK-PZ) and tetragastrin (TTG) on pancreatic juice secretion were studied in the rats pretreated with atropine and hexamethonium (C₆), and compared with each other.
The inhibiting effects of atropine and C₆ on the polypeptide-induced pancreatic juice secretion were observed at 40.60 min after the administrations of the polypeptides, while the inhibition by atropine and C₆ on amylase activities in the juice was not found. Atropine-and C₆-induced depression for the pancreatic juice volume-increase was found to be most remarkable in TTG, moderate in CCK-PZ and least in CDA. It is shortly discussed that the neurons suppressed by atropine and C₆ in the present experiments might belong to the extra-pancreatic vagal nervous system, especially, controlling the inter-organ responses such as the gastropancreatic reflex.

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Statistics prove that complications of vascular lesions in patients with diabetes mellitus have been on the increase as to causes of death in recent years. Especially in Japan, the high frequency of cerebrovascular accidents is of noteworthy.
In this co-nrnunication, the author has investigated the cerebrovascular lesions on patients with diabetes mellitus from a pathological point of view.
In the first part of the study, cerebrovascular lesions including non symptomatic small lesions were observed macroscopically on 52 diabetic and 292 non diabetic autopsy cases.
In the second part, the histological ischemic changes in cerebral parenchyma, where no evident macroscopical lesions had been found, were observed light microscopically. Moreover, angiosclerotic changes of the perfusing small arteries and arterioles, using the specimens obtained from bilateral basal ganglia, pons and cerebellum on 27 diabetic and 12 non diabetic autopsy cases were also observed.
The results obtained from the macroscopical investigations are as follows : In those cases with diabetes, the incidences of encephalomalacia were approximately 2.3 times more frequent than in non diabetic cases, and especially small encephalomalatic foci were seen in high frequency. On the other hand, the incidences of intracerebral hemorrhage were about 0.40 time less frequent in diabetic cases as compared to the non diabetic cases. However, no discernible difference of the frequency of subarachnoid hemorrhage was noted between them.
The results obtained from the histological investigations are as follows: In basal ganglia, the advanced angiosclerotic changes of the intracerebral small arteries and arterioles and ischemic changes, which were comfirrned by the histological study in cerebral parenchyma, were seen more frequently in diabetic subjects than in non diabetic subjects. The tendency was particularly prominent in hypertensive diabetic cases. In pons, the pronounced angiosclerotic changes in the non hypertensive diabetic cases were seen less frequently than in the hypertensive cases similar to the non diabetic cases. However, marked histological ischemic changes of cerebral parenchyma were seen more frequently in the non hypertensive diabetic cases than in the non diabetic cases, and moreover no obvious differences were seen between non hypertensive diabetic cases and hypertensive diabetic cases. In the cases with diabetic nephropathy, relatively striking histological changes, angiosclerotic changes as well as ischemic changes in parenchyma, were observed in high frequency especially in basal ganglia. Based on this investigation, it was concluded that deterioration of diabetic nephropathy may have a close interrelation with the progression of the cerebrovascular lesions.

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The atrial fibrillation is the arrhythmia which is frequently encounterd in the valvular disease of the heart. The author has investigated the conduction system and its supplying arteries by light microscopical study on serial section. The cases subjected for investigation were as follows; aortic valvular disease (AVD) 4, mitral valvular disease (MVD) 4, and combined valvular disease (CVD) 5 cases.
A special attention has been paid for the correlation of the ECG findings with histo-pathological observations of conduction system and of its supplying arteries. The histo-pathological study revealed that the extensive loss of conduction cells as well as the sclerotic involvement of the central artery was noted in the cases having atrial fibrillation of the long term duration.
Concerning to the Sino-Atrial node, injury to the S-A node and its supplying artery was much more striking in the cases of MVD & CVD rather than AVD. The changes of A-V node and His Bundle were more remarkable in the cases of AVD and CVD compared with MVD.
The author inclines to attribute the genesis for these pathological changes of conduction system and of its supplying arteries to the circulatory disturbance involved in the valvular heart disease. The persisting derangement of the circulation in the supplying arteries of these region would result in their sclerotic changes and in loss of conduction cells. These changes were much more pronounced than those of control study.

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The increased capillary permeability in the skin of the guinea pig and the rat was investigated by using peptidoglycan (PG) fraction extracted from cell walls of group A Streptococci.
The following results were obtained:
1) The pattern of the reaction in the increased capillary permeability consists of two phases: the leakage of the dye which appeared immediately after the intracutaneous injection of PG fraction in the first phase, and vasculitis observed in the second phase.
2) From the microscopic examination in the first phase, edema was observed in the extravascular spaces of the dermis and subcutaneous tissues; in the second phase, degeneration of the vascular wall and a remarkable number of polymorphonuclear leukocytes and monocytes in the extravascular spaces were observed.
3) From the electromicroscopic examination in the first phase, swelling and vacuolation of the endothelial cells and the appearance of mast cell-like cells in the extravascular space were observed; in the second phase, cytolysis and necrosis of endothelial cells were observed and the basement membrane was irregularly thick and disintergrated into many fragments.
4) By pretreatment of an anti-histamine or anti-serotonin drug, the inhibitory effect against the increased capillary permeability in the first phase was observed. The inhibitory effect against the leakage of dye in the second phase was observed not only by the pretreatment of steroidhormcme but also by the anti-histamine or anti-serotonin drug.
These results suggest that increased activity of capillary permeability by PG fraction may play an important role in inducing an initial change of tissue injury by streptococcal cell walls.

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Since the prominent negative U wave is frequently observed during the attack of variant angina, relationships between its appearance and clinical features were studied in 54 patients with variant angina (VA) and 33 patients with resting angina showing ST depression (RA). The negative U wave was observed in 71.4% of VA, while only in 30.0% of RA. There was a significant difference. In VA, it appeared in the same leads as those showing ST elevation. No significant relationships were observed between the appearance of the negative U wave and the history of hypertension, the size of cardiothoracic ratio, occurrence of arrhythrnias, and repetitive tendency of attacks, but its incidence was higher in patients showing left ventricular hypertrophy pattern in the period without attack and in those with longer duration of the attack and marked elevation of blood pressure during attack. ST elevation and increase of amplitude of the R wave were more prominent inpatients showing negative U wave.
Incidence of the negative U wave on exercise test was morefrequent in VA than RA. In both VA and RA, which showed the negative U wave on the exercise test, the negative U wave was observed also in the spontaneous attacks. Its incidence on the exercise test was significantly higher in patients with exertional angina showing ST elevation than in those showing ST depression.
There were no relationships between the incidence of the negative U wave and the severity of coronary artery narrowing and the number of the diseased branches in coronary arteriogram in both VA and RA. However, patients with multivessel disease were found more frequently in patients with exertional angina with negative U wave than those without it. Although in most patients with VA the negative U wave was observed in the leads corresponding to the sites perfused by coronary artery having organic stenosis or spasm, a closer correspondence was found to the portion showing abnormal ventricular wall motion in left ventriculogram. These findings suggest that the negative U wave in VA reflects the abnormal left ventricular wall motion produced by ischemic change rather than the ischemic change per se.
No significant relationships were present between theappearance of the negative U wave and the effects of the drugs or prognosis in both VA and RA. Calcium antagonists were effective in 84.8% of VA and in 85.7% of RA.

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The promoting effect of phenobarbital (PB) on the tumor induction by naturally occurring carcinogens was investigated in this communication in inbred ACI rats.
In experiment A, the effect of PB on the development of neoplastic lesions by cycasin was investigated. Tumor development in the liver and the kidney was observed in groups of rats treated with a single oral administration of cycasin (100mg/kg body weight) and maintained on either a control diet or one supplemented with 0.05% PB. The feeding of PB diet after the application of cycasin significantly increased the incidence of liver tumors in female rats but not in male rats. On the other hand, the administration of PB did not affect the incidence of kidney tumors in either sex. In addition, many large γ-glutamyl transpeptidase (GGT) -positive foci, which were thought to be preneoplastic lesions, developed in the liver of rats treated with cycasin and then PB, whereas a small number of tiny foci were seen in rats treated with cycasin alone. Long-term feeding of the 0.05% PB diet without treatment of cycasin induced many GGT-positive foci which, however, were small in size and observed only in periportal area of the liver. These data indicated that PB might possess a tumor promoting effect in terms of induction on neoplastic lesions in the liver. However, the effect was not observed in the kidney.
In experiment B, the effect of concomitant administration of PB on the carcinogenicity of Petasites japonicus MAXIM., a kind of coltsfoot containing a carcinogenic pyrrolizidine alkaloid, petasitenine, was examined. The hepatocarcinogenicity of petasites was found to be enhanced by concomitant administration of PB. This was substantiated by confirming the significant increase of the size of hemangioendothelial sarcoma of the liver, which is nonepithelial tumor, and a significant increase of lung metastases. However, PB did not influence the incidence or the size of epithelial tumor of the liver called neoplastic nodule.

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Bradykinin, as well as histamine which has been considered as one of the chemical mediators in immediate type allergic reaction, increases cyclic adenosine 3′ 5′-monophosphate (cAMP) of murine lymphocytes, especially T lymphocytes and it is also shown that both bradykinin and histamine suppress T cell mitogens (PHA-P, Con A) - induced proliferation of murine splenic lymphocytes.
These results suggest that bradykinin as well as histamine may have some suppressive effect on cellular immunologicarle sponses. From this aspect the present experiment was undertaken to study the effect of chemical mediators such as bradykinin, histamine, serotonin and acetylcholineo n the production of antigen-inducedm igrationi nhibitoryf actors in the immune guinea pig peritoneal exudate cells. The results obtained were as follows
(1) The antigen-inducedM IF production was remarkablys uppressed by the addition of bradykinin or histamine. The migration inhibition percent by the treatment of bradykinin (10^-6-10^-7M) or histamine (10^-4-10^-6M) was about the same and the dose response fashion was observed between the dose of the drug (bradykinin or histamine) added and the inhibition percent.
(2) No suppressivee ffect on MIF productionw as observed by the treatment of serotonin or acetylcholine.
(3) The suppressive effect of bradykinin or histamine on MIF production was observed when bradykinin or histamine was added immediately after the addition of antigen, but the suppressive effect slightly decreased when it was added 30-60 min after the addition of antigen. The suppressive effect decreased ren-arkably when it was added 2 hr after the addition of antigen.
These findings suggest that bradykinin or histamine exerts its effects at an early stage in the MIF response, perhaps interfering with an antigendependents tage.
(4) The suppressive effect of bradykinin or histamine on MIF production was only slightly blocked by the treatment of H₁antagonist, but clearly blocked by the treatment of H₂-antagonist or H₂agonist.
(5) No synergistic effect- of bradykinin and histamine was observed on the suppressive action of MIF production.

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It has been shown that histamine and bradykinin as well as catecholamines and methylxanthins elevate cellular cyclic AMP levels. In the present investigation, the inhibitory effects of bradykinin or histamine on the induction of immediate type and delayed type allergic skin reactions were studied in comparison with those of isoproterenol and theophylline. The results obtained were as follows
1) The 48 hr heterologous passive cutaneous anaphylaxis (PCA) in the rat using mouse IgE antiserum was employed as the experimental model of the immediate type allergic skin test.
(2) Bradykinin (10^-4-10^-6 M) or histamine (10^-3-10^-5 M) was intracutaneously injected to the site of antiserum. Ninety minutes after the injection PCA was tested and it was found that PCA manifestation was remarkably suppressed.
(3) The 48 hr heterologous PCA in the rat was also suppressed by the administration of isoproterenol (10^-3-10^-6 M).
(4) The delayed type skin reaction was tested in the guinea pig immunized with the emulsion of orthochlorbenzoyl boivin gamma globulin (OCB-BGG) and complete Freund adjuvant. In order to know the effects of bradykinin (10^-4M), histamine (10^-3′ M), isoproterenol (10^-4M) and theophylline (10^-4 M) on the skin reaction, these drugs were intracutaneously injected together with antigen (OCB-BGG)
(5) Bradykinin or histamine significantly suppressed the delayed type skin reaction in the guinea pig. H₂ antagonist completely blocked the suppressive effect of bradykinin or histamine, whereas H₁ antagonist scarecely blocked it.
(6) The inhibitory effect of isoproterenol or theophylline on the delayed type skin reaction in the immunized guinea pig was observed, but the effect was not dependent on dose.
(7) The results obtained suggest that the inhibition of the cellular immunological response by bradykinin, histamine, isoproterenol or theophylline may depends on the elevation of cellular cAMP through 1-12 receptors of lymphocytes.

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