There have been a lot of studies on the correlation between hypertension and vascular lesions.
Since Winternitz and Asscher produced vascular lesions by administering kidney homogenate in dogs and rats, many kinds of experiments were attempted to separate the vasotoxic factor from the pressor substance.
In Japan too, there have been made various studies, some reported that the cause of vascular lesions in experimental hypertension is vascular permeability substance existing in the kidney and some others showed the vascular changes in the experimental animals administered with non-pressor substance of the renal cortical extracts.
The vascular necrotizing fraction was obtained by ultracentrifugation of norml rat kidney, which contained non-pressor substance in our present experiment.
Characteristic lesions 24 hours after administration of vascular necrotizing fraction of the renal extracts to bilateral nephrectomized rats were necrosis of the small arteries.
In electron microscopic observation, early vascular damage occured in medial smoth muscle cells and sometimes with serous permeation in subendothelial matrices.
Another experiment of ours was to produce the vascular lesions by freezing the renal cortex in vivo.
Vascular changes of the mesentery and intestinal tract observed in this experimental rats were similar to those lesions produced by renal cortical extracts.
By two our experments, we confirmed that the renal cortex contains necrotizing substance for vascular walls.
It seems very important to investigate the necrotizing substance extracting from the renal cortex participates in the development of the vascular lesions.

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We have already elucidated that the vascular permeability of large and medium-sized arteries in different sites vary in pattern and intensity. Therefore, when the development of atherosclerosis was considered from the standpoint of vascular permeability, there might be some difference in atherogesis between intracranial artery and aorta and/or coronary artery.
In this study, in addition to the permeability pattern of aorta and intracranial artery already reported, rabbit coronary artery was examined in respect to the fine structure and permeability pattern by using protein tracers.
1) As a distinct feature of coronary artery was there frequent presence of fenestration in the internal elastic lamina and this might contribute to the more enhanced permeability, especially by virtue of junctional transport, than aorta.
2) Long term subcutaneous injection of epinephrine induced the intimal thickening composed of smooth muscle cells where junctional transport was slightly enhanced.
3) Cholesterol feeding for 1 week, induced the enhanced junctinal transport.
4) Long term cholesterol feeding induced the foam cell lesions where both junctional and vesicular transport were enhanced.

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Numerous foam cells containing much lipid are observed in the intima of human and experimental atherosclerotic lesions. To elucidate the origin of such foam cells, that is, to clarify through what route the intracellular lipid is deposited in the intima, light and electron microscopies were performed with the human aorta and arteries of rabbits given 1% cholesterol diet.
The intima of the human aorta contained smooth muscle cells-derived foam cells with basement membrane, myofilaments and dense bodies, hematogenic large foam cells with numerous lipid vacuoles, monocytes having a kidney shaped nucleus and lysosomes but no lipid vacuoles, and lymphocytes.
These monocytes were not inherent in the intima but had invaded here from circulaling blood. They are considered to phagocytize lipid which insudated into the intima, to turn into foam cells.
In the aorta of rabbits fed on cholesterol diet there were two kinds of foam cells-those lacking the traits of the smooth muscle cell and containing large lucid lipid vacuoles and electron dense lipid granules and those having the traits of the muscle cell. Light and electron microscopy and a Häutchen preparation of rabbit's artery presented a picture of foam cells migrating into the subendothelium through endothelial cell junction. Also foam cells were demonstrated in the blood both light and electron microscopically. It is consequently assumed that some of the foam cells in the intima may be derived from the circulating blood.
As to the derivation of the lipid in the arterial intima, the above described facts suggest that not only the insudation of plasma lipoprotein and lipid synthesis in the intimal cells, but also transportation of lipid into the intima by the blood foam cells may be responsible. In atherosclerotic lesions of human and cholesterol-given rabbits, there are two kinds of foam cells. One is smooth muscle cell-derived, and the other, blood-derived. As to the origin of intimal foam cells derived circulating blood, the following two possibilities are considered: Circulating macrophages phagocytize lipids in blood plasma and pass across the endothelium as foam cells; monocytes migrate from the blood into the vascular wall and phagocytize the lipids which insudated into the intima and turn into foam cells. The conversion of blood-derived mononuclear cells into foam cells was observed in an experiment in which hypercholesterolemic plasma was injected into the rabbit's cornea. In this case, the cornea was first infiltrated by mononuclear cells and polymorphonuclear leukocytes, and with the lapse of time numerous foam cells came to be observed. These foam cells seemed to be derived from blood mononuclear cells, which had phagocytized the lipids at the site of injection.

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It has been first shown by the author and his collaborators (1972) that the strong contracting and swallowing activity of arterial endothelial cells is elicited by various active agents and meets the requirements for the cliteria as the key mechanism in atherogenesis and thrombogenesis.
In this experiments with 65 rabbits, the author administered intravenously the carbon particles with a size of prebetalipoprotein and then visualized the transportation of them by the contracting and swallowing activity of endothelial cells from the blood stream into the aortic wall serially sacrificing the animals thereafter. As a carbon particle, 50% Perikan ink diluted in saline was used mixed with or without angiotensin II (10μg/kg). At five and thirty minutes after injection of the carbon suspension in a dose of 5ml per kg, the aorta of rabbits was fixed by 2.5% glutaraldehyde, which was directly given to the aortic lumen as a perfusate by a catheter inserted surgically into the aorta through the left ventricle under the urethane anaesthesia and subjected to the electron and light microscopical observations.
The formation of nuclear pinch and the statistically significant decrease in the size of tightly contacting parts (gap junction, Hüttner 1973) of intercellular junctions of the endothelial cells due to their contraction were seen 5 and 30 minutes after the carbon challenge (P<0.01, P<0.01). In specimens sampled 5 minutes after the challenge, some carbon particles were found in the endothelial cells and their intercellular junctions were partially widened. In specimens sampled 30 minutes after the challenge, many carbon particles were transported by some group of endothelial cells by the membrane flow and membrane vesiculation (Bennett 1956) and also by widened intercellular junction from the blood stream to the subendothelial space. Such a contracting and swallowing activity seems somewhat exaggerated by the concomitant injection of angiotensin II, but not much. Just two intercellular jnnctions were thus found to have been opened and carbon particles were found in the opened junctions. However the further transportation of carbon particles through holes of the internal elastic lamina seemed almost impossible and in animals sacrificed 2 days after the challenge and even in animals sacrificed 40 days after the challenge the carbon particles still remained almost unchanged in almost the same amount in the subendothelial space surrounded by smooth muscle-like cells. It is also important to note that the entry of carbon particles takes place predominantly in the well known susceptible parts of the arterial system to atherosclerosis. Namely in such parts of the aorta, the trunks of coronary artery, but no entry of carbon particles was found in the artery of circulus Willissi in young rabbits. (In another experiments in rats and dogs, which are nonsusceptible animals to atherosclerosis, no carbon particles enter the subendothelial space by the same challenge with carbon and angiotensin II.)
Endothelial-cell relaxants, EG467 (1 and 10mg/kg p. o.) and EG626 (0.1 and 1.0mg/kg p. o.) exhibited a striking preventive effect against the contracting and swallowing activity of endothelial cells elicited by the carbon challenge or the carbon and angiotensin II challenge. The formation of nuclear pinch was prevented and the tightly contacting parts of the intercellular junctions was statistically significantly enlarged by relaxing effect of those substances and the carbon entry was strikingly prevented by EG467 (1mg/kg and 10mg/kg p. o.) and especially powerfully by EG626 (0.1mg and 1mg/kg p. o.).
The subendothelial entry of carbon particles was also photographed by light microscope in the whole luminal surface of thoracic or abdominal segments of the aortas, in which the aortic lumen was carefully washed in situ by saline and then fixed by a standard formaldehyde fixative and the amount of carbon particles entere

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Post-ischemic reactive blood flow (RBF) measured by Xe-133 clearance method was studied from the view point of diagnostic use and of evaluation of therapeutic effect of medications in peripheral vascular diseases.
The present work includes methodological observation and study of the relation between the RBF and clinical symptom of arteriosclerosis obliterans (ASO) followed up before and after Pyridlnolcarbamate administration.
1) Repeat variability of RBF
RBF was measured twice at 2-4 weeks interval in 9 normal legs and in 17 abnormal legs with ASO.
The ratio of the first to the second measurement (1st/2nd) were ranged from maximum 1.63 to minimum 0.57 and mean & S. D. was 1.067±0.3035 (P<0.05).
2) One year natural course of RBF in a patient with ASO
The mean & S. E. in 6 serial RBF measurements without any treatment was 11.82±1.03ml in the right leg and 10.15±0.82ml in the left leg. Coefficients of variation were 25% in the right and 23% in the left.
3) RBF
The means & S. E.'s were 10.59±0.61ml in 46 legs with intermittent claudication, 11.80±1.37ml in 9 legs without intermittent claudication with ASO, and 21.69±1.22ml in 20 normal legs.
The difference between the normal and the patient with ASO were statistically significant (P<0.01). But there was no statistical significance between the legs with and without intermittent caludication in patients with ASO.
4) Latency time and RBF
Latency time, the duration from the cuff opening to the begining of the down slope in Xe-133 clearance curve had tendency to be prolonged with the RBF decreased.
5) Toe-plethysmogram and RBF
RBF was decreased in the groups with the crest time prolonged more than 0.3 seconds compared to the subjects with normal crest time (p<0.01 or p<0.05).
The ratio of pulse amplitude in toe-pletysmogram before and after reactive hyperemia was decreased in the groups in which RBF was decreased. There were statistically significant differences among four groups (p<0.01 or p<0.05).
6) Clinical signs and RBF
3 cases were presented showing how the changes in RBF were parallel to the clinical signs and symptoms.
After pyridinolcarbamate adminisration, the RBF was increased with improvement of intermittent claudication in 3 of all 6 patients.
However, there was no significant change in RBF in 2 of all 6 patients in spite of clinical improvement.
In one of all 6 patients, RBF was fluctuated according to the fluctuation of intermittent claudication.

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