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Norepinephrine 및 Sodium Chloride 유발 고혈압이 백서동맥(白鼠動脈) 및 각장기(各臟器)에 미치는 영향

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 Effects of hypertension induced by norepinephrine and sodium chloride upon the arteries and various organs of rats 
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[영문]The influence of a hypertensive state on atherosclerosis has been thoroughly investigated using human materials or animal experiments, but as yet the cause and mechanism of the effect of hypertension on atherosclerosis have not been well established. In human, the hypertensive state is accompained by an increased incidence and severity in the atherosclerosis. Also a cause and effect relationship between hypertension and atherosclerosis has not been established, that is whether the former causes atherosclerosis, or vice versa (Bell, 1951, Waters, 1954). Hueper (1944) and Pickering (1955) reported that the severity of atherosclerosis in hypertensive patients was strikingly greater than in normotensive individuals. Gofman(1957) noted that in coarctation of the aorta, not only is the blood pressure strikingly higher on the proximal side of the coarctation, but also extensive arteriosclerosis was more often found on the proximal side than on the distal, a well known fact. Arteriosclerosis in the pulmonary artery has been widly described in patients with marked pulmonary hypertension. Boyd (1943) reported marked arteriosclerosis, in the branches of the pulmonary artery in the patients, with mitral stenosis, in cases where there was very little arteriosclerosis in the aorta. Generally, in patients without pulmonary hypertension, arteriosclerosis in the pulmonary artery was absent even when there was an appreciable involvement of the aorta. These two findings in the human suggest that blood pressure, at least for particular vascular beds, definitely is a factor which predisposes to the development of arteriosclerotic lesions. Wakerlin and his associates (1951) reported that, in a series of hypertensive dogs, their placement upon the thiouracilcholesterol regimen, resulted in a massive elevation of low-density serum lipoproteins and serum cholesterol levels, also there developed a marked increase in the degree of aortic arteriosclerosis in the hypertensive dogs as compared with the nonhypertensive dogs. When these facts are considered together with the human data referred to above, it appears that high blood pressure can accentuate the rate of development of arteriosclerotic lesions. But Pal (1934) reported that hypertension was not often observed in severe arteriosclerotic patients, and the relation between hypertension and arteriosclerosis was not necessarily interdependent. Davis and Klainer (1940) stressed that there is no relationship between hypertension and arteriosclerosis though both may be present together. Through a study of human materials, Moritz and Oldt(1934) postulated that hypertension may be a result of arteriosclerosis rather than the cause. To clarify this controversy, various investigations are still being made. The human data and the animal experiments suggest a close relationship between the hypertensive state and atherosclerosis. However, as yet the mechanism(s) for the effect of hypertension on the development of arteriosclerosis has not been well established. Through the experimental studies, many investigators (Goldblatt, 1938, Dill and Isenhour, 1942, Deming et al., 1958, and Kolestsky et al., 1964) stressed that elevation of pressure might injure the wall of the aorta and small arteries. Timiras et al. (1949) and Selye (1950 observed similar arterial changes in suitably sensitized rats with the administration of DOCA. They stressed that these arterial changes were a part of a generalized change and termed the "hyalinosis syndrome". however, Masson et al. (1950, 1952, 1953-a, 1953-b) observed, similar arterial changes following the combined administration of steroids, and renin or angiotonin, and used the term "hypertensive arteriolopathy". The atheromatous lesions, like those of hyalinosis, may be already visible in young children(Holman et al., 1958) and progress slowly with age. Baker and Selikoff(1952) suggested that cholesterol in hyalin may have the same significance as that in atheromas. Therefore, it may be of much interest and importance to study further the relationships between atherosclerosis and atheroma formation,and between atheroma formation and hyalinosis. The purpose of this study is to investigate in elevated blood pressure the histopathological effects due to norepinephrine and sodium chloride. Particularly the effects produced by high cholesterol feeding, upon the arteries and various organs such as the hear, kidneys, and adrenals of rats have been studied. In rats cholesterol produced atherosclerosis does not easily occur. Finally, the effects of hypeertension and cholesterol feeding was studied to evaluate the changes in the arteries and various organs secondary to the administration of norepinephrine and sodium chloride. Materials Methods Healthy male albino rats weighing around 150 Grams were used. The animals were divided into 8 groups; Group Ⅰ consisted of 9 rats as normal controls; Group Ⅱ of 9 rats receiving cholesterol only; Group Ⅲ of 9 rats receiving norepinephrine only; Group Ⅳ of 5 rats receiving sodium chloride only; Group Ⅴ of 5 rats receiving cholesterol and norepinephrine; Group Ⅵ of 9 rats receiving cholesterol and sodium chloride; Group Ⅶ of 4 rats receiving norepinephrine and sodium chloride; Group Ⅷ of 4 rats receiving cholesterol, norepinephrine and sodium chloride. The cholesterol was given in 600 mg. doses daily per animal for 3 months. The dose of norepinephrine was 0.05 mg. per kg. per day into the peritoneal cavity for 3 months. The concentration of sodium chloride as sea salt was gradually increased; 0.5% solution during the first 4 days, 1.0% during the following 4 days, 1.5% during the following 4 days, and finally 2.0% solution until the end of the 3 month' experimental period. During the experiment, blood pressure was checked by the Williams method(1936) at 10 day-intervals underlight ether anesthesia. The body weight was measured every 10 days. The surving animals were sacrificed at the end of 3 months, and the total serum cholesterol was determined by the method of Kingsley and Schaffert (1949). The aortas were dissected out and examined grossly and microscopically. The selected organs such as the heart, kidneys, and adrenals were grossly inspected and the weight of the organs recorded. Fixed in 10% formalin, paraffin sections were prepared for hematoxylin-eosin, for aldehyde fuchsin staining of Gomori, for colloidal-iron method of Rinehart-Abul-Haj, for McGregor's modification of the Heidenhain-Azan variant (Lillie, 1954), for the periodic acid Schiff's technique (McManus, 1948), for Mallory's phosphotungstic acid hematoxylin staining. And Oil Red 0 staining after frozen sections was made. Results and Discussion The body weight was increased slightly in groups (Ⅱ and Ⅲ) without significant statistical differences among the groups. However, the salt loading groups (Ⅳ, Ⅵ, Ⅶ and Ⅷ) show significant differences as compared with the normal control group. Differences among the groups appeared due to the probable effect of the administration of cholesterol, norepinephrine and sodium chloride. The blood pressure rose significantly, particularly in the groups receiving sodium chloride (Ⅳ, Ⅵ, Ⅶ and Ⅷ), especially abruptly at the end of 3 months. In the groups receiving norepinephrine blood pressure showed a tendency to a gradual increase as compared with the normal control group. Total serum cholesterol levels showed no significant statistical changes in the group receiving only norepinephrine. However the remaining groups showed significant elevations. There were no significant differences among the remaining groups, all of which appeared to be a common effect from the administration of cholesterol. The weight of heart was decreased in the group receiving only norepinephrine. The kidneys showed a significant increase in weight, particularly in the groups receiving norepinephrine and sodium chloride with or without cholesterol Ⅶ and Ⅷ), but , on the contrary, showed a significant decrease in weight in the group receiving only norepinephrine. The weight of the adrenal glands showed no significant differences among the various groups of rats. In the aorta, there were no gross nor histopathologic changes, and also the periadrenal arterioles showed no particular changes. In the coronary arteries, arteriolar spasm, arteriolar hypertrophy with structureles,, homogenous, eosinophilic hyaline materials in the subendothelial layer, media or adventitia, which were positive in P.A.S. reaction, purple in P.T.A.H. staining, and brilliantly red in McGregor's staining, were definitely identified in all groups except Ⅰ and Ⅱ. The arteriolar hyalinosis was particularly prominent in the groups receiving norepinephrine and sodium chloride, encircling mostly the entire wall admixed with a small number of pale clear cells, with perivascular fibrosis and cellular infiltration, and was rater prominent in the groups receiving sodium chloride than norepinephrine. In the renal arteries, the arteriolar hyalinosis was much more evident than in the coronary arteries, and was particularly prominent in the groups receiving norepine phrine and sodium chloride. In these groups the proliferative and necrotizing arteriolar changes associated with glomerular sclerosis were similar to the histopathologic features noted in human malignant hypertension. This finding is of special interest for the further investigation of malignant nephrosclerosis. In the heart, hypertrophy of myocardial fibers, papillary muscle fibers, focal myocardial fibrosis and myocarditis were observed in all groups except Ⅰ and Ⅱ. However, no endocardial thickening, fibrosis, nor myocardal infarction were noted. In the kidneys, the glomeruli were more cellular than the controls, and showed hyaline materials I the tufts. The tubules were remarkably dilated and contained hyaline cats in all groups except Ⅰ and Ⅱ. There were several cases which showed the changes of chronic pyelonephritis. In the adrenal glands, there was a marked atrophy of the zona glomerulosa of the cortex which was completely devoid of sudanophilic lipid droplets, a finding particularly noted in the groups receiving sodium chloride(Ⅳ, Ⅵ, Ⅶ and Ⅷ). The zona fasciculata appeared to be broadened in all groups of animals. Particularly in the outer fasciculata, large watery vacuoles in the cells were noted. Lipid droplets in the zona fasciculata were increased in all groups as compared with the controls. In the zona reticularis there were no significant changes but the lipid droplts appeared to be increase in the groups receiving norepinephrine and/or sodium chloride(Ⅲ, Ⅳ, Ⅴ, Ⅵ, Ⅶ and Ⅷ). In 4 rats there was a nodular cortical hyperplasia in the groups receiving norepinephrine and sodium chloride(Ⅲ, Ⅵ, and Ⅶ). The cells in the medulla showed large, remarkably clear, granular cytoplasm in groups Ⅰ and Ⅱ, but in the remaining groups the cells in the adrenal medulla were atrophic and showed a basophilic cytoplasm in a typical glandular structure. These changes were especially marked in the groups receiving norepinephrine. Summary Elevation of blood pressure in male albino rats by norepinephrine and sodium chloride was induced, and with additional feeding of cholesterol, the effects on the aorta, arteries and various organs, were studied histopathologically. 1. Elevation of blood pressure was observed in the groups receiving norepinephrine and/or sodium chloride, and was marked in the groups receiving sodium chloride, and rose abruptly toward the end of 3 months. 2. The hypertrophic and proliferative changes in the coronary and renal arteries were of interest. The hypertrophic changes in arteries were especially due to hyalinosis in the vascular walls. In several cases proliferative changes were associated with a necrotizing and inflammatory reaction which was histologically similar to that noted in malignant hypertension. 3. Atheroma formation in the aorta after administration of cholesterol was not observed. It appears that the development of experimental cholesterol atherosclerosis in rats in combination with elevation of the blood pressure may not be produced easily. 4. The adrenal cortex, particularly the zona glomerulosa was remarkable atrophic and completely devoid of lipid droplets in the sodium chloride groups, and adrenal medulla was atrophic especially in norepinephrine groups. This appears to be a physiologic reaction due respectively to the excessive administration of sodium chloride and norepinephrine. It was observed that induction of hypertension caused hypertrophic changes mainly hyalinosis, and proliferative and necrotizing changes mainly in the renal and coronary arteries. It appears that these arterial changes are due to the elevation of blood pressure. The further study of malignant nephrosclerosis using this experimental method for its production would be of special interest.
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