Possible chemical mediators contributing to 48 hour passive cutaneous anaphylaxis (PCA) in rats were investigated. Forty-eight hour PCA was inhibited considerably by mepyramine and methysergide given intravenously, a finding suggestive of a major role for histamine and serotonin in the reaction. AA-861, a selective 5-lipoxygenase inhibitor did not inhibit the PCA, and leukotriene (LT)D4 or LTE4 and the combination with prostaglandin (PG)E2 had no significant skin reaction. In addition, only small amounts of slow reacting substance of anaphylaxis (SRS-A) were detected in skin fragments, in vitro. Although CV-3988, a selective platelet activating factor (PAF) antagonist, dose-dependently inhibited the PAF-induced skin reaction, the PCA was not affected by treatment with this compound. Indomethacin also had no inhibitory activity on PCA. Thus, sulfidopeptide LTs, PAF and arachidonate cyclooxygenase metabolites probably do not contribute to PCA, at least in rats.
Pathomorphologic analysis was employed to evaluate diet-induced atherosclerosis in cynomolgus monkey aorta and regression by administration of a hypolipidemic agent for six months after the atherogenic ration. Twenty-seven male cynomolgus monkeys were divided into three groups. Group A was fed individually with a high-fat diet containing 0.3% cholesterol under identical conditions for six months. Group B was fed with normal monkey chow for six months after the same atherogenic ration. Group C was fed with normal monkey chow and administered a hypolipidemic agent 1% of 4-[2-(4-isopropylbenzamido)ethoxy] benzonic acid for six months after the same atherogenic ration. Each thoracic and abdominal aorta of animal models was separately analyzed. Lipid composition analysis and esterified cholesterol (CE) in aortic wall, ratio of free cholesterol to phospholipid, surface involvement, and atherosclerotic index after Sudan IV staining were studied for evaluation of progression and regression. The configurations of atherosclerotic involvement were histologically evaluated among each group. These observed lesions, features specific to cynomolgus lesions, mainly consisted of lipid-rich foam cells, lipid debris, and proliferated extracellular matrix. No different lesion composition was noted between the thoracic and abdominal aorta. This may suggest that some local factors play an important role for development of atherosclerosis after the initial event. Group C had remarkable reduction of foam cells and of CE accumulation in both the thoracic and abdominal aortic wall. Accelerated regression in group C as compared with group B was demonstrated both biochemically and pathohistologically. These results suggest that substantial regression of atherosclerosis in both the thoracic and abdominal aorta can be expected. This hypolipidemic agent exerts notable antiatherosclerotic activity, along with a lowering effect on plasma total cholesterol levels.
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