Effects of monatepil maleate, a new Ca2+ channel antagonist with alpha1-adrenoceptor antagonistic activity, on cholesterol absorption and catabolism in high cholesterol diet-fed rabbits.

The mechanism of the prophylactic effect against hyperlipidemia by monatepil maleate was investigated in animal models. Monatepil maleate is an antihypertensive agent with Ca2+-channel antagonistic, alpha1-adrenergic receptor-blocking, and lipid peroxidation inhibitory activity. In high cholesterol diet-fed rabbits, monatepil maleate (30 mg/kg, p.o., once daily for 9 weeks) showed a prophylactic effect against increases in total cholesterol and beta-lipoprotein. Monatepil maleate significantly accelerated the clearance of radioactivity from the blood after intravenous injection of low-density lipoprotein (LDL) labeled with [1alpha,2alpha (n)-3H]cholesterol, increasing biliary excretion of [3H]-bile acids without modifying bile acid composition. Furthermore, monatepil maleate tended to inhibit the absorption of orally administered [1alpha,2alpha (n)-3H]cholesterol from the gastrointestinal tract in these rabbits. In Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of hepatic LDL receptor deficiency, monatepil maleate (30 mg/kg, p.o., once daily for 6 months) did not suppress the increase in plasma lipids. These results suggest that the plasma lipid lowering effect of monatepil maleate requires the presence of hepatic LDL receptors. It is also suggested that monatepil maleate improves plasma lipid metabolism through two mechanisms: enhancement of clearance of plasma LDL, which may be mediated by up-regulation of hepatic LDL receptors, and acceleration of conversion of free cholesterol to bile acids in the liver.

Effect of OP-2507, a stable prostacyclin analogue on cerebral ischemia induced by unilateral ligation of common carotid artery in gerbils.

Effects of OP-2507 [15-cis-(4-propylcyclohexyl)-16,17,18,19,20-pentanor-9-deoxy -9 alpha-nitrilo- PGF1 methylester] on cerebral ischemia induced by unilateral ligation of common carotid artery in gerbils were investigated with reference to behavioral and neuropathological changes. A good coincidence between neurological symptoms and neuropathological changes was observed in gerbils after unilateral ligation of common carotid artery as revealed by the high percentage of coincidence (90% of total animals). All gerbils which showed neurological symptoms, either circling behavior or rolling fit, had cerebral infarction in their ipsilateral hemisphere. In these animals, neuropathological changes of cerebral regions were observed in cortex, corpus callosum, hippocampus, basal ganglia, interbrain and midbrain, in contrast with medulla oblongata and cerebellum which did not show any neuropathological changes. Pretreatment with a dose range of 1-30 micrograms/kg, s.c. of OP-2507 showed a protective effect in the occurrence of neurological symptoms, such as circling behavior and rolling fit, in a dose-dependent manner. The effect of OP-2507 was also confirmed in neuropathological examination which was performed with observation of neurological deficits in the same animals. The severity of cerebral infarction of all brain regions was significantly prevented by treatment with OP-2507. The results suggested that the protective effect of OP-2507 on regional infarction gave apparent protection against the occurrence of neurological deficits for this compound.

Histopathology of pulmonary alveolar proteinosis spontaneously occurring in aged KK mice.

Histopathological findings of pulmonary alveolar proteinosis occurring spontaneously in aged KK mice (72 weeks of age) were described. The lung tissues examined were obtained from the mice used for a one-year toxicity study of some oral hypoglycemic drugs, but there was no relationship between the incidence of the disease and the drug treatment. The disease occurred in 67 of 319 males (21.0%) and 124 of 284 females (43.7%). The gross lesions of the lungs were solitary or multiple nodules. Microscopically, the lesions developed in the peribronchial areas and were well-circumscribed. The initial lesions consisted of the aggregation of foamy cells in the alveoli. In the advanced lesions, amorphous substance resulting from destructed foamy cells and proteinous material accumulated in the alveoli. In the more advanced lesions, neutrophils and nuclear fragments were contained in the proteinous material and some of the alveolar walls were thickened with cell infiltration, fibrosis and so-called epithelialization. The etiology of the present condition was unknown.

Spontaneous nephroblastoma in Sprague-Dawley rats.

Pathological findings were described on nephroblastomas occurrred spontaneously in 3 young Sprague-Dawley rats. One side of kidneys was affected in each animal. Microscopically, the tumors consisted of epithelial elements showing undifferentiated to well-differentiated tubular arrangements, sometimes with glomeruloid and glomerular structures. A metastatic tumor nodule was found in the lung of one rat.