The hypolipidemic and antiatherosclerotic effects of NIP-200 (3, 5-dimethyl-4, 6-diphenyl-tetrahydro-2H-1, 3, 5-thiadiazine-2-thione) were studied in experimental models of 1 % cholesterol diet (HCD)-fed rabbits. The increases of total lipids, total cholesterol (TC), free cholesterol (FC) and phospholipid (PL) in plasma by HCD-feeding were inhibited by the treatment of NIP-200. The plasma contents of TC in high density lipoprotein (HDL-TC) and HDL-PL in the treatment of NIP-200 were increased more than that of the control and the HCD-fed group, but the former was not significantly different compared to the HCD-fed group. Both atherogenic index using TC-HDL-TC/HDL-TC and PL-HDL-PL/ HDL-PL were reduced by NIP-200. There was a slight deposition of fatty plaques on the lumen surface of the thoracic aorta in the HCD-fed and NIP-200-treated rabbits. In the scanning electron microscopic study on the lumen surface of the aortic arch, NIP-200 reduced fatty plaques. NIP-200 also prevented the loss of endothelial fissures and swelling of the nuclei. It is suggested that the hypolipidemic action of NIP-200 may be the inhibition of lipid absorption in the intestine and the acceleration of lipid excretion in the liver. The antiatherosclerotic action of NIP-200 may be due to the improvement of lipid metabolism by the increases of HDL-TC and HDL-PL in plasma.

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The interaction between the renin-angiotensin (RA) system and thromboxane A₂ (TXA₂) was examined in dogs, before and during the renal artery pressure (RAP) was decreased. Intrarenal arterial administration of a small dose of angiotensin II (All) reduced renal blood flow (RBF) and glomerular filtration rate (GFR) in non-treated dogs when RAP was maintained at the normal level. When mean RAP was decreased to 60 mmHg by means of an aortic clamp, All reduced RBF, but increased GFR up to 122% of the control value. In dogs pretreated by captopril, GFR decreased when RAP was reduced to 60 mmHg, while RBF was well maintained. However, with the administration of All, RBF decreased markedly. By indomethacin pretreatment, GFR and RBF decreased during reduced RAP, and their reduction rates were accelerated with the administration of All into the renal artery. By pretreatment with the thromboxane A₂ synthetase inhibitor UK38485, the changes of RBF and GFR following All infusion were similar to nontreated dogs at normal RAP, but during reduced RAP, All infusion into the renal artery decreased GFR to 80% of the control value. The thromboxane B₂ (TXB₂) production by the renal cortex during reduced RAP increased to 2.7-fold that at normal RAP, but TXB₂ production did not increase during reduced RAP in captopril pretreated dogs. These results suggest that the RA system and prostanoids, especially TXA₂, are important factors for maintaining GFR at low RAP.

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Cepharanthine, a biscouclaurine alkaloid of Stephania cepharantha, has been used for various clinical purposes. Cepharanthine was known to inhibit histamine release from mast cells obtained from sensitized animals. In vitro studies suggested that the mechanism of action of cepharanthine may be ascribed to the membrane stabilizing action. The membrane stabilization may be attained by reducing the elasticity of the membrane. However, in vivo mechanisms of the anti-allergic action of cepharanthine have not been examined. In the present in vivo study, the anti-allergic action of cepharanthine was examined using experimental allergic rhinitis in rats. The locally administered cepharanthine solution (0.1 mg/ml), by perfusing the nasal cavity, inhibited the dye leakage and an increase in lysosomal enzyme activity due to antigen stimulation. This is the reason for the membrane stabilization by cepharanthine. In the metyrapone (20 mg/kg, s.c., 5 days) pretreated rats of the rhinitis models, the anti-allergic action of cepharanthine was weaker. On the other hand, the effect of ketotifen was not altered by such an effect. The experimental results suggest that the anti-allergic mechanism of cepharanthine might be exerted by its membrane stabilizing action and by stimulation of the pituitary-adrenotropic function.

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We have developed a new method for perfusing isolated and blood-perfused rabbit thoracic aortae by using conscious support rabbits. The vasoconstrictory and vasodilatory responses to vasoactive substances were recorded as the decrease or the increase in intra-chamber pressure of the glass container in which the rabbit thoracic aorta was mounted. Examined were the vascular responses to dl-norepinephrine (NE) and l-isoproterenol (Iso) at different pressure loads to the vessel. NE produced a dose-dependent vasoconstriction which was effectively suppressed by i.v. phentolamine (3 mg/kg). In contrast, Iso produced β-adrenoceptor-mediated vasodilations in a dose-dependent manner (dl-propranolol, 0.5 mg/kg, i.v.). The present experiments were performed at different pressure loads (pressure changes both in the vessel-mounted chamber and a Starling pneumatic resistance set connected in the way of a series circuit). Our newly developed system for perfusion of isolated vascular vessels with conscious support rabbits has some advantages over the existing methods for analysing vascular reactivity in terms of being perfused with arterial blood, having a simulated peripheral resistance apparatus in the circuit and showing a distinct vasodilatory response to i.a. Iso.

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The electroencephalographic (EEG) effects of 7-chloro-5-(o-fluorophenyl)-1, 3-dihydro-l(2, 2, 2-trifluoroethyl)-2H-1, 4-benzodiazepine-2-thione (Sch 161, quazepam) were investigated in unanesthetized rats and rabbits with chronic electrode implants, and the effects were compared with those of flurazepam and diazepam. In freely moving rats, quazepam at doses of 10 to 30 mg/kg, p.o., induced an increase in drowsy EEG pattern periods: high amplitude slow waves and spindle bursts in the cortical EEG and desynchronization of the hippocampal theta waves. Quazepam at doses of 10 to 30 mg/kg significantly decreased the onset of the drowsy EEG pattern after p.o. administration of rats in a dose-dependent manner, while flurazepam and diazepam reduced it only at higher doses of 20 to 30 mg/kg, p.o. In rabbits, quazepam at doses of 0.5 to 5 mg/kg, i.v., evoked a drowsy EEG pattern similar to that of flurazepam (1 to 5 mg/kg) or diazepam (1 to 2 mg/kg). Quazepam at higher doses caused sedation and a slight muscle relaxation in both rats and rabbits, which were weaker than those of flurazepam or diazepam. In both rats and rabbits, quazepam and flurazepam depressed the EEG arousal response to auditory stimulation but not to electrical stimulation of the midbrain reticular formation or the posterior hypothalamus, while the arousal response to either auditory or brain stimulation was markedly suppressed by diazepam. The recruiting response was not altered by quazepam, flurazepam and diazepam. Quazepam has no effect on the photic driving response to flash light in the occipital cortex of the rabbit, while the response was suppressed moderately by flurazepam and markedly suppressed by diazepam. Quazepam (2 mg/kg) suppressed either the hippocampal or amygdaloid afterdischarges. These results suggest that the EEG effect of quazepam is different to those of flurazepam and diazepam in qualitative aspects and that quazepam is likely to be an effective sleep-promoting drug with slight adverse reactions.

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Oral administration of 450191-S to humans at 4 mg/man led to the formation of the same plasma metabolites as those found in animals; i.e., M-1, M-2, M-A, M-3 and M-4. Unlike in animals, M-4 was the major metabolite in human plasma for 6 hr after dosing. 450191-S was not found in human plasma after administration of the commonly used dose of 450191-S (1 ?? 2 mg/man). The major human urinary metabolite was also M-4, and 44 ?? 68% of the dose was excreted as M-4 into 0 ?? 24 hr urine. The unchanged 450191-S excreted into the urine was scarcely detectable. Minor metabolites also seemed to be present in the urine, such as the 4OHM-3 conjugate, M-1 and its conjugate, M-2 and its conjugate, M-A and its conjugate, and M-3 and its conjugate. However, all of them together came to not more than 1 % of the dose.

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