The actions of shakuyaku-kanzoh-toh (SK), a prescription of the traditional Chinese medicine, on an isolated guinea pig ileum were studied by comparing those of shakuyaku (S)(peony root, Paeoniae Radix) and kanzoh (K)(licorice root, Glycyrrhizae Radix). SK, S and K suppressed the neurogenic contractions of ileum induced by electrical stimulation and ganglionic stimulating agents such as DMPP and nicotine. Although S did not influence acetylcholine (ACh)-induced contraction of ileum, K inhibited ACh-induced contraction to the same extent as the neurogenic contraction. Also SK inhibited ACh-induced contraction but its inhibition was smaller than the inhibition of the neurogenic contraction. SK and K inhibited 40mM KCl-induced contraction of ileum and the specific binding of ³H-QNB on muscarinic receptors in ileum, but S at 3×10^-4 and 10^-3g/ml, which were enough to suppress the neurogenic contraction of ileum, did not inhibit them. These results suggest that the inhibitory actions of S and K on the neurogenic contraction are due to an inhibition of ACh release from choliergic nerve and an inhibition of ACh action on ileum smooth muscle, respectively, and that the inhibitory actions of SK are responsible for both inhibitions by S and K. The inhibitions of ACh action by SK and K are presumed to be due to inhibitions of ACh binding on muscarinic receptors and of contractile machinery of smooth muscle.

View full abstract

In order to establish quantitative expressions of inhibitory kinetics in renal tubular secretion of p-aminohippurate (PAH), bolus i.v. injection and constant i.v. infusion of PAH were loaded to rabbits. Time courses of plasma concentration and urinary excretion rate were analyzed using compartment model with saturable rate process. Effects of sulfamethizole (SMZ) constant infusion and bolus injection on PAH renal excretion were also examined. Multi-compartment model for concurrent disposition of PAH and SMZ is presented. Excretory processes are composed of non-saturable filtration, saturable secretion which is subject to mutual inhibition, and reabsorption.

View full abstract

The effects of N-(4-methylbenzylthiocarbonyl)-L-phenylalanine (KF 1492) on the intestinal lipid absorption, the biliary lipid composition and α-glycerophosphate dehydrogenase (GPD) activity have been investigated in rats in comparison with clofibrate. KF 1492 did not have inhibitory activity on intestinal absorption of cholesterol and triglyceride. In the KF 1492-treated group (100mg/kg, 8d), an increase of bile flow (25.9%) per g liver was observed. The increase of excretion of bile acids (29.9%), phospholipids (45.2%) and cholesterol (33.4%) due to the increase of bile flow was clearly observed but no significant change in the concentration of each lipid was observed. In clofibrate-treated group, the concentration of bile acids and cholesterol in bile was decreased and output of biliary phospholipids was increased. Approximately 5 to 10 times increase of GPD activity was observed in mitochondrial fraction of the KF 1492- or clofibrate-treated rats (0.25% (w/w) in rat chow, 3 weeks). Thus, the increased degradation and excretion of cholesterol to bile may explain the hypocholesterolemic activity of KF 1492.

View full abstract

The distribution of three sulfonylureas and six diuretics in rabbit erythrocytes was studied in vitro at 37°C. The drugs were taken up by the erythrocyte compartment, and distribution equilibrium was reached within 60min of incubation. A distribution percentage in erythrocyte compartment was maintained at roughly constant value over the whole concentration range of drugs. Therefore, a linear relationship was established between total concentrations of drug in whole blood or erythrocyte suspension and in the erythrocyte compartment. Bovine serum albumin combined with the erythrocyte suspension appeared to reduce drug distribution in the erythrocyte compartment. Whole blood obtained from renal failure rabbits showed greater distribution of drug in the erythrocyte compartment compared with the whole blood of a normal rabbit. This might be due to a change in plasma protein binding ability related to the progress of renal failure.

View full abstract

Effects of some diphenyl and monophenyl compounds on grip strength in mice and spinal reflexes in young chicks were investigated in order to study structure-activity relationships between muscle relaxant activity and neolignane compounds, magnolol and honokiol extracted from Magnolia officinalis THUNB. Diphenyl produced a long-lasting suppression in the spinal reflex and relatively weak inhibition in the grip strength. An introduction of a hydroxyl into 2-position of diphenyl, o-phenylphenol, increased the muscle relaxant activity and accelerated the onset, although the duration was still long. In the spinal reflex preparation the duration of action became short. The introduction of two hydroxyls into 2-and 2'-position of diphenyl, 2, 2'-dihydroxydiphenyl, further strengthened the activity and shortened the duration of the inhibitory effect on the grip strength and the spinal reflex. When two allyls are introduced into 5, 5'-position of 2, 2'-dihydroxydiphenyl, it corresponds to magnolol. Magnolol, 5, 5'-diallyl-2, 2'-dihydroxydiphenyl, produced potent inhibitory effects of gradual onset and of long duration on the two test preparations. Position of allyls and hydroxyls in honokiol, 5, 3'-diallyl-2, 4'-dihydroxydiphenyl, is different from magnolol, although the pharmacological characteristics are quite similar to magnolol. These results suggest that a hydroxyl accelerates the onset and shortens the muscle relaxant activity of diphenyl and an ally influences the activity in the opposite direction. Both radicals appear to intensify the activity.

View full abstract

It was examined whether the anticonvulsant activity of valproic acid (di-n-propylacetic acid, DPA) was exerted via the inhibitory GABA system in the central nervous systems (CNS). Dorsal root reflexes (DR-DRR) were not augmented but intensely suppressed following the administration of DPA (50 and 200mg/kg, i.v.). DPA did not depolarize the resting dorsal root potentials. These electophytsiological findings may indicate that DPA does not potentiate GABA system in the spinal cord of rats. DPA (1 and 10mM) neither affected the binding of 2 or 40nM of [³H] muscimol nor the binding of [³H] diazepam in the rat brain membranes ; the same concentrations of DPA did not affect the enhancement of binding of [³H] diazepam induced by the addition of GABA (100μM). The result obtained from binding assays indicates that DPA does not interact with the GABA-benzodiazepine receptor complex. The findings in the present study do not support the proposal that the anticonvulsant action of DPA is exerted by potentiation of the GABA system in the CNS.

View full abstract

The relationship between urinary excretion of sex-dependent low molecular weight proteins (LMWP) in male rats and narcotic dependence is described in this study. Rats were intermittently infused with narcotics at one hour intervals through an implanted intravenous cannula. Development of physical dependence on morphine, pethidine, and pentazocine was detected by withdrawal signs including body weight loss and abnormal behaviors after naloxone challenge. In these animals, a significant decrease in urinary LMWP excretion was found following the second day of each drug treatment without significant changes in albumin excretion, and this decrease was observed continuously throughout the experiment. The markedly decreased level of LMWP recovered to the control level within 7 d after withdrawal of the drugs. These results suggest that the decrease in urinary excretion of sex-dependent LMWP in male rats is a phenomenon closely related to narcotic dependence.

View full abstract

Kinetic study of disappearance of γ-butyrolactone-γ-carbonyl-L-histidy-L-prolinamide (DM-1417) from human plasma has been performed by a sensitive and specific radioimmunoassay (RIA) using antiserum against DN-1417 isobutylamide. Antibody against N-[2-hydroxy-4-(isobutylcarbamoyl)butyryl]-L-histidy-L-prolinamide (DN-isobutylamide) did not cross-react with any other TRH-related peptides tested. DN-isobutylamide was radioiodinated with ¹²⁵I by the chloramine T method and the product had a specific activity of about 160μCi/μg. The sensitivity of the RIA was 50pg per tube, and the intra- and inter-assay coefficients of variation at concentrations of 1-10ng/ml were 7.0-11.6%. DN-1417 in the plasma was converted to a stable form, DN-isobutylamide, by incubation with isopropanol-isobutylamine at room temperature for 2h. DN-Isobutylamide was separated from 2-hydroxy-4-carboxybutyryl-L-histidyl-L-prolinamide (DN-COOH) using a SEP-PAK^TM C₁₈ cartridge before RIA. The recovery of DN-isobutylamide from plasma was 86.2-98.2%. The half-life, volume of distribution and plasma clearance rate of DN-1417 examined in 6 normal male volunteers by intravenous injection of 500μg DN-1417 citrate were 11.5±5.6min in the first phase and 89.5±33.5min in the second phase, 25.3±10.0 liters and 745.8±278.6 1/d, respectively. These results indicate that RIA of DN-isobutylamide is useful for analysing DN-1417 metabolism in humans.

View full abstract

Mode of relaxant effect of papaverine on guinea-pig taenia coli was compared with that of amytal, especially in regard to their actions on the calcium movements. The present results provided evidence that the mode of relaxant effect of papaverine differs from that of amytal. Papaverine relaxed the taenia coli even in the Na-free solution although its relaxant activity was markedly reduced, while amytal failed to reveal relaxant activity in the same condition. Reintroduction of a small amount of sodium ion to the Na-free solution restored the relaxant activities of papaverine and amytal but their sodium ion dependencies of the restoration were not equal. Amytal was more sensitive to sodium ion that papaverine. Papaverine induced the muscle relaxation with synchronous acceleration of ⁴⁵Ca-efflux, while the relaxation in response to amytal was not accompanied by acceleration of ⁴⁵Ca-efflux. The cellular ⁴⁵Ca-uptake was inhibited by papaverine, but not by amytal. In these experiments, both papaverine and amytal were used at sufficient doses to inhibit the mitochondrial respiration. From these findings, it is concluded that papaverine relaxes the smooth muscle through different mechanism from that of amytal and thus the relaxant effect of papaverine may not be related to its inhibitory action on the mitochondrial respiration.

View full abstract

The incorporation of radioactively labeled palmitic, stearic, oleic, linoleic and arachidonic acid into the phospholipids of lymphocytes was studied. When concanavalin A (Con A) was added a gradual increase in the incorporation was found over the period investigated (0-4h). Changes were not detected over the first 15min. The increased incorporation at 4h was shown to be Con a dose dependent and the Con A concentrations for the maximum effect on fatty acid incorporation (at 4h) and on [³H] thymidine incorporation (at 72h) were the same. With the exception of stearic acid all the other fatty acids showed an increased incorporation into phosphatidyl choline on addition of Con A, linoleic and oleic acids also had an increased incorporation into phosphatidyl ethanolamine.

View full abstract