Most of the criteria for identification of a neurotransmitter were satisfied for γ-aminobutyric acid (GABA) in the mammalian intestine. 1) GABA and its synthesizing enzyme, glutamic acid decarboxylase, and the neurons which specifically accumulate GABA were demonstrated to localize in Auerbach's plexus of the intestine. 2) GABA was demonstrated to be released from nerve terminals of the intestine when the nerve fibers were stimulated. 3) The application of GABA depolarized the neurons within Auerbach's plexus. 4) The actions of GABA were mimicked by muscimol on the GABA_A receptor and by baclofen on the GABA_B receptor. The GABA_A antagonist is bicuculline, but no antagonist to GABA_B is known at present. Thus, GABAergic neurons may be present in the enteric nervous system of the intestine. GABA and bicuculline changed the propulsive activity and the spontaneous motility of circular muscle, and the neuronal interactions, substance Pergic-GABAergic-postganglionic cholinergic neurons were found in the enteric nervous system, thereby suggesting that GABAergic neurons play a key role in the control of peristalsis.

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Thyrotropin-releasing hormone (TRH) and its analog, DN-1417 (γ-butyrolactone-γ-carbonyl-L-histidyl-L-prolinamide citrate), significantly antagonized against reserpine-induced reduction of the spontaneous motor activity and the electroconvulsive threshold in mice. To search for sites of action and mechanisms, effects of DN-1417 on reserpine in local cerebral glucose utilization (LCGU) and cerebral monoamine levels were also investigated in rats. Reserpine (2 mg/kg, i.p., 24 hr pretreatment) reduced LCGU and the levels of cerebral monoamine in all the brain regions. DN-1417 (5 mg/kg, i.v.) significantly reversed the reduction of LCGU induced by reserpine in the thalamus dorsomedial nucleus, mamillary body, septal nucleus, caudate-putamen and nucleus accumbens. The effects of DN-1417 were completely abolished by pretreatment with a dopaminergic (DA) and a serotonergic (5-HT) receptor blocker, pimozide (1 mg/kg) and methysergide (5 mg/kg), respectively. DN-1417 (20 mg/kg, i.p.) reversed 5-HT level in the hypothalamus depleted by reserpine. These results suggest that the antagonistic effects of DN-1417 against reserpine-induced reduction of the locomotor activity and the electroconvulsive threshold seem to be mediated by DA and 5-HT-ergic activations mainly in the nucleus accumbens and hypothalamus, respectively.

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Changes in the incorporation of ³H-glucosamine into the macromolecular glycoprotein during the healing process of acetic acid induced gastric ulcer in rats were sequentially examined in the ulcer region and the intact region at 2, 10, 40, 80 and 365 days after the operation. 1) The total radioactivity (Tissue+Medium) and the radioactivity which remained in the tissue after incubation of the ulcer region were increased significantly as compared with those of the control at 2 days after the operation (275, 175% of the control, respectively), and then total radioactivity returned to the control level. On the other hand, the radioactivity in the tissue was gradually decreased, and then it became 50% of the control at 365 days. In contrast, the incorporating activity into the macromolecular glycoproteins was decreased to 50% of the control at 2 days, and was once recovered to the control level at 10 days. After 40 days, it was again decreased to 50% of the control and became 30% at 365 days. 2) Changes in the incorporation of 3H-glucosamine into the macromolecular glycoproteins of the intact region of rats with ulcers were the same as that of the ulcer region. 3) Elution profiles of gel filtration of the macromolecular glycoproteins isolated from the relapse and recurrence region of rats with ulcers at 365 days were the same as that of the healing region, and their radioactivities were decreased to 30% of the control. The results suggested that such a decrease in the biosynthetic activity of the macromolecular glycoproteins extending over the whole gastric tissue is one of the reasons for the increased relapse and recurrence.

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Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of isosorbide dinitrate (ISDN), verapamil and propranolol. In anesthetized open-chest dogs, intravenous injection of 5-ISMN (1 mg/kg, 3 mg/kg) scarcely decreased cardiac contractile force (CCF) and heart rate (HR). The systolic blood pressure (SBP) fell in a dose-dependent manner, and the degree of the change was greater than that in diastolic blood pressure (DBP). Especially, left ventricular pressure (LVP) and left ventricular dp/dt (LVdp/dt)were significantly decreased, and a considerable reduction in left ventricular end-diastolic pressure (LVEDP) was also observed. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered DBP. While HR, CCF, LVP and LVdp/dt were markedly decreased, LVEDP showed a moderate increase. Propranolol (0.5 mg/kg, i.v.)greatly decreased LVdp/dt together with HR and CCF. Conversely, LVEDP showed a slight increase. There was no change in SBP, DBP and LVP. The vasodilating potency of 5-ISMN was 150 times smaller than that of ISDN on the contractile response in isolated rabbit thoracic aorta. On the other hand, in terms of decrease in pulse pressure, the potency exhibited by 5-ISMN was about 4 times (intravenous administration in anesthetized dogs) or 1.5 times (oral administration in conscious dogs) smaller than that of ISDN. The present results suggest that 5-ISMN shows a high bioavailability and a potency comparable to ISDN, especially in the case of peroral administration. Taking these results together with the fact that transient left ventricular failure occurs during myocardial ischemia into consideration, it is thought that peroral 5-ISMN preparation may be useful in the therapy of angina pectoris.

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Antiedema effects of basic nonsteroidal anti-inflammatory drugs that don't inhibit prostaglandin biosynthesis were investigated with carrageenin-induced hind paw edema in rats. Locally administered mepirizole, tiaramide.·HCl and aminopyrine, the basic nonsteroidal anti-inflammatory drugs, didn't show any suppression against the edema formation. In the case of indomethacin, phenylbutazone and ketoprofen, inhibitors of prostaglandin biosynthesis, they inhibited the edema formation. Inhibitory effects of orally and subcutaneously administered basic nonsteroidal anti-inflammatory drugs such as tiaramide·HCl and benzydamine on the edema formation were more potent in fasted rats than in nonfasted rats. In the case of acidic nonsteroidal anti-inflammatory drugs such as indomethacin and ibuprofen, their inhibitory activities were almost the same in both the fasted rats and the nonfasted rats. These results suggest that the site of aciton of the basic nonsteroidal anti-inflammatory drugs such as tiaramide.HCl and mepirizole is not the inflamed site, and certain systemic effects may contribute to the anti-edema effects.

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Mechanisms for hypercholesterolemia and hypertriglyceridemia and the effects of KCD-232, a new hypolipidemic agent, on them were studied in male Wistar rats with daunorubicin (DR)-induced nephrosis. Single intravenous injection of DR dose-dependently increased urinary protein loss and serum lipid levels (0, 3, 6 and 12 mg/kg). Twenty-four days after the injection of DR (6 mg/kg), serum cholesterol (Ch) and triglyceride (TG) levels markedly increased and free fatty acid level tended to decrease with no effects on liver lipid levels. Hepatic Ch synthesis from [¹⁴C]acetate in vitro increased by 2.1-fold, while exogenous Ch absorption slightly decreased. The clearance of intravenously injected [³H]Ch from the circulation was delayed. Hepatic fatty acid (FA) synthesis also increased by 2.7-fold, and hepatic TG lipase activity tended to decrease. KCD-232 improved the hypercholesterolemia and hypertriglyceridemia of DR-treated rats. The drug inhibited the elevated hepatic Ch synsthesis and exogenous Ch absorption and thus improved the delayed Ch clearance from the circulation. KCD-232 markedly inhibited the elevated hepatic FA synthesis and stimulated both hepatic FA oxidation and lipoprotein lipase activity from the epididymal adipose tissue of the nephrotic rats. These results suggest that J. DR-induced iypercholesterolemiaa is due to both an increased Ch synthesis in the liver and delayed clearance of Ch from the circulation; 2. DR-induced hypertriglyceridemia is caused by both an increased hepatic FA synthesis and depressed TG hydrolysis in the circulation; 3. KCD-232 improves the hypercholesterolemia by inhibiting the elevated Ch synthesis and Ch absorption from the gut; and 4. KCD-232 improves the hypertriglyceridemia by inhibiting the elevated hepatic FA synthesis and by stimulating both hepatic FA oxidation and TG hydrolysis activity in the circulation.

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Cetraxate hydrochloride was administered either orally or intravenously to rabbits, and its concentration in body fluids was determined by using the HPLC method. Cetraxate was easily hydrolyzed in the gastrointestinal tract and blood, and it was metabolized to p-hydroxyphenylpropionic acid (PHPA) and a new metabolite, p-hydroxybenzoic acid (PHBA). After oral administration of cetraxate hydrochloride, a large amount of unchanged drug was distributed to the gastric wall. PHPA was distributed in all the organs examined, excluding the brain. To determine whether or not the anti-ulcer action of cetraxate hydrochloride was due to the unchanged drug, PHPA, or tranexamic acid, studies with aspirin and water-immersion -induced gastric ulcers in rats were performed. As a result, it was found that tranexamic acid had an anti-ulcer action similar to that of cetraxate hydrochloride.

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Investigations were made of 2-(nicotinoylaminoethanesulfonylamino)pyridine (NTP), a new compound with anti-ulcer effects, to clarify the relationship between its biotransformation and pharmacological effects. The effect of NTP was investigated by using two types of experimental gastric ulcer models in rats. The anti-ulcer effect was revealed to be an action of NTP itself. In order to study the biotransformation of NTP, a quantitative analysis method by HPLC was established. When NTP was orally administered to rabbits, 2-(aminoethanesulfonylamino)pyridine (TP), which is a metabolite of NTP, appeared in plasma and lymph. When NTP was orally administered to rabbits to investigate its distribution in organs, a massive amount of NTP and TP appeared in various organs within 7 hr after administration. We conclude that the pharmacological effect of NTP appears to be associated mainly with the unchanged substance.

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The effects of dl-erythro-4-benzyl-α-(4-hydroxyphenyl)-β-methyl-l-piperidine-ethanol tartrate (ifenprodil tartrate) on rabbit platelet aggregation in vitro and ex vivo were studied. Ifenprodil tartrate inhibited platelet aggregation in vitro induced by ADP, collagen and epinephrine. It also inhibited 5-hydroxytryptamine (5-HT) uptake into platelets and 5-HT release from platelets. Since these inhibitory effects of ifenprodil tartrate on the functions of rabbit platelets were similar to the effects of imipramine, the effects of ifenprodil tartrate may be due to the stabilizing action of ifenprodil tartrate on the platelet membrane. The platelet aggregation by ADP was significantly inhibited in rabbits after oral administration of ifenprodil tartrate, the maximal plasma level of ifenprodil being reached at 20 ng/ml ex vivo, while the maximal level was only 1/40 of the minimal concentration of ifenprodil tartrate necessary to inhibit platelet aggregation in vitro. These results indicate that factors other than ifenprodil tartrate acting directly on the platelets (e.g., PGI₂ which is an endogenous inhibitor of platelet aggregation) are involved in inducing the inhibitory effects of ifenprodil tartrate on platelet aggregation ex vivo. The effects of ifenprodil tartrate on both PGI2₂ release from the aorta and the inhibitory effects of PGI₂ on platelet aggregation in vitro were investigated: PGI₂ was found to intensify the inhibitory effects of ifenprodil tartrate on platelet aggregation in vitro, but there was little effect, if any, on PGI₂ release. Therefore, it is considered that the ex vivo effects of ifenprodil tartrate might be due to its interaction with endogenous PGI₂ in the blood.

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Effect of tritoqualine (TRQ) on liver regeneration after partial hepatectomy in normal rats and chronically injured rats treated with carbon tetrachloride (CCl₄) for 12 weeks were investigated by the measurement of serum and liver biochemical parameters concerning the hepatic function. The results are as follows: 1) In normal rats, the liver regeneration rate after partial hepatectomy was increased dose-dependently with the administration of TRQ for 7 days after the operation. TRQ improved BSP retention rate which was decreased after partial hepatectomy. In addition, protein synthetic activity in the liver microsomes prepared from TRQ-administered rats was higher than that prepared from control rats, and the contents of serum total protein, serum albumin and liver protein were also higher in TRQ-administered rats. 2) In the rats treated with CCl₄ for 12 weeks, the liver re-generation rate after partial hepatectomy was increased dose-dependently with the administration of TRQ for 6 days. TRQ also improved the contents of serum total protein, serum albumin and liver protein. Though the amount of collagen in the liver chronically injured by CCl₄ increased more than twice compared with that in the normal liver, the amount of collagen in the regenerating liver of CCl₄-treated rats whose liver regeneration was accelerated by TRQ was not different from that in the normal liver. These results suggest that TRQ has the effect of improving the various hepatic functions through the activation of the protein synthesis in hepatocytes.

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The anti-inflammatory activity of the dry distillation tar of delipidated soybean (GL, 0.1 ?? 10%) was investigated by its topical application to mice, rats and guinea pigs; and the effects were compared with those of betamethasone 17-valerate (BV, 0.12%), ibuprofen (IP, 5%), phenylbutazone (PB, 5%) and flufenamic acid (FA, 5%), which were all prepared with the same ointment base. GL (1 ?? 10%) showed a concentration-dependent inhibition of the increased vascular permeability induced by histamine and bradykinin in guinea pigs. GL significantly inhibited rat paw edema induced by carrageenin, but in serotonin-induced paw edema, GL showed only a weak effect. GL also inhibited the erythema formation induced by ultra-violet rays, and the activity was equal to that of PB. The inhibitory potency of GL against the erythema formation induced by arachidonic acid in guinea pigs was equal to that of IP. It is suggested from these results that the mode of action of GL is similar to that of other acidic non-steroidal anti-inflammatory drugs. However, GL did not inhibit paper disk granuloma in rats. Furthermore, GL markedly inhibited the delayed-type hypersensitivity induced by picryl chloride, and the activity was stronger than that of III, PB and FA. Here GL showed the mode of action seen with steroidal anti-inflammatory drugs. The present data provide evidence that GL applied externally possesses a potent effect as an antiinflammatory drug.

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Adjuvant arthritic rats develop marked changes in the distal limb joints. These changes were observed by soft X-ray photography at appropriate intervals. It was confirmed that the “cotton wool appearance” surrounding the bones, which was readily discernible from the radiographs, was a good indicator for following the progression of bone damages. Standard radiographs were selected to represent the various bone changes based on the “cotton wool appearance”. When the incidence rates of bone deformation confirmed on the basis of the above method were plotted against Weibull Probability Paper, the plots conformed with the Weibull distribution function. Thus, it was possible to evaluate bone changes in adjuvant arthritic rats by observing the “cotton wool appearance” surrounding the bones.

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