The properties of soluble and microsomal thiamine triphosphatase (TTPase) in rat brain were examined. The subcellular distributions and the pH optima of these enzyme activities differ markedly. TTPase seems to be distinct from a general nucleoside triphosphatase. The TTPase activities have an absolute divalent cation requirement which is fulfilled by Mg⁺⁺ or Ca⁺⁺ in microsomes and by Mg⁺⁺, but not Ca⁺⁺, in the soluble fraction. Addition of a physiological concentration of Ca⁺⁺ markedly inhibited the soluble TTPase activity.

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The effects of various agents on the activity of brain thiamine triphosphatase (TTPase) in vivo and in vitro were studied. Thiamine deficiency caused a significant increase in soluble TTPase activity and a decrease in membrane-associated TTPase activity. Insulin and a fasting state did not affect these enzyme activities. DL-Methamphetamine (10 mg/kg i.p.) increased the activity of the soluble TTPase, whereas reserpine (2.5 mg/kg i.p.) caused no change in the enzyme activities. A single injection of chlopromazine (25 mg/kg s.c.) had no effect on the microsomal or soluble TTPase activities, but repeated injections reduced the activity of the microsomal enzyme. The effects of various neuroactive agents on microsomal TTPase activity were examined in vitro. Among the drugs tested, only chlorpromazine caused marked inhibition of the enzyme activity.

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In the mesencephalon of the chicken, the two large groups of CA terminals and fibers appeared to correspond to the dorsal and ventral bundles of the CA containing fibers in the rat. These ran rostrally in the medial forebrain bundle and appeared to terminate within the thalamus, hypothalamus, preoptic region and corpus striatum. 5-HT containing terminals and fibers also were observed in the mesencephalon and appeared to run rostrally in the medial part of the medial forebrain bundle. In comparison with the CA terminals, however, 5-HT terminals were for the greater part, difficult to observe in many areas of the brain. Based on the observation concerning postnatal ontogeny of monoamine-containing neurons, the chicken brain appears to acquire behavioral and functional maturity at an earlier stage after birth than does that of the rat. Effect of reserpine, nialamide, L-Dopa and 5-HTP on the monoamine-containing terminals and fibers are briefly discussed.

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For studies on the lysosome-stabilizing effect of D-glucaric acid derivatives which have been found to have anti-inflammatory effects, the available and soluble enzyme activities of acid phosphatase of rat liver lysosomes were determined. Salicyclic acid and phenylbutazone which are well-known lysosome-stabilizers were employed as standards. Lysosomes were incubated with drugs under specific conditions which allowed the data on the stabilizing activity of the drugs to be reproducible. The inhibitory effects of D-glucaro-l, 4-lactone, salicylic acid and phenylbutazone on the increase in the available enzyme activity and the increase in the soluble enzyme activity appear to have a close correlation. The lysosome-stabilizing effect of D-glucaro-1, 4-lactone was the greatest among the D-glucaric acid derivatives and was greater than that of salicyclic acid and phenylbutazone over a wide range of concentrations. D-glucaro-1, 4-lactone as well as salicylic acid exhibited concentration-dependent lysosome-stabilizing effect whereas phenylbutazone had an optimum concentration for its lysosome-stabilizing effect. In addition, D-glucaro-l, 4-lactone, salicylic acid and phenylbutazone were also examined for their effects on heat-induced and saponin-induced hemolysis of rat erythrocytes. Both salicylic acid and phenylbutazone exhibited potent stabilizing and labilizing effects on heat-induced and saponin-induced hemolysis of erythrocytes, respectively. D-glucaro-1, 4-lactone, however, was incapable of affecting the hemolysis of erythrocytes. There appears to be a difference in the mechanism of the lysosome-stabilizing effects between D-glucaric acid derivatives and other anti-inflammatory drugs.

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The β-adrenergic blocking and hemodynamic properties of 5-(3-tert-butylamino-2-hydroxy) propoxy-3, 4-dihydrocarbostyril hydrochloride (OPC-1085) were investigated and compared with those of propranolol and pindolol on myocardial contractile force, heart rate and arterial blood pressure in pentobarbital anesthetized dogs. OPC-1085 showed almost the same β-adrenergic blocking potency as pindolol, but was approximately 30 and 20 times stronger than propranolol against isoproterenol and cardiac nerve stimulation, respectively. Slight negative inotropic and chronotropic responses were observed with OPC-1085 in effective blocking doses from 1 to 10 μg/kg but were converted to positive ones in doses from 30 to 3000μg/kg in non-reserpinized dogs. In reserpinized dogs, both OPC-1085 and pindolol induced only positive responses. These responses were more evident with OPC-1085.

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All experiments were performed on cats immobilized with gallamine. In the rostral part of spinal trigeminal nucleus (STN), single fiber action potential with a consistent and short latency was elicited by electrical stimulation of the locus coeruleus (LC). When 2 mg of 6-hydroxydopamine (6-OHDA) dissolved in 5% ascorbic acid solution was applied into the lateral ventricle, the STN field potential produced by LC stimulation was reduced in amplitude within 20 hr. The STN potential elicited by trigeminal nerve stimulation, however, was unaffected until 24 hr after 6-OH DA. The drug also blocked the inhibitory effect of LC conditioning stimulation on the STN potential elicited by trigeminal nerve stimulation, whereas it did not modify the inhibitory effect of conditioning stimulation of the sensory cortex on the STN potential. Ascorbic acid solution, a solvent, affected neither the STN potential by LC stimulation, nor the inhibitory effect of LC neurons on the STN potential elicited by trigeminal nerve stimulation. These results strongly suggest the existence of nor-adrenergic fiber from the LC to STN, through which inhibition of the STN neurons is produced.

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Studies on the activity of the glucuronic acid pathway in alloxan diabetic rabbits were carried out. Amount of D-glucaric acid, L-ascorbic acid, and D-glucuronic acid in urine increased in the case of the alloxan diabetic rabbits. The transformation from D-glucuronolactone to D-glucaric acid was higher than normal in the diabetic animals. The expired ¹⁴CO₂ decreased and urinary excretion of labeled L-gulonic acid increased after administration of 6-¹⁴C-glucuronolactone in the diabetic rabbits. L-Gulonic acid dehydrogenase, lactonase II, and β-glucuronidase activities were reduced, and UDPGA-pyrophosphatase, D-glucuronic acid-1-phosphatase, and UDPGA-transferase activities increased in the diabetic rabbit liver. From these results, it may be concluded that an increase of endogenous D-glucuronic acid in the diabetic states could be attributed to a metabolic defect in the step of L-gulonic acid dehydrogenation and to the enhancement of UDPGA-pyrophosphatase and D-glucuronic acid-l-phosphate phosphatase activities.

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We previously reported that the pressor action of propranolol was observed in the rat anesthetized with urethane. In the present study, rats, anesthetized with pentobarbitone or ether, treated with curare or unanesthetized, were used to investigate the influence of anesthetics on the blood pressure response to propranolol. Propranolol always produced a pressor response under these experimental conditions as well as urethane anesthesia. But under pentobarbitone anesthesia, the magnitude of the pressor action was significantly lower than that obtained under the other experimental conditions. It is concluded that the choice of urethane as the anesthetic does not create a situation irrelevant to that found with other anesthetics and that the cardiovascular responses of rat to propranolol are unique when compared to other species.

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Cardiovascular toxicity induced by dimetacrine (DMC), an antidepressant, was investigated in isolated guinea pig atria and anesthetized dogs, and compared with those of imipramine (IMP) and amitriptyline (AMT) which have been widely used as antidepressants. In the electrically driven guinea pig left atria, these three agents depressed the atrial contraction; a statistically significant difference from nontreated control atria was observed in IMP and AMT, 3 × 10^-6M, and DMC, 10^-5M. The following order of potency was obtained; AMT≥IMP>DMC. In the anesthetized dogs treated with the increasing doses of each agent, hypotensive responses were observed in the doses more than 1 mg/kg i.v. ; the order of potency was as follows, AMT≥IMP>DMC. A pronounced tachycardia was induced by IMP and AMT, 0.1-3 mg/kg i.v., and DMC, 1-3 mg/kg i.v., and the maximum response was observed in the doses of 1, 1 and 3 mg/kg i.v., respectively. When infused at the rate of 1 mg/kg/min i.v., the agents elicited hyperpnoea, tachycardia (except DMC) and hypotension, followed by respiratory arrest and cardiac arrest. Various changes in the ECG, including extrasystoles and supraventricular or ventricular tachycardia were also observed 10 to 15 min after the onset of infusion of AMT and IMP. However, DMC caused no visible modification in the ECG. The doses of AMT, IMP and DMC required to produce cardiac arrest were 25.4±1.2 (S.E.M.), 27.5±3.8 and 64.0±2.2 mg/kg i.v., respectively. The present study confirmed that fewer cardiovascular complications are caused by clinical use of DMC as compared to other tricyclic antidepressants such as IMP or AMT.

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The effect of (+) INPEA on various stimulant drugs was examined on isolated rat uterus. Addition of (+) INPEA (1 × 10^-5 g/ml) to the organ bath, produced marked potentiation in the contractile responses of oxytocin and prostaglandins. Potentiation was less significant to 5-HT, vasopressin, angiotensin and bradykinin. (+) INPEA did not potentiate the responses of oxytocin on isolated rat mammary strip and the responses of prostaglandins on rat stomach (fundus) strip, guinea-pig tracheal chain and guinea-pig ileum. The significance of these findings has been discussed.

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L-glutamine markedly suppressed the development of the gastric lesions induced by aspirin in pylorus-ligated rats. In non-ligated normal rats, aspirin was absorbed rapidly after administration and was maintained in the blood in high salicylate concentration thereafter. When aspirin was administered in combination with L-glutamine, the absorption of aspirin was at nearly the same level as when aspirin had been given alone. In pylorus-ligated rats, administration of aspirin was followed by slow increment in blood salicylate concentration. Blood salicylate level in these rats was higher when aspirin was administered in combination with L-glutamine than when it had been given alone. Combined administration of aspirin and L-glutamine produced little influence on the antipyretic, analgesic and anti-inflammatory effects of aspirin in non-ligated normal rats.

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Effects of catecholamines were investigated on isolated strips of the guineapig stomach. In the circular muscles, the relaxation and biphasic response caused by adrenaline and noradrenaline were suppressed partly by phentolamine and also partly by propranolol. The relaxation by catecholamines in the longitudinal muscles was inhibited mainly by propranolol. Thus, there are probably two types of relaxation. Alpha relaxation was more dominant in the circular muscles and β relaxation in the longitudinal muscles. Contractions in both muscles were mediated through alpha-effects. The circular muscle is more sensitive to the alpha effect and the longitudinal muscle to the beta effect. In the presence of propranolol, isoprenaline caused a mono-phasic contraction. This is evidence of an alpha effect of isoprenaline. Field stimulation which excited intramural nerves resulted in contraction followed by relaxation in both circular and longitudinal muscles. The inhibition of the electrically evoked contractions by adrenaline and noradrenaline in both circular and longitudinal muscles was abolished by phentolamine but the electrically evoked relaxations were affected little.

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