In a study of structure-activity relationship in antitussive agents, a working hypothesis has been presented that the introduction of a piperidino group into a compound showing any actions on the central nervous system, can produce antitussive activity if the activity has been latent, or strengthen it if such activity is already manifest (1, 2). In the previous study, antitussive activity of 2-allyloxy-4-chloro-N-(2-diethylaminoethyl) benzamide (264-CE, Hexacol®) had been investigated and it was found that the activity of the drug was 1/4 to 1/3 as potent as that of codeine (3).
Therefore, in order to strengthen the antitussive activity, 2-allyloxy-4-chloro-N-(2-piperidinoethyl) benzamide (abbreviated as 264CP) in which a piperidino group was introduced in stead of a diethylamino group in the structure of 264CE was synthesized. Other 6 compounds including amino groups such as pyrrolidino, morpholino, piperazino, dimethylamino and primary amino groups in stead of a diethylamino group, and a trifluoromethyl group in stead of chlor (2-allyloxy-4-trifluoromethyl-N-(2-diethylaminoethyl) benzamide, 305-CE) were also synthesized for testing their antitussive activities.
In the present experiment, the antitussive actions and other pharmacological actions of these 7 compounds, especially those of 264CP, have been compared with those of 264-CE.

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Recently interest in investigations of adrenergic agents (stimulants and inhibitors) on gastric secretion, motility, and ulceration in experimental animals has increased (1-7). Pradhan and Wingate (6) have demonstrated that phentolamine and tolazoline enhanced the spontaneous gastric secretion in dogs while phenoxybenzamine and dichloroisoproterenol showed inhibitory effects on spontaneous as well as induced secretion by food, bethanechol, and histamine. Bass and Patterson (3) have shown that both adrenergic and adrenergic blocking agents (including phentolamine and tolazoline) possessed antisecretory properties on rat gastric secretion. Hence, if gastric acid is a primary element in experimental ulcer, adrenergic and adrenergic blocking aegnts which have antisecretory effect should inhibit gastric ulceration. However, phentolamine, MJ 1999, and isoproterenol did not affect the incidence of histamine-induced ulcer in guinea pigs (6). Moreover, propranolol and phenoxybenzamine increased the incidence of ulceration in fasted rats immobilized for 8 hours (7). In this study, therefore, an attempt was made to investigate the effect of several adrenergic blocking agents on gastric secretion and stressinduced ulcer in rats and to clarify a part of the mechanism of gastric ulceration by stress.

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Recently, the function of the myocardium has been explained by means of the classification of adrenergic receptors proposed by Ahlquist (1). The presence of beta adrenergic receptors in the myocardium was already established by Nickerson and Chan (2), Moran and Perkins (3), and Moran et al. (4), while that of alpha adrenergic receptors was reported on the isolated rabbit's atria by Govier et al. (5-7). Hence, this investigation has been prompted by interests to re-evaluate the existance of myocardial alpha and beta adrenergic receptors in the isolated papillary muscle of the cat, and to study the location of these two receptors. During the experiments of the action of dibenamine on adrenergic receptors, it was unexpectedly found that dibenamine has two different actions, either a short-reversible effect or a long-lasting effect, according to the duration of the administration.

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A number of the mesoionic compounds known as a new class of heterocycles have been examined in the search for potential therapeutic agents and their biological activities have been reviewed recently by Kier and Roche (1), and Ackermann (2). Oehme et al. (3) studied some mesoionic 3- or 3, 4-substituted sydnonimines and found that in urethane anesthetized rats the sydnonimines were hypotensive only in high doses (0.02 mM/kg i.v.), the effect not being pronounced, and reported that in the rat duodenum and the guinea pig ileum 3, 4-diphenylsyndnonimine had a spasmolytic effect equipotent to papaverine. However, no detailed cardiovascular actions of sydnonimines have so far been reported. Recently we found that the newly synthesized 3-substituted sydnonimines (4) have potential pharmacological actions such as vasodilating, vasoconstricting, hypotensive, hypertensive, sympathomimetic, or spasmolytic actions. This paper reports the chemical structureactivity relationship and mechanisms of the cardiovascular actions of 3-substituted sydnonimines, especially those of 3-morpholinosydnonimine hydrochloride (CV-664, SIN-1), a potent hypotensive and spasmolytic compound.

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A close positive correlation has been found in this laboratory between serum β-glucuronidase activity and blood glucose level immediately following administration of glucose, epinephrine and insulin to normal fasted rabbits (1). Similar correlation has also been shown in hyperglycemia of a long term produced by alloxan administration to rabbits (2). On the other hand, it has been known that serum β-glucuronidase activity is higher in diabetic patients than in normal subjects (3-9). In view of the possible bearing of the serum β-glucuronidase-blood glucose level correlation on diabetes mellitus in man, it was felt essentially important to investigate this relationship in more detail.
There are several questions to be answered in this study: 1) dose the serum β-glucuronidase activity increase occur following administration of sugars other than glucose; 2) specifically, is it not merely due to physicochemical changes of blood such as the increase in the osmolarity; 3) if this phenomenon is specific for certain sugars, is such specificity related to possible disturbances in glucose metabolism ; and, 4) what effects do different types of antidiabetics have on serum β-glucuronidase activity.
The study reported here thus describes the relationships between the serum β-glucuronidase activity and blood glucose level and between the activity and the levels of administered sugars, following administration of various sugars and antidiabetics to rabbits.

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It is now commonly postulated that the electrical excitability of neural cells depends on the concentration gradients of Na⁺ and K⁺ across the cell membrane and the gradients are maintained by active cation transport system. Further, a membrane-bound, Na⁺ and K⁺-stimulated and ouabain-sensitive adenosine triphosphatase (Na-K-ATPase) has been proved to be involved in the active cation transport system in the brain as well as in many other tissues (1). While cardiac glycosides have been well known to be specific inhibitors of Na-K-ATPase, some biogenic substances were also considered to participate in the transport mechanism. In this respect, two biogenic substances, ascorbic acid and cysteine, came to light. They were described as rather specific inhibitors of Na-K-ATPase in the electric organ of eel (2) and the liver of rat (3). The present report describes how ascorbic acid and cysteine affect Na-K-ATPase and Mg-ATPase of the rabbit brain, histochemically and biochemically. For reference the enzymes of rabbit liver were tested.

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In spite of the availability of much evidence showing the sympathetic nature of the hypogastric nerve innervating the guinea-pig vas deferens (1-8) a persistent resistance of the contractile response to hypogastric nerve stimulation to various adrenergic α-blocking agents in vitro has still remained unexplained.
Boyd et al. (9) and Ohlin and Strömband (10) observed that the contractile response to hypogastric nerve stimulation was not depressed by moderate doses of various α-blocking agents but rather potentiated owing to their anti-cholinesterase activity. Burnstock and Holman (8) have also demonstrated that the junction potentials in response to hypogastric nerve stimulation had a considerable resistance to the α-blocking agents in the guinea-pig vas deferens in vitro.
The present study was, therefore, designed to reappraise the well known in vitro resistancy, of mechanical and electrical responses of guinea-pig vas deferens to hypogastric nerve stimulation to α-blocking agents, using an in vivo preparation, in which the intravenously administered drugs would reach the receptor sites through the blood stream with active pressure.

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In our previous papers (1, 2), we reported that a new fraction of licorice root (F_M100) showed a protective effect on ulceration in the pylorus ligated rats and gastric antisecretory activities in rats and dogs in spite of being devoid of anticholinerigc properties. F_M100 decreased non-stimulated gastric secretion volumes and acid outputs in the pylorus ligated rats and gastric acid secretion induced by instillation of peptone into the antrum separated from the fundus in acute fistula rats. Effects of histamine and methacholine on gastric secretion were partially antagonized by F_M100. On the contrary, F_M100 did not exert the inhibitory action on secretion induced by crude gastrin. Then, we propounded the hypothesis that the mechanism of gastric antisecretory activity of F_M100 is probably due to inhibitory action of the release of gastrin from the antral mucosa. The aim of the present investigation was to study the mechanism of gastric antisecretory activity of F_M100, especially concerning the mechanism of the release of gastrin from the antral mucosa of the rat.

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The existence of a bradykinin-like substance in nervous tissue has been reported (1), and the enzymatic inactivation of bradykinin by a neural tissue extract are also confirmed (2, 3).
The purification and properties of the enzyme in rat brain inactivating bradykinin were reported in preceding papers from this laboratory (4, 5).
This communication describes changes of spontaneous motor activity in mouse after intracerebral injection of bradykinin and the role of the enzyme inactivating bradykinin (kininase) in mouse brain.

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Peripherally administered 5-hydroxytryptophan (5-HTP) has been shown to increase the amount of 5-hydroxytryptamine (5-HT) in brain (1, 2). The pretreatment with reserpine inhibited this increase (2). After monoamine oxidase inhibitor a large amount of 5-HT could be found to be accumulated by the administration of 5-HTP regardless of whether the animals were treated with reserpine or not (1-3). Histochemical studies have shown that most of 5-HTP-induced 5-HT was ascribable to increased amine content in 5-HT neurons in the central nervous system (4), but part of it was found in an extraneuronal site (2). However, because the majority of these structures are small, being of submicroscopical size, it seems difficult for histochemical procedure to identify the subcellular site of uptake and storage of 5-HTP-induced 5-HT. Therefore, in this paper an attempt was made to fractionate rabbit brain stem homogenate after intravenous administration of 5-HTP and to determine 5-HT concentration in each fraction. In addition the effects of pretreatment with reserpine, pheniprazine and desipramine in the increased amount of 5-HT were also investigated.

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The concept of two adrenergic receptor mechanisms or α- and β-adrenergic receptor systems, originally postulated by Ahlguist (1) is presently accepted. Furchgott (2) has presented evidence suggesting that there may be different types of receptors in the β- class. This conclusion was based on differences in relative potencies of isoprenaline, epinephrine, norepinephrine and phenylephrine in variety of isolated organs.
On the other hand, some partial agonists in a series of cholinergic drugs contract the isolated taenia caecum (or taenia coli) of the guinea pig and at the same time the contraction which they produce is inhibited by their non-secific inhibitory action, so that maximal responses to partial agonists are smaller than that to full agonists (3-5). Furthermore, ephedrine which was classified as an adrenergic partial agonist relaxes the taenia caecum and at the same time the relaxation which it produces is antagonized by its own excitatory action, so maximal relaxation by it is smaller than that by a full agonist, epinephrine (5). DCI was also reported as an adrenergic partial agonist (6-8). However, mode of action of DCI is not precisely examined.
The purpose of this paper is to compare the activities of some β-adrenergic blockers in various organs and to determine if there are different types of the β-adrenergic receptors in the organs. Furthermore, mode of action of DCI which is known as a dualist on some organs was precisely tested.

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The studies on structure and action of 3-substituted sydnonimines and their ring-opened derivatives (1, 2) indicated that hypotensive action induced by the compounds was closely related to the chemical stabilities of their sydnonimine rings and ring-opened derivatives. That is, a ring-opened derivative of 3-morpholinosydnonimine hydrochloride (SIN-1), N-nitroso-N-morpholinoaminoacetonitrile (SIN-1A), is unstable but a rapidacting and very potent vasodilator comparable to nitroglycerin. On the other hand, N-nitroso-N-cyclohexylaminoacetonitrite is stable and proved to be inactive. SIN-1 has less rapid but longer hypotensive action than SIN-1A. The former is chemically stable to acid but suffers ring-opening in alkali, leading to the formation of the latter and to the release of NO ion (3). It was also revealed that N-acylation of imino group of sydnonimine greatly increased chemical stability (4) and resulted in gradually developing and prolonged hypotensive action as well as in decreased toxicity.
This paper mainly reports hemodynamic action of N-ethoxycarbonyl-3-morpholinosydnonimine SIN-10, one of the least toxic, mild- and long-acting N-acylated sydnonimines. SIN-10 is a white, crystalline substance with a molecular weight of 242.2 and a melting point of 140 to 141°C. It is soluble in water as a 1.45% solution at room temperature and has the following structural formula.

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Harper et al. (1) and Cragg and Evans (2) showed reflex relaxation of the stomach of cats and rabbits by electrical stimulation of the central cut end of the abdominal vagus nerve. One of the present authors reported that a single shock stimulation of the central end of the abdominal vagal trunk evoked a reflex discharge which was conveyed to the abdominal vicera via the other trunk (3). The transmedullary pathways involved in this reflex may exist in the immediate superficial caudal region of the obex (4). These evidences indicate that the vagus nerve provides afferent and efferent pathways for the reflex influence on the stomach.
There is a considerable amount of literature which suggests that the efferent vagus nerve to the stomach contains both excitatory and inhibitory nerve fibres (See review of McSwiney (5)). Recently, the existence of the non-adrenergic inhibitory nerve fibres in the vagus was shown by Martinson (6, 7) in cats, and by Campbell (8) in guinea-pigs. Bülbring and Gershon (9) confirmed the presence of such inhibitory fibres in the vagal pathway to the stomach in guinea-pigs and mice, and suggested that 5-HT, with acetylcholine, may be a neurotransmitter at the ganglionic synapse in the inhibitory pathway. The aim of the present investigation is to obtain information concerning the nature of the efferent pathways participating in the vago-vagal gastric relaxation of the dog. Some of the results have already been described briefly (10-12).

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There are numerous reports concerning the effect of sympathetic nerve stimulation on gastric motility. In most of them, both excitatory and inhibitory effects are observed. Authors have emphasized that such reciprocal effects of sympathetic stimulation depended on the tonic condition of the stomach, the change of the gastric circulation, the types of stimulation, the difference of anesthetics and of types of nerve fibres. The most reasonable interpretation seems to be that the motor response to stimulation of the splanchnic or periarterial nerves is cholinergic (1-4) and the inhibitory one is adrenergic in origin (3, 5-7). However, since adrenergic motor response has also been reported (8-11), the problem is more complicated. The aim of the present experiment was to accumulate more detailed information on the causes of the contraction and relaxation of the stomach in response to stimulation of the sympathetic nerve. Recently, it has been reported that the gastric relaxation caused by vagal stimulation was non-adrenergic in origin (6, 7, 12-14). Therefore, in this paper the gastric responses to stimulation of the splanchnic and periarterial nerves and to close arterial injection of noradrenaline and isoproterenol were analysed comparatively using the autonomic blocking agents, together with the vagal gastric response serving as a control.

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The first insect moulting hormone called Ecdysone was isolated by Butenandt and Karlson (1) from the prothoracic gland of the pupa of silk worm. However, mainly due to minute supply of the compound the pharmacological study has not been made in the mammals. In 1966, Nakanishi, Takemotc et al. (2) found metamorphosing substances of the plant origin. They were closely related in chemical structure with Ecdysone. It is now possible to supply these hormones in large amounts obtained by the extractive or synthetic means. Since the demonstration by Karlson et al. (3) that the activation of certain genetic site of the insect chromosomes by Ecdysone derives from the increased synthesis of DNA-dependent RNA, the possible activation of the protein synthesis has stimulated the pharmacological studies of the hormones in the mammals. Otaka et al. (4, 5) have shown that the intraperitoneal injection of the metamorphosing plant hormone in mice activates an uptake of amino acids by the liver cells and therefore a biosynthesis of protein in the liver. However, Ecdysone itself is lacking in this effect (6). It is also reported that though long-term administration of the hormones does not affect markedly the body weight gain, some of the liver cells show a histological sign of increased metabolism (7). An activation of RNA synthesis by the metamorphosing hormones is also reported almost equipotent with that by 4-chlorotestosterone (5). By administering orally 200 to 800 μg/kg/day of Ponasterone A mixed in the diet to quail chicken. Kato et al. (8) have observed a dose-dependent activation of the molting change of feathers at the age of 17 to 20 days. In the present experiments attempts were made to observe the pharmacological effect of the metamorphosing steroids including Ponasterone A, Ecdysterone and Inokosterone in order to discuss the availability as therapeutic agent in mammals.

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A number of foreign compounds of high lipid-solubility are oxidatively metabolized to more water soluble compounds by liver microsomal hydroxylase system, called drugmetabolizing enzymes, in the presence of NADPH and oxygen (1, 2).
There are marked species differences among various animals in the activity of drugmetabolizing enzymes, and these species differences are assumed to be responsible factors for the species differences in the effect and toxicity of a variety of drugs (2-5).
Recent studies have established that a hemoprotein called P-450 (6) is involved in the monooxygenase reactions in liver microsomes as the oxygen-activating component (7-9). More recently, Imai and Sato (10), and Schenkman et al. (11) have reported that a number of drugs, substrates of hepatic microsomal monooxygenases, react with the microsomal cytochrome to give two characteristic types of spectral change. These results have suggested that the spectral changes observed are indicative of substrate interaction for enzymic hydroxylation (11) and that the magnitude of the substrate binding with cytochrome P-450 is one of important factors for the rate of the over-all hydroxylation of drugs by liver microsomes. It was therefore of interest to investigate whether the magnitude of the substrate binding with P-450 is related to the activity of hydroxylations of drugs by liver microsomes of various species of animals. In the present communication, the magnitude of the substrate binding with P-450 has been investigated in both sexes of rats, mice and rabbits.

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