Following the study of antiarrhythmic action of chlorpromazine by Arora and Madan (1, 2), Courvoisier et al. (3) and Burn (4), several others phenothiazine derivatives have been found to possess arrhythmia combating properties (1-10). The correlation of chemical structure with antiarrhythmic activity among phenothiazine derivatives has been studied by Sato et al. (9), and Singh and Sharma (10). In the present study, 10-N substituted phenothiazines have been examined in ventricular ectopic tachycardia and an attempt has been made to find the essential structural features responsible for antiarrhythmic activity.
Isoxsuprine, a vasodilator agent, 2-(3 phenoxy-2 propylamino)-1-(p-hydroxyphenyl)-1-propanol hydrochloride, was synthesized by Moed and Van Dijk in 1956 (1) and has a β-stimulatory and adrenolytic action and a papaverine-like or a direct action as reported by Brücke et al. (2) and Ariëns and Simonis (3). Lish et al. (4, 5) attributed a relaxing activity of the drug to the adrenergic β-stimulatory action in some tissues and the direct action in other tissues when different kinds of non-vascular smooth muscle were used. However, Drinnon and Yelnosky (6) and Manley and Lawson (7) reported that the vasodilator action of isoxsuprine was attributable mainly to the direct action of the drug. Preliminary observations showed atrial biphasic responses—initial stimulatory and then inhibitory responses—to a relatively high dose of isoxsuprine. This study was undertaken to investigate in details a mechanism of atrial biphasic responses to the drug in the rabbit and guinea pig.
Effects of the sydnonimine derivatives on cardiovascular system have been studied (1-5), and the results in our laboratory are summarized as follows: 1) the substitution by the group containing nitrogen with —N—N—linkage in the 3-position (SIN-series) showed vasodilator and consequently hypotensive effects resembling to those of nitrites, and 2) N-acylation of imino group of sydnonimine made the compounds stable chemically (6), which probably resulted in gradual development and prolongation of the hypotensive effects as well as in decreased toxicity (4). These findings prompted us to study the effects of the derivatives on coronary collateral circulation, because nitroglycerin, the most important antianginal agent, was reported to dilate the collateral vessels which developed as a result of chronic myocardial ischem:ia (7, 8), and because the effects of agents on the collateral circulation have received considerable attention as one of the approaches to evaluate antianginal activity in laboratory experiment (9). The present study was carried out to investigate the effects of N-ethoxycarbonyl-3-morpholinosydnonimine (SIN-10) and related compounds on the coronary collateral circulation.
In previous papers (1, 2), it has been reported that in male rats the administration of morphine and also starvation caused a marked decrease in the activities of drug-metabolizing enzymes of liver microsomes for hexobarbital hydroxylation and aminopyrine N-demethylation, but this was not the case in female rats. On the other hand, the activities of drugmetabolizing enzymes for aniline hydroxylation and zoxazolamine hydroxylation were not significantly altered in both sexes or even increased by the same treatments. The castration of male rats markedly decreased the activities of hexobarbital hydroxylation and aminopyrine N-demethylation, while the activities were not altered by the castration of female rats (1, 2). The administration of methyltestosterone to the castrated male and female rats increased the activities of hexobarbital hydroxylation and aminopyrine N-demethylation in liver microsomes and these activities again decreased by the administration of morphine and by starvation in the androgen-treated rats (1, 2). These results indicate that both morphine and starvation decrease the activities of drug-metabolizing enzymes which are stimulated by androgens, probably through the impairment of an androgen-dependent stimulating mechanism (1-4). Recent studies have established that an unique hemoprotein clled P-450 (5) is involved as the oxygen activating component in a number of NADPH-dependent monooxygenase reactions, such as hydroxylations of drugs and steroid hormones (6-10). Imai and Sato (11) and Schenkman et al. (12) have recently reported that a number of drugs, substrates of hepatic microsomal hydroxylases, react with the microsomal cytochrome to give two characteristic types of spectral change. These results suggest that the spectral changes observed are indicative of substrate interaction with cytochrome P-450 presumably representing the primary binding of substrate for enzymic hydroxylation (13, 14). Moreover, Schenkman et al. (15) demonstrated that the magnitude of the hexobarbital-induced spectral change was greater in liver microsomes isolated from male rats than in those from female rats and castration of male rats abolished this sex difference. These observations suggested that the sex difference in the hydroxylation of hexobarbital may be due to the difference in the substrate interaction with P-450. The purpose of the present communication is to investigate whether the decrease in the hexobarbital hydroxylation and aminopyrine N-demethylation in liver microsomes from morphine-treated and fasted male rats is related to an impairment of androgeninduced stimulation of the substrate-P-450 interaction.
Early works by Augustinsson (1-4) demonstrated that three types of esterases exist in vertebrate plasma in regard to substrate specificity and susceptibility to selective inhibitors, and he classified them into arylesterases [EC 3. 1. 1. 2], aliesterases (carboxylesterases) [EC 18.104.22.168] and cholinesterases [EC 22.214.171.124]. However, physiological and clinical significance that the altered activities of these esterases imply is still obscure. Recently, Takahashi et al. (5) suggested that decrease in the activity of phenyl acetate esterase (corresponding to arylesterases, according to the Augustinsson's classification) was correlated with the degree of liver damage and that, clinically, the activity of the enzyme in serum decreased greatly in the case of liver cirrhosis. In the present paper, changes in the total activity and the electrophoretic pattern of arylesterases were studied in CCl4-induced mouse liver injury using β-naphthyl acetate as substrate.
The rhizoma of Alisma Plantago-aquatica L. var. orientate Samuels used as a component of various preparations of Chinese medicine has long been accepted to have a diuretic effect. The availability of this plant as a pulver in the preparations is a good contrast concerning the presence of practically water insoluble triterpenes to many of the raw plants usually used as a decoctum. Several years ago the extract of this plant with organic solvents was demonstrated to exert a lipotropic effect, which was somewhat different in mode of action from those of other lipotropic agents (1), Further chemical studies on this extract succeeded to isolate the active triterpenes including alisol A-24-monoacetate (ALMA) and its related compounds (2, 3). The present paper describes mainly the hypocholesterolemic activity in the rats maintained on an atherogenic diet.
In the previous report (1) from our laboratory, a series of dithiocarbamate derivatives have been demonstrated to have a potent protective effect against experimental hepatic injury induced by carbon tetrachloride (CCl4) in rats, and relationship between the chemical structures and their biologically activity has been described with respect to plasma transaminase levels. In this paper, with the purpose of investigating the action mechanism of these dithiocarbamate compounds, sodium taurine N-carbodithioate (TDT) was chosen as a typical dithiocarbamate, and correlations between the hepatoprotective effect of this compound and its administration route, dose, and time were studied in terms of plasma transaminase levels (p-GPT and p-GOT) and microscopical findings of liver cells. In addition, influences of this compound, when administered to rats before or after CCl4 poisoning, on the developmental or recovery processes of the hepatic injury, were also studied, employing p-GPT levels, liver lipid contents, and histological findings as indices to evaluate the degree of the liver lesions.
Since all of the so-called “major tranquilizers” have the ability to induce catatonic states in experimental animals, this characteristic pharmacological property is commonly being used as a clue to detecting new compounds in screening tests. However, not all compounds that produce the catalepsy in animals are “tranquilizers”. One remarkable example is bulbocapnine, an alkaloid isolated from Corydalis cava; it was first reported by Peters (1) that a catatonic state in mammals followed bulbocapnine treatment. Although it has been suggested that bulbocapnine catalepsy could serve as an experimental model for schizophrenia or Parkinson's disease, little is known of its effects on the neural components of the motor system. In earlier experiments we found that bulbocapnine selectively depressed the spinal monosynaptic reflex response in the rat with little effect on the polysynaptic neuronal systems (2). These observations have subsequently been confirmed by Willis et al. (3, 4) in the cat. The present report describes a further investigation of the actions of bulbocapnine on spinal reflex systems. The rat was employed in the present experiments so that the electrophysiological data could be accurately compared with the numerous behavioral observations in this species.
Pradhan et al. (1-3) carried out pharmacological and clinical studies on hayatin methiodide from Cissampelos pareira for its muscle relaxant properties. In the present paper the curariform actions of hayatinin methochloride (Fig. 1), the other structurally similar alkaloid from the same plant are being reported.
Sydnonimine derivatives, a series of mesoionic compounds, have a peculiar feature in their molecular structure and biological activities. The smooth muscle relaxing action of the compounds has been reported on the rat duodenum and the guinea-pig ileum by Oehme et al. (1) and hypotensive effect by Daeniker and Druey (2). Recently, 3-substituted sydnonimines were newly synthetized (3) and were found to have potent vasodepressor activities (4, 5). Of these compounds, a derivative, whose imino radical at 5 position was acylated with ethoxycarbonyl group to make N-ethoxycarbonyl-3-morpholinosydnonimine (SIN-10), became more stable and was reported to produce a potent and persistent hypotension in anesthetized dogs and rabbits (4, 5). The present study deals with the effects of SIN-10 on cardiovascular system and the analysis of mechanism of action involved in hypotensive effect of the drug in anesthetized dogs and cats.
Administration of 4-nitroquinoline 1-oxide has been known to produce pulmonary tumors in rodents (1-3). An electron microscopic examination on the lung of rats shortly after an injection of this compound revealed induction of nucleolar segregation in the alveolar epithelial cells (4). In this experiment, it was further shown that an injection of 4-nitroquinoline 1-oxide could produce pulmonary edema in rats as well as in guineapigs and rabbits.
The interaction of a drug with a specific site of tissue cells, i.e. drug receptor, is generally assumed for explaining the mode of action of some drugs, but very little is known on its substantial existence and further on its chemical natures. The best method available for solving this problem is specific alkylation of the receptor with a labeled β-haloethylamine in combination with an antagonist or agonist. Testing the parallelism between incorporated radioactivity and pharmacological phenomena, rather specific labeling of drug receptors can be expected. The point on which emphasis was laid in this study was to distinguish the pharmacological blocking effect of dibenamine from its chemical alkylating ability. All the amount of radioactivity found in the tissue is not limited to dibenamine concerned in the pharmacological blocking action. During this study (1-4) several papers were published on specific labeling of α-adrenergic receptor in various tissues with labeled β-haloethylamines utilizing simultaneously an antagonist and/or an agonist (5-10). In these reports, however, the correlation between the incorporated radioactivity and the pharmacological effect of a β-haloethylamine was not sufficiently confirmed. To avoid these weak points following experimental designs were chosen. 1. Three kinds of pharmacologic protective drugs were used. 2. Three kinds of pharmacologically non-protective drugs were also employed in the same manner as the protective drugs. 3. Six kinds of tissues with different histamine sensitivities were treated in the same way as the cat small intestine. These principles will testify the assumption that the receptor is specifically labeled with dibenamine.
For many years there has been an extensive search for agents as effective as morphine in the relief of pain yet free from the hazard of addiction. Until recently it had appeared that this search would be fruitless. Authors have investigated acetylpiperazine derivatives, and found that 1, 4-bis (2-methoxy-4-propylphenoxyacetyl) piperazine had an analgesic activity without narcotic action (1). This drug, however, does not have good solubility in water and cannot be absorbed from the intestine easily. Thus, this drug appeared to have less analgesic potency when administered orally. In order to overcome this disadvantage, we have carried out further investigations on many other piperazines and found that 1-butyryl-4-cinnamylpiperazine hydrochloride (hereafter referred to as AP-237) had high analgesic potency (2) and good solubility in water. This paper describes the results of more detailed studies on the analgesic effects of AP-237.
In 1958, Powell and Slater (1) first described that DCI had beta-adrenergic blocking activity even though it included beta-adrenergic stimulations. Such property was found also in methoxamine besides its alpha-adrenergic stimulant activity (2, 3). In the following decade, many beta-adrenergic blocking agents have been synthesized successively (4-8) and one of them, propranolol was first introduced in the clinical medicine. Since Ahlquist classified alpha and beta-adrenergic receptors, it has been well established that positive chronotropic and inotropic effects and vaso and broncho-dilator actions of catecholamines are mediated through an interaction between drug and beta-receptor. However, it is not gotten clear, whether all beta-adrenergic blocking agents would have the same potency to block beta-adrenergic receptor in different organs. In many experiments, the blockade of the positive chronotropic response to catecholamines has been chosen in order to evaluate the potency of beta-adrenergic blocking agents. Excised preparation of atria (3, 9) and also whole animals (5, 7) were used, while drug was added in the bath or given intravenously. James and Nadeau (10) examined the effect of DCI on the sinoatrial pacemaker activity when it was given selectively into the sinus node artery. In this paper we compared the effect of beta-adrenergic blocking activity of DCI (1), methoxamine (2), propranolol (4), MJ 1999 (5), H 56/28 (6), LB 46 (7) and I.C.I. 50 172 (8) selectively administered into the sinus node artery, while isoprenaline was used as an agonist.