In the recent past, evidence has accumulated that there is an interesting but obscure relationship between genesis of mast cells and functions of thymus (1). In the present work, the effects of removal and direct antigenic stimulation of thymus on tissue histamine and mast cell contents in various tissues were studied on albino rats. In view of the existence of blood-thymus barrier as postulated by Nossal and Mitchell (2), injections of antigen were given directly into the substance of the gland.
Since bilateral ablations of the olfactory bulb were found to induce characteristic hyperemotionality in the rat (1-5), this behavior, particularly aggressiveness, has come to be used for evaluating the taming effect of tranquilizing agents, though the neural mechanisms underlying this abnormal behavior have remained unknown (6). It would be worthwhile to know the changes in drug sensitivity of such abnormal animals, even from the ceinical point of view, and the effects of psychotropic drugs are known to be different qualitatively, as well as quantitatively, depending on the disease. Studies concerning the changes in drug sensitivity in abnormal animals with such brain lesions have so far been few (7-11). Recently, Malick et al. (12) compared the efffects of psychoactive agents on three models of aggression induced by lesioning of the septum, the ventromedial hypothalamus and the olfactory bulb in rats, and found significant differences in potencies of these drugs among these models with lesions in different brain areas. Questions may arise as to whether or not these potency differences are also relevant to effects other than anti-aggressive action, and as to whether the drug sensitivities of these models are different from that of intact animals, as aggressiveness is rarely observed in normal laboratory rats. This investigation was therefore undertaken to determine changes, if any, in sentisivity to electroshock- and drug-induced convulsions in mice with bilateral olfactory bulb ablations, since convulsions could be measured quantitatively and compared between the intact and abnormal animals with brain lesions.
Lyoniol-A is a toxic component isolated from a poisonous tree in Japan (Lyonia ovalifolia var. elliptica). In our previous studies, it was shown in experimental animals that injection of lyoniol-A caused postures characterized by torsion, retrocollis, spasm and locomotive ataxia (1), and moreover it was suggested in the evoked electromyographic (EMG) study (2) that the sites of action involved the supraspinal and spinal structures. One of the interesting properties of lyoniol-A is that it causes remarkable locomotive ataxia. It was found in rabbits that administration of lyoniol-A for about 15 days caused a histological degeneration in certain nuclei of the extrapyramidal system (3). Since extrapyramidal nuclei are closely related to gamma-system, the effect of lyoniol-A on the intercollicular decerebrate rigidity mainly due to hyperactivity of gamma-efferent outflow from the brain (4) was examined. For comparison with lyoniol-A effects of chlorpromazine which markedly abolished the rigidity of this type (5), mephenesin (6, 7) and strychnine were studied. While analyzing the action of lyoniol-A in electroencephalographic (EEG) study, the compound was found to accelerate the arousal pattern in the motor cortex of curarized rats. For this reason, the effects of lyoniol-A on the cortical and subcortical EEG patterns in the encephale isole and cerveau isolé rats were examined. The stereochemical structure of lyoniol-A has been established (8) (Fig. 1).
3-Acetoxy-2, 3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one hydrochloride is a now compound having a strong coronary vasodilator activity (1). Its vasodilator action on the coronary as well as femoral artery was found to be stereospecific for the d-cis-isomer (CRD-401). It is inferred that the new 1, 5-benzothiazepine derivative and its stereoisomers exert their effects by acting directly on the blood vessels (2). In the present study, the effects of d-, dl- and l-cis-isomers of the compound were investigated on the isolated smooth muscle of guinea pig. The general pharmacological properties of these compounds were also studied in various experimental animals.
The question whether or not biotransformation of two drugs, especially hydroxylation, is catalyzed by one “drug-metabolizing enzyme” (1) inevitably arises when one considers possible changes in the effects due to metabolic modification by simultaneous administration of several drugs. Recently, evidence has accumulated toward the view that multiple oxidative enzymes are present in hepatic microsomes (2-9). It was found in our laboratory (10) that a wide difference exists in the magnitude of induction of hepatic activities between aniline hydroxylation (aryl 4-hydroxylase, EC 22.214.171.124) and p-nitrotoluene hydroxylation (EC126.96.36.199) when rats are pretreated with phenobarbital. This observation led us to speculate that the two compounds of closely related structures are hydroxylated by different enzymes. Although an exact comparison waits further progress in solubilization of hepatic microsomes (11, 12), an attempt is made in the present study to justify our hypothesis by comparative studies on hepatic activities between sexes and species of rodents as well as on the effects of inducers and inhibitors on the kinetics of the two hydroxylation activities.
The pharmacology of bradykinin has enticed investigators to prove the involvement of the kinin system in various pathological states, including protozoan diseases. In Plasmodium knowlesi malaria of rhesus monkeys, the significance of the kinin system was reported by British investigators, who showed that plasma kininogen of the infected primates was almost depleted near death, in spite of failure of the detection of free kinin in the plasma (1, 2). In addition, the increase of kallikrein contents and kininase activity in plasma were also reported in the infected monkeys (2, 3). On the other hand, Urbanitz, et al. claimed that the reduced concentration of plasma kininogen did not mean directly the involvement of the kinin system in various types of shock, because the reduction of plasma kininogen levels was simultaneously accompanied with the reduction of plasma protein concentration in shocks (4, 5). As it is known that plasma protein concentration decreases gradually with the increased degree of parasitaemia in the monkey n malaria (6), the apparent reduction of plasma kininogen in the infection mentioned above may be one of the features of the general prostration without true consumption of kininogen and release of kinin. Therefore, the reduction of kininogen in malaria must be re-examined in these respects. The present paper reports, in the severe cases of mice infected with Plasmodium berghei (NK 65), the success of the detection of free kinin in venous blood and the real consumption of plasma kininogen. The latter finding was supported by the reduction of the concentration expressed in μg/mg protein or globulin. Its pathophysiological significance is also discussed.
It is now generally agreed that Ca ion is essential for the contraction of smooth muscle. On the role of Ca ion in the contraction cycle of smooth muscle, many electrophysiological studies have suggested that the action potential of the muscle cell is associated with an inward movement of Ca ions from anionic sites of cell membrane or from extracellular space and this Ca flow may initiate contractile response (1, 2). It has also been suggested from radioisotope studies (3-6) that contraction in smooth muscle may be triggered and maintained by release of cellular Ca and/or by influx of extracelluar Ca. Although Ca ions activating contractile protein of smooth muscle are said to be inactivated and stored in the cell until expelled (7), the mechanism is still obscure. In previous experiments, tissue Ca of taenia coli was tentatively divided into two fractions; a fraction which exchanges within 4 min and another fraction which is exchangeable but does not exchange within 4 min, the latter more slowly exchangeable fraction was named as “tightly bound fraction”(TBF) (4). The size of TBF increased during tonic contraction induced by carbachol, pilocarpine (3), histamine (4), barium (5) and 40 mM potassium (5, 6), and decreased during abolition of tension by specific antagonists oft he stimulants (3, 4), metabolic inhibiting factors and factors inhibiting active Na transport (8, 9). from these data., it was suggested that the increase in the size of TBF, i.e., a shift of cellular Ca to a more slowly exchangeable fraction, could be related to contraction of smooth muscle, and the movement of Ca related to metabolism. In the experiment reported here, the effect of external phosphate on the slowly exchanging Ca fraction, the change in the fraction in the course of muscle contraction and relaxation and exchange kinetics of the fraction were studied to clarify the nature of the shift of cellular Ca to a more slowly exchanging fraction in smooth muscle of taenia coil and the role of this Ca movement in excitation-contraction coupling in smooth muscle.
The clinical utility of proteolytic enzymes is reported as anti-inflammatory agent in literature (1-3) on the therapy for traumatic or infectious diseases. The anti-inflammatory action is considered to be effectual even with oral administration. Such being the case, gastrointestinal absorption of the enzymes is essential. Qualitative evidence of the gastrointestinal absorption of small amounts of proteins has been reported by a number of workers. Schloss et al. (4-6) employed a qualitative precipitin reaction and an indirect anaphylaxis test to demonstrate that ingested proteins were absorbed from the gastrointestinal tract, and additional studies involving complement fixation methods7) and passive transfer tests8) were also performed to demonstrate the absorption of intact proteins. Lamanna9) studied the gastrointestinal absorption of botulin given rats orally in connection with its toxic reaction. Quantitative absorption studies on bromelain were made by Smyth et al.10) in details with the use of I131-labelled bromelain, but questions remain as to their findings: 1) the maximum absorption level in the blood was as high as 6.3% absorption of the administered dose; 2) no radioactivity was detected of the low molecular I131-tagged substances in the circulation; and (3) excretion of the absorbed I131-bromelain was to the extent of 26% of the administered radio-activity in 4 hr. This communication is primarily concerned with the anti-inflammatory effect of orally administered bromelain, and also deals with the gastrointestinal absorption of bromelain determined by a radioisotope iodine-125 tracer method in combination with immunological techniques of precipitin and Ouchterlony, gel filtration, and electrofocusing.
It is known that mercury derivatives are transported into eggs developing in the reproductive organs of birds (1-12). An egg consists of three components; yolk which develops in the ovary, albumen and shell which are secreted from the site of magnum and the site of uterus of the oviduct, respectively (13). It is known also that alkoxy mercury derivatives (9, 10) and inorganic mercury (10, 12) are transported mostly into egg yolk, and alkyl mercury compounds into egg albumen (1, 3, 5, 6, 10) and shell (1). The difference in the mode of the transportation may be due to the difference in chemical form among these mercurials (9, 12). On the other hand, the onset of laying in domestic fowls is accompanied by changes in the majority of the plasma components (13-30). Similar changes in the plasma were induced in immature pullets, nonlaying hens, cockerels, and other birds by treatment with estrogens (20, 23, 30-52). Large quantities of phospholipids and phosphoprotein in the serum of the laying hen are synthesized in the liver in response to estrogens (20, 49, 52), and the phospholipids and the phosphoprotein are transported and accumulated into ovarian follicles (20). Rissanen and Mietinen reported that inorganic mercury or alkoxy mercury derivatives possibly bound to the yolk proteins (9). These forms of mercurials would be transported into ovarian follicles via the circurating blood plasma in a yolk-protein bound form. There is a possibility that retention of mercury in birds may be controlled by treatment with estrogens. In this paper, the effect of estrogenization on distribution of radiomercury is compared between male and immature female quail and laying quail, and interrelationship among all the four entities, i.e., laying plsama, estrogens, plasma radiomercury, and yolk radiomercury, is discussed.
It is well known that physical stress such as electroshock, exercise, immobilization, cold exposure, etc., produce significant alterations of catecholamine (CA) metabolism in the brain and adrenal medulla. The findings vary however with different types and intensities of stress used. Some investigators have reported the depletion of brain norepinephrine (NE) by cold exposure or electroshock (1, 2). Others have reported the elevation of brain NE by repeated electroshock, restraint, or cold exposure (3-5). Gordon et al. (6) observed an appreciable decrease in adrenal epinephrine (EP) despite little change in brain NE level by exercise. On the other hand, Fujiwara and Mori (7) found that tetrabenazine and reserpine worsened stress-induced ulcers and that a MAO inhibitor prevented ulcers. This finding suggests that stress-induced ulcers correlate with an alteration in the central endogenous amines. It has also been found that chlorpromazine (CPZ) and imipramine have preventive effects on stress-induced ulcers (8-10), however effects of these drugs on CA metabolism under particular conditions have been little investigated. The purpose of the present study was to examine the change of CA levels in the brain and adrenal medulla of rats subjected to stress producing peptic ulcers, and also the effects of psychotropic drugs on CA levels in the state.
A previous work (1) has shown that an individual propagated impulse recorded at the sensory nerve terminal of the frog muscle spindle was always followed by a long-lasting positivity of up to 0.1 sec in duration and of 0.1-0.3 mV in the maximal amplitude, during which the appearance of propagated and abortive spikes was suppressed. Time course of the positive after-potential was similar to that of the after-hyperpolarization following spike discharge of amphibian motoneuron, during which excitatory processes were depressed (2). Matthews (3) has suggested that similarity in the electrical responses of the motoneuron and the sensory ending may result from similar properties of polarized surfaces. Objectives of the present experiments are to determine whether or not the positive afterpotential is selectively modulated by certain ions or drugs and to clarify the root of the selective modification from the effects of the drugs on the sensory terminal.
Oxidative dealkylation is an important step in the metabolism of various foreign compounds including a number of clinically useful drugs (1). Studies to establish a comparison between aromatic hydroxylation of aniline and side chain hydroxylation at methyl moiety of p-nitrotoluene (2) are further extended in the present report to other types of microsomal oxidative reactions, i.e., N- and O-demethylation, the two possible variations of hydroxylation (1).
The action of the antibiotics on the uterus has been mainly investigated to determine the degree of their efficacy in the treatment of the local infections, with little attention to the possibility of their eventual interference with the uterus tone and motility. On the other hand, it is well known that the antibiotics can interfere with the smooth muscle of the extra-hepatic biliary tract (1, 2), the extra-renal urinary tract (3), the bronchial tract (4) and the intestinal tract (5-9). Concerning the influence of some antibiotics on uterine motor activity, Popovici et al. (10) found in the guinea-pig that Erythromycin, Streptomycin, Chlortetracycline, and Chloramphenicol had a stimulating action. While with Erythromycin only this effect was seen, independent of the dose used. Inhibitory action, in larger doses, constantly appears after use of Streptomycin and very seldom after Chlortetracycline and Chloramphenicol. The mechanism producing these effects is different in pregnant and non-pregnant states. In the present paper the action of Gentamicin, Aminosidin and Ampicillin on the uterine tone and motility of guinea-pig and dog, both in vitro and in situ, is described.