Since Fourneau and Bovet (1) reported 2-isopropyl-5-methyl phenoxy-ethyl-diethylamine as a potent anti-histaminic, many publications on the central action of anti-histaminics have appeared during the last three decades. However, no report on the action of anti-histaminics to the neuromuscular junction has appeared, despite the fact that listlessness of the limbs occurs when a small dose of anti-histaminics is administered, as in the case of succinylcholine administration. In the present paper, the neuromuscular blocking property of several anti-histaminics was first screened, and then its mechanism of action was studied using rat phrenicdiaphragm preparation.
Recent numerous studies have indicated that uptake and storage of circulating catecholamine by tissues are important in its physiological disposition. At present, however, experimental evidence is not enough to support the view that the uptake of the circulating amine is a rate-limiting factor in synthesis and liberation of the tissue amine and consequently it controls servo-regulation of the amount of circulating amine. King and Marrazzi (1) have suggested that the depressant effect of adrenaline on the pressor response to centrifugal splanchnic nerve stimulation in the eviscerated cat is due to inhibition of transmission through the adrenal glands. Robinson and Watts (2) have shown that the secretion of adrenaline from the adrenal glands markedly decreased during the infusion of catecholamine. However, they did not discuss the decrease of the liberation or the secretion in relation to the uptake of amine by the tissues. In the present experiments the content of noradrenaline or adrenaline in tissues such as brain, heart, spleen and adrenal glands of the unanesthetized but restrained rabbits in response to continuous infusion of noradrenaline was determined chemically.
While it has clearly been demonstrated by Heymans and Heymans (1, 2) that vagovagal reflex participates in the production of bradycardia by cardiac glycosides, other investigators have reported that cardiac glycosides were capable of producing bradycardia even after administration of atropine (3) or severance of both vagus nerves (4, 5). Thus, these evidences seem to be contradictory to the results obtained by Heymans and Heymans (1, 2). On the other hand in 1939, Gold and his associates (6, 7) pointed out that two factors (vagal and extravagal) participated in the production of bradycardia by cardiac glycosides. This suggestion is convenient for the interpretation of the contradictory evidences stated above. On the extravagal factor of bradycardia, however, reports are conflicting and no complete opinion has been established. In a previous paper, Abiko (5) suggested hypothetically that the reflex route composed of the carotid sinus nerve, medulla, cervical cord, stellate ganglion, and the sympathetic fibers to the heart was an extravagal factor of bradycardia produced by cardiac glycosides. And, the hypothetical reflex pathway was supported partially by the evidence (8) that bradycardia produced by strospeside was in accord with inhibition of the efferent discharges in the pre and post-ganglionic stellate fibers in vagotomized cats. The present study was also designed to test the possibility of the sympathetic portion of the hypothetical reflex pathway as one of the extravagal factors of bradycardia produced by cardiac glycosides. The present experiments were conducted on the basis of the following expectation: “If the extravagal mechanism of bradycardia by cardiac glycosides is really concerned with sympathetic cardiac nerves, bradycardia by cardiac glycosides may be prevented by blocking the neuro-muscular transmission at the site of adrenergic receptor of the heart in vagotomized animals.” For this purpose, dichloroisoproterenol (DCI) (9-12) was used as the beta-type adrenergic blocking agent in this experiments. Strospeside was used as a cardiac glycoside because of its high potency to produce bradycardia.
The experimental atheromatosis in various animals fed on high-fat, high-cholesterol diet has widely been used for the elucidation of the pathogenesis of clinical arteriosclerosis and for the laboratory evalution of lipolytic agents. Page et al. (1) and Myasnikov (2) have shown that rabbits are highly susceptive to the exogenously administered cholesterol, while rats are relatively resistant to the effect of cholesterol feedings. For the sake of producing the increased level of serum cholesterol and the aortic atheromatosis in rats, the feeding of the animal on high-cholesterol diet mixed with cholic acid or taurocholic acid has been recommended (1, 3, 4). In comparative studies on the effects of lipolytic agents in rabbits, rats and chicken, Loustalot et al. (5) have emphasized that it is impossible to generalize a conclusion from experimental results of lipolytic agents obtained in one species. In the course of a series of studies on the hypolipemic effects of thyroxine derivatives in rats and rabbits fed on high-cholesterol diet, the authors have noticed marked differences of serum and liver cholesterol levels between both species. These differences are likely to give an important clue to know the cholesterol metabolism and also the mode of action of lipolytic agents in both species.
In the previous paper (1) the effects of the adrenolytics on the transmembrane potential of the extirpated rabbit's heart were reported. The adrenolytics exerted depressive effects on the action potential, i.e. decrease in the rate, prolongation of the de- and re- polarization phases and depression of the amplitude with subsequent complete abolition of the atrial non-pacemaker potential. The resting potential was slightly decreased. However, the pacemaker potential, though it was slightly or moderately depressed, continued to fire rhythmically. In this condition addition of adrenaline or noradrenaline in the concentration which exerted a positive inotropic effect on the intact heart restarted the potential rhythm. However, the recovery of the transmembrane potential was transient and incomplete even by addition of higher concentration of either amine. Physiological role of noradrenaline in the heart (2-5) on the spontaneous automaticity of the atrium has not been hitherto fully elucidated. Though the effects of the adrenolytics on the transmembrane potential of the heart may relate with the adrenergic mechanism, Matsuo et al. (6) have shown the increase of noradrenaline in the rabbit's heart in response to the intravenous injection of dibenamine (10 mg/kg) but not to the same procedure of yohimbine (5 mg/kg) or chlorpromazine (5 mg/kg). The biphasic responses of the heart to acetylcholine have been observed by several authors (7-14). The restarting effect of acetylcholine on the atrial preparation in which rhythmical contraction had been abolished by quinidine, eserine and paludrine (12, 13) and by the lowering of environmental temperature (14) has been reported. The present investigation has been attempted to elucidate the mechanism of the standstill of the atrial transmembrane potential induced by the adrenolytics by studying the restarting and recovering effects of adrenaline, noradrenaline and acetylcholine in the isolated atrium of rabbit which had been pretreated with reserpine. It has been also expected to explain the mode of action of the endogenous catecholamine and acetylcholine on the atrial non-pacemaker potential.
The main pharmacological effects of methamphetamine are the psychomotor stimulation and the sympathomimetic effects on the peripheral adrenergic structures. There is evidence which indicates the facilitatory action of amphetamine on the synaptic transmission (1). By increasing the dose of amphetamine the inhibitory action and the reversal of facilitation have been demonstrated in the synaptic transmission of severalparts of the central nervous system (2). It has been emphasized by many authors that the central actions of various sympathomimetic amines probably are not related to their peripheral sympathomimetic actions. It is possible that methamphetamine acts on the adrenergic system directly, and indirectly through interference with the metabolism of endogenous catecholamine or through liberation of the latter from local sites of storage. Analyzing the dose-response curves of the normal, the denervated, the cocainized and the reserpinized nictitating membrane of cat, Burn and Rand (3) have classified the sympathomimetic amines into following two groups, i.e. the sympatomimetic amines with direct action, and those with indirect action. They have shown that amphetamine exerts its adrenergic effects indirectly through liberation of noradrenaline from the target organs. The liberation of noradrenaline from the central nervous system as well as the peripheral adrenergic structures has been confirmed biochemically by several investigators. This experiment was designed to study whether the systemic administration of methamaphetamine depletes noradrenaline in the central nervous system of rabbits to the same extent that it does in the autonomic structures such as heart, adrenal glands. Further, the effects of the repetition of the injection on the level of noradrenaline or adrenaline in these structures were studied since the repetitive administration of the drug is known to produce tachyphylaxis in the autonomic structures.
In the previous report (1), the authors showed that the brain noradrenaline level in rat was induced to elevation, in the state of electric shock, compared with that in non-treated animals. On the other hand, pretreatment with some tranquil lizing agents, chlorpromazine, azacyclonol inhibited the increase of noradrenaline level in shocked state, while, chlordiazepoxide had no effect on noradrenaline level. In addition to the previous paper, other tranquillizing agents, tetrabenazine, thioridazine and cyproheptazine were employed in this experiment in order to examine their effect on both noradrenaline and dopamine levels of rat brain in abnormal environment, i.e., electrically shocked state.
The thermal change in the hypothalamus, the thermoregulatory center, of the experimental animals has been usually measured by use of a thermocouple or a needleformed thermistor inserted through the skull and the brain parenchyma. However, these procedures may be unsuitable for a longterm, observation of the body temperature because the insertion of the thermodes causes considerably widespread damage of the brain tissues, particularly the hypothalamus. Recording the intracardiac, rectal and muscular temperatures of the rabbit by means of the thermistor equipped on the apex of the venous catheter or of the metal-needle, Yasuda (1-3) of this laboratory has reported the influence of various pyrogenic substances on the temperature. Using the same technique, Takashima (4) has compared the effects of pyrogenic substances in the intact and the liver-damaged rabbits. There exist some reports on the tympanic membrane temperature. Benzinger (5) has chosen the tympanic membrane of a human for the measurement of internal body temperature as close as feasible to the hypothalamic heat center. He has introduced 36-gauge twin wires of copper and constantan into the external auditory canal and has placed the thermoelectric junction of the wires at the tympanic membrane. But little work has been done to study the correlation between the brain temperature and the tympanic membrane temperature. The present experiments have been designed to determine whether the tympanic membrane temperature changes in parallel with the hypothalamic temperature or not. In these experiments a decline of the tympanic membrane and brain temperatures was produced by cooling the common carotid arteries or by the administration of some hypothermic agents. An elevation of the temperature was produced by the carotid warming or by the administration of pyrogenic substances. Moreover, the influences of the carotid cooling and warming on behaviors, respiration, blood pressure and heart rate were studied.
During the experiments observing the drug effects on the steady potential of various brain structures, the authors (1) found that the steady potentials of certain subcortical structures such as the hypothalamus and hippocampus were more sensitively altered by psychopharmacological agents than the EEG activity in the same areas. Although many attempts (2-4) have been made to explain the steady potential, its physiological significance has been still unknown. The authors have been interested in this electrical phenomenon from their belief that changes in the steady potential would indicate the CNS activity in some different way from EEG changes. In order to elucidate the correlation between a steady potential and EEG in the various states of activity of the brain, the more primitive brain structure seemed desirable to persue. The authors thus selected the olfactory bulb, because this structure showed a distinct afferent activity in response to olfactory stimulation and its excitatory as well as inhibitory states could be easily demonstrated. Ottoson (5, 6) has observed a slow potential elicited by odoriferous stimulation in the olfactory epithelium as well as in the olfactory bulb. Ottoson's slow potential is regarded as a DC potential change in this structure. The present study was conducted to ascertain the effects of drugs on the DC potential, slow potential and EEG activity of the olfactory bulb, in the hope of elucidating if any mutual correlations of these electrical phenomena exist.
It has been shown that tetrabenazine depletes the brain serotonin and noradrenaline (1, 2). The action of tetrabenazine resembles that of reserpine but differs from it in certain important respects. Tetrabenazine depletes the brain noradrenaline more than brain serotonin, having little effect peripherally (2). Although Mathis et al. (3) and Bente (4) reported on the electroencephalographic studies of tetrabenazine in man, more precise electrophysiological analysis on the site of action of tetrabenazine remains to be investigated. The present investigation was designed to determine the site and mode of action of tetrabenazine on the central nervous system by means of the electrophysiological methods.