Changes in the motor or functional activity of the gastro-intestinal tract are believed by some to induce a significant change in the distribution of the blood in the body, which, according to Yokota (1), results in the alternation of the portal, and consequently of systemic blood pressure (2, 3). Machida and Yamamoto (4, 5) also point out a close relation between the motor activity and the circulation of the intestine. Ueda (6) raised an objection to this view, however, by emphasizing the importance of the individual responses of the musculatures of the vessels and of the intestinal tract to drugs. Few works have been reported on the circulation of the stomach except those of Debreff (7), Minamidani (8) and Carlson (9). Our previous papers (10-13) dealt with the changes in the blood volume in the stomach wall in response to the drugs or physical stimuli. These experiments have been carried out with an aid of a photo-electric device, based on the principle that the translucency of the stomach wall should be affected by the amount of the blood present within the wall of the stomach. The work to be described in this paper was designed to solve a question that the gastric movement may modify the translucency to such an extent that the experimental results are mistakenly interpreted. The present investigation, accordingly, is directed to determine the extent of the influence of the gastric movements on the translucency of the stomach wall, and its relation to the results of previous experiment (10, 12, 15).
Previously a new type of flowmeter has been presented in this journal (1). The principle of this method is based on Poiseuille's formula indicating that the volume of blood flow is a function of the pressure difference between the two points of flowing tube. A rolling manometer system was devised to measure the above pressure difference. This method was tested, modified and confirmed that it is inexpensive, durable, sensitive and versatile (2). In the present study the blood flow through the coronary artery of the isolated perfused heart was measured continuously by using the rolling manometer. For perfusing the isolated heart a modified Heymans and Kochmann's method (3) was employed in which a donor animal supplied its own blood for perfusion.
Best and Taylor (1) quoted in their textbook, that the secretory function of the gland is regulated in two ways, one being nervous and the other hormonal. When the quick response is required, it is regulated ordinarily by the former, otherwise, however, by the latter. But there is no experimental evidence in respect to the significance of either regulations of the salivary secretion in any literature. Anatomically the salivary glands are innervated by two nervous systems, i.e., the parasympathetic and the sympathetic. Since the works of Bernard (2), and Heidenhain (3) it has been conclusively decided that the secretory nerves of the glands are cholinergic. Some questions on the mode of the sympathetic innervation of the glands yet remain to be settled. Although the salivary flow of the submaxillary or parotid gland was caused by the systemic administration of adrenaline or noradrenaline by Langley (4), Emmlin and Stromblad (5), the secretion thus obtained was less in volume except with the parotid gland of the cat. The amount of the drugs required to induce the secretion were 10 to 20 γ/kg (6). By electrical stimulation of the cervical sympathetic nerve the liberation of adrenaline-like substances in the gland was proved by Cattell (7). From these results, it is described in many textbooks of physiology that the sympathicus is also the secretory nerve of the salivary glands. While the parasympathetic saliva is serous and poor in organic substances, the sympathetic saliva is mucous and rich in organic substances. Originating from the histological studies of Stormont (8) and Rawilson (9), that the serous cell which is seen in the submaxillary and the parotid glands is innervated by the parasympathetic, and the mucous cell which is seen in the submaxillary and the sublingual glands is innervated by the sympathetic, and that the composition of the saliva secreted accords with the variety of the secretory cell stimulated and further that each cell responds to each stimuli in a characteristic histological change, Babkin (10) set up the innervating and the secretory theory of the salivary glands. Based on the studies on the potential change of the cells of the submaxillary gland during secretion Langenskiöld (11) concluded that each cell of the gland is innervated by both nerves. The most potentially supporting evidence of Babkin's theory that the sympathicus is also a secretory nerve is a so-called paralytic secretion (12) which was detected by Bernard for the first time and has been widely investigated. Although chorda denervation of the glands sensitizes the response to adrenaline and noradrenaline, the salivary secretion in response to the drugs is less in volume in comparison with the response to stimulation of the parasympathetic nerve. Moreover the physiological significance of the phenomenon still remains a question. Therefore it may be concluded that the sympathicus is also a secretory nerve of the glands. In the course of studies on the action of ganglion blocking agents upon the salivary secretion in the dog (13), the authors noticed some different effects of adrenaline and noradrenaline. Systematic studies of the mode of the sympathetic innervation of salivary glands are planned, but in this report the studies on the secretory response of the submaxillary gland will be mainly described.
Although it is generally accepted that pilocarpine affects the postganglionic cholinergic receptors and reveals a strong muscarinic action selectively, evidence has been cited to conclude that the drug affects other sites of the effector organs. Large doses of the drug do not induce a rise of blood pressure in an atropinized animal. But Dale and Laidlaw (1), Marrazi (2) and Ambache (3) concluded that pilocarpine stimulated the superior cervical ganglion in the cat, based on the experimental results that the drug potentiated the contraction of the nictitating membrane and the postganglionic electrical potential in response to preganglionic sympathetic stimulation. Feldberg et al. (4) proved that pilocarpine induced a discharge of adrenaline from the adrenals. The authors all agreed that the ganglion stimulating action of pilocarpine was abolished after the administration of atropine in large doses. The evidence that pilocarpine induced a strong pressor action on the blood pressure after the administration of such ganglion blocking agents as nicotine (5), d-tubocurarine and tetraethylammonium (6), hexamethonium, laurifoline and menisperine (7) raises the question regarding other sites of the action of pilocarpine. Another question to be investigated is raised by the evidence that in the course of recovery from the augmenting effect of pilocarpine the salivary response of the submaxillary gland to stimulation of the chorda tympani was depressed (8). Lastly, there is the problem of the innervation and the response of the sweat glands to nerve stimulation. The sweat glands are innervated by the sympathetic postganglionic fibers, but they respond not to adrenergic but to cholinergic drugs. These former three questions were studied in the present investigation to clarify the mechanism and the site of the action of pilocarpine.
In 1943 in Switzerland, A. Hofmann (1) working on the synthesis of lysergic acid diethylamide (LSD-25), a common fragment of ergot alkaloids, noticed the peculiar sensation of vertigo and restlessness. Thenceforce it was reported by Stoll et al. (1, 2), Forrer et al. (3) and Rinkel et al. (4) that a small dose of LSD caused predominantly schizophrenic symptoms that were manifested in disturbances of thought and speech, changes in behavior and mood, production of hallucinations and delusions. Gaddum et al. (5, 6) and Woolley et al. (7) demonstrated that LSD antagonized the action of serotonin which is normally present in the brain. Thus LSD has been considered as a most interesting drug in psychopharmacological studies. On the other hand, both chlorpromazine and reserpine have been used in psychiatric practice, and the therapeutic effects of these have been widely recognized. In our labolatory, Fujita et al. (8, 9) recorded the potential changes to afferent stimulation of the various parts of the central nervous system and peripheral nerves, and investigated the influence of analgesics on these potential change in order to determine the site of action of such drugs on the afferent pathways of these nerves. Takagi and Takaori (10, 11) analysed the mode of action of chlorpromazine, diethazine and promethazine on the central nervous system with the aid of various evoked potentials following stimulation of the peripheral nerves and central nervous structures, and spinal reflex discharges. Yamamoto (12) studied the site of action of Ohton on the central nervous system by means of the same method. The present investigation has been designed to determine the mode of action of LSD and reserpine on the central nervous system by means of the electrophysilogical methods mentioned above, and to trace the antagonism between LSD and chlorpromazine or reserpine.
The present report deals with the pharmacological properties of a series of quaternary tetrahydrobenzylisoquinoline, phenylethylamine and phenanthropyridine alkaloids, isolated from Magnolia and Cocculus plants by Prof. Tomita et al. (1). Marsh et al. (2) reported that some of the quaternary alkaloids isolated from the Cocculus plants showed a considerable curare-like activity. Ogiu and Morita (3) showed that magnocurarine and salicifoline, the tetrahydroisoquinoline and phenylethylamine derivatives of the alkaloids revealed potent curare-like actions on the extirpated rectus abdominis muscle of frog, which resembled to d-tubocurarine type of action. Laurifoline (4) and menisperine (5, 6), the phenanthropyridine derivatives of the alkaloids proved to have a potent ganglion blocking property.
Sedation induced by reserpine has been considered “true” sedation because anesthesia or loss of the righting reflex is never produced by reserpine even in very large doses [Berger, 1957 (1)]. Reserpine might be a serotonin liberator and its central actions are attributed to the liberated serotonin [Brodie, et al. 1957 (2)]. On the other hand, lysergic acid diethylamide (LSD), a specific psychotomimetic agent, is well known as a potent inhibitor of serotonin [Gaddum, 1953 (3)]. Actually, LSD not only blocks the reserpine-induced sedation, but also inhibits the potentiating effect of reserpine on barbiturate hypnosis in mice [Brown, 1957 (4)]. Burton (1957) (5) found that both LSD and amphetamine have a selective analeptic action on the reserpine-sedation among various kinds of agents including central stimulants or autonomic blocking agents. According to Teschler and Cerletti (1957) (6), reserpine is rather a potentiator of the central stimulatory action of LSD. Kumagai and Yui (1950) (7) reported on the general pharmacology of agroclavine and dihydroagroclavine which Abe and his collaborators (1951) (8) had newly isolated from the saprophytic culture of a certain ergot fungus. Agroclavine caused some characteristic symptoms with central excitation, while dihydroagroclavine drowsiness as a sign of central depression. Recenty, Abe (1956) (9) has obtained a lot of derivatives of ergot alkaloids, the so-called “agroclavine-type” compounds (illustrated in Table 1), by means of cultural and chemical procedures. This paper is concerned with the central action of these compounds, with special reference to their reserpine-antagonism.
Lysergic acid diethylamide (LSD), a compound derived from ergot alkaloids, produces in human subjects a characteristic mental disturbance with visual hallucinations and other psychotic symptoms in a very small dose. Studies of the effects of LSD on spontaneous cortical activity in animals have been reported by a number of investigators. Bradley and Elkes (1) reported that LSD produced rhythms not unlike those seen in the normal alert animal, i.e., low amplitude, diffuse fast (15 to 30 c/sec) activity in all regions of the brain of the conscious cats. Rinaldi and Himwich (2) studied the effects of LSD on the spontaneous cerebral activity in curarized rabbits and found that it caused a continuous “alert pattern” in small doses (10 to 15 μg/kg). Recently, Yui and Takeo (3) reported on central actions of a new series of ergot alkaloids isolated by Abe et al.. The excitor group among these alkaloids produced in various species of animals characteristic symptoms with hyperpnoea, mydriasis, increase in the spontaneous activity and anxiety which were similar to those induced by LSD, and antagonized markedly reserpine-sedation. Moreover, some of these alkaloids antagonized some action of serotonin in vitro as well as in vivo. On the other hand, in contrast to the above-mentioned alkaloids, some of their dihydro-derivatives (the inhibitor group) produced in animals a syndrome probably attributed to depression of central nervous system. From these results, it may be expected that these alkaloids produce certain electrophysiological changes of cerebral activity. The experiments were performed on agroclavine and elymoclavine as representatives of the excitor group and dihydroagroclavine and dihydroelymoclavine of the inhibitor group. This report is concerned with ; 1) the effects of these four alkaloids on the spontaneous cortical activity of curarized or non-curarized rabbit in comparison with LSD, methylamphetamine and physostigmine, 2) how these EEG-effects are modified by some central depressants.