The adjuvant arthritic rat (AAR) and experimental allergic encephalomyelitic rat (EAE) are models for studying inflammatory reactions triggered by immunologic processes (1-3). In the AAR the disease manifests itself in a systemic inflammation which can be evaluated by measuring the swelling of the hind paws. In the EAE the inflammation encompasses the myelin sheath which results in hind limb paralysis. Although there are similarities between these two models, the response varies according to the classes of drugs. Anti-inflammatory drugs, both steroidal and nonsteroidal as well as immunosuppressants are active in the AAR while only steroids and immunosuppressants are active in the EAE (4, 5). Clonixin* [2-(2'-methyl-3'-chloroanilino)nicotinic acid] is a nonsteroid anti-inflammatory agent with analgesic and antipyretic properties (6-8) and prevents inflammation in AAR when rats are treated either prophylactically or therapeutically. The demonstrable antiinflammatory activity of clonixin raised the possibility that it might also be effective in EAE. The aim of this study was to more fully evaluate the activity of clonixin in the AAR and to compare same with the effects observed in the EAE. Betamethasone, a steroidal antiinflammatory agent, was included in this study for comparative purposes.
Clonixin (Sch 10304) [2-(2' methyl-3' chloro anilino) nicotinic acid] has been reported to be an orally effective analgesic and a non-steroidal anti-inflammatory agent in rodents (1). Clonixin has no dependence liability in monkeys (2) and its analgesic effect is not antagonized by naloxone in mice and rats (3). Clinical results with clonixin have shown degrees of analgesic effects not usually observed with non-narcotic agents. Single oral doses of clonixin ranging from 300-600 mg produced pain relief comparable to that seen with parenteral administration of morphine (4). Procedures employing electric shock in monkeys have been used by other investigators for analgesic assessment (5-7). Thus far, only narcotic and narcotic antagonist analgesics have been shown to be effective in this procedure. This investigation describes the analgesic properties of clonixin on behavior maintained by nociceptive electric shock in Rhesus monkeys (Macaca mulatta) using a shock-escape procedure.
Long exposure to morphine or its surrogates to humans inevitably results in an intoxicated state which is characterized by two types of morbid phenomena, tolerance and dependence. This state is fully or partially reproducible in some species of laboratory mammals and forms a basis to explore the mechanisms underlying those symptoms and also to screenm orphine-like untoward properties of newly developed analgesics in laboratory level. Recently, Maggiolo and Huidobro (1, 2) have defined abstinence syndrome in morphinepellet implanted mice. Later, using jumping response as a criterion, Way et al. (3) attempted to quantify the degree of physical dependence, thus adding this animal species to the list of animal models usable in this research field. Further, the utilization of mice seems to have been confirmed in more recent experiments by Cheney and Goldstein (4) and Saelens et al. (5). In previous papers (6, 7), it was reported that continuous infusion of morphine could develop tolerance in mice as early as a few hours and that concomitant development of physical dependence was detected by the precipitation of abstinence signs with naloxone. To the present, various techniques have been developed in order to morphinize the laboratory animals and, according to the conditions employed, obtained tolerance or dependence differed in degree one from another, however, it is not yet known whether or not their properties also differ. Thus, using various techniques we investigated how rapidly in terms of hour(s) the animal could become sensitive to naloxone, namely physically dependent, and in what aspects the rapidly inducible type of dependence would differ from that after long exposure to morphine.
Testing drugs on intact animals is considered to be the best method for investigation (1) and since there have been a few reports concerning the action of psychotropic drugs on unlearned behavior, the authors were interested in their effects on emotional behavior of animals. Hall's open-field test, the optimum conditions of which were established by Broadhurst, has been used for many years to study behavior (2-4). This test is generally accepted as a valid measure of emotion in rats. The principle of the test is that the novel situation of the open field evokes in the animal a pattern of behavior characterized by exploration (ambulation and rearing), emotional defecation and urination (5). It has been considered that the exploration evoked under an unfamiliar environment is modified with psychological factors such as curiosity, fear and anxiety as well as with psychotropic drugs (6-11). For example, chlorpromazine and reserpine produced a graded parallel reduction in all types of behavior in rats in open fields, although haloperidol and perphenazine were capable of inhibitory ambulation and rearing without ataxia (7, 12). Boissier and Simmon have investigated the effects of psychotropic drugs on head-entering behavior of mice into the holes in unlearned field (13). Thereafter, Krnjevic and Videk have presented the method of investigation of the behavior in rats confronted by a hole on the animal cage (14). In this paper a new method for investigation is presented on reference to the exploratory behavior of inexperienced rats placed in a square holed open field. The suitability of the method is examined and effects of various kind of psychotropic drugs are discussed. As a result, this method has proved to be useful for investigation of the effects of psychotropic drugs.
There have been few studies on actions of divalent cations on mammalian skeletal muscles (1) as compared to amphibian muscles, which have been used in the study of the role of calcium in the excitation-contraction coupling process (2, 3). Related studies on mammalian denervated skeletal muscle are also few. Denervated skeletal muscles were generally reported to be more sensitive to acetylcholine (ACh) (4, 5), but Kiku-iri (6) indicated that twitch and tetanus evoked by direct electrical stimulation were reduced gradually with the lapse of time after denervation in the sartorius muscle of the frog, while the pattern of caffeine-contracture in the denervated muscle was not different from that in the innervated muscle. Gutmann and Sandow (7) reported that a decrease in twitch and tetanus tensions became progressivly greater with increased duration of denervation in the extensor digitorum longus muscle of rats, whereas the denervated muscle became more sensitive to caffeine. The aim of the present study was to investigate effects of some divalent cations, electrical stimulation and substituting strontium ions for calcium ions in the bath solution on the rat denervated skeletal muscle.
When nerve cells are stimulated, influx of Na+ and efflux of K+ increase and the action potential thus produced is propagated as a nerve impulse. On the other hand, a transmitter must be released from synaptic terminals to transmit nerve impusles to the next cell and the presence of extracellular Ca++ is required for this release. It is therefore considered that the concentration of intracellular free Ca++ increases with change in the membrane potential and release of the transmitter (1, 2). In relation to the Ca++ movement in synaptic area, Ca++-uptake by brain microsomes (3-7), and synaptosomes (3, 8, 9) were studied and the regulatory function was proposed. Ca++ uptake by synaptic membrane was not studied herein. Whittaker et al. (10, 11) isolated a nerve ending fraction (synaptosomes) by discontinuous sucrose density gradient centrifugation of rat brain crude mitochondrial fraction. Synaptic membranes having high Na-K ATPase (12-14) and Ca++-stimulated ATPase (7, 14) activities were then prepared from this fraction by treatment under hypotonic conditions and sucrose gradient centrifugation. In this work, Ca++-binding by synaptic membranes was studied and it was found that the ATP-dependent Ca++-binding had a specific character.
Among research reports on antibiotics, clinical reports on the treatment of infection occupy an overwhelming majority. In basic animal experiments, studies of antibiotics on antibacterial activity, concentration of antibiotics in the blood and distribution in the organs have received almost all of the attention, while studies on the pharmacological actions have apparently been neglected. One of the main reasons for this has been that the toxicity of antibiotics is far milder than that of most other synthetic drugs, and also because there is seldom any cardiovascular action at the usual therapeutic dosages. Recently the side effects resulting from large doses of antibiotics have presented various problems. The toxicity and pharmacological actions of the antibiotics, however still remain to be clarified. In 1955, Bushby et al. (1) reported the participation of a histamine liberating action in the side effects of polymixin B, pointing out for the first time the presence of histamine-like releasers among antibiotics. In 1970, Matsumoto (2) reported the histamine liberating action in colistin derivertives of the same series. In the present study, the effects of four representative macrolide antibiotics: erythromycin, oleandomycin, spiramycin and leucomycin were studied to examine depressor effects on the blood pressure of dogs.
In a previous paper, it was reported that in rats treated chronically with ethanol, the side-chain oxidation of hexobarbital, N-demethylation of aminopyrine and p-hydroxylation of aniline in vitro from either 9, 000 g supernatant; fraction of liver homogenates or washed microsomes was identical with that of control rats when ethanol was withdrawn and substituted for tap water 24 hr prior to sacrifice. In contrast, the activity of aniline hydroxylase of the rats which continued to ingest ethanol ad libitum up to the time of sacrifice was approx. 1.5-fold increased, compated with that of controls, in spite of no change being detected in hexobarbital oxidase and aminopyrine demethylase activities (1, 2). It is known that pretreatment of rats with phenobarbital markedly increases the activities of several hepatic drug-metabolizing enzymes in smooth-surfaced microsomes relative to rough-surfaced ones. The ratio of enzyme activity in smooth microsomes to that in rough microsomes increases in the liver from the phenobarbital-treated animal as compared with that from the control animal (3, 4). Fouts and Gram (5) reported that ratios of smoothversus rough-surfaced microsomal aminopyrine N-demethylase and hexobarbital oxidase of rabbits decreased after 3-methylcholanthrene treatment. The present experiments were conducted to determine the intramicrosomal distribution of drug-metabolizing enzyme activity in the rats treated chronically with ethanol. Parallel experiments were done to determine the intramicrosomal distributions of cytochrome P-450, protein and phospholipid phosphorous contents of the liver from the rats treated chronically with ethanol.
It is well known that anticholinergic agents such as atropine and scopolamine are effective as anti-motion sickness drugs, however, the mechanism of action in the vestibular system is inadequately understood. It has been demonstrated by several investigators (1-5) that neurons in the vestibular nucleus are excited by local application of acetylcholine. Gerebtzoff (6) has shown a histochemical localization of cholinesterase in the vestibular nucleus of cats. Contents of the enzyme were relatively high in the superior and lateral parts of the nucleus, but low in the medial and inferior parts. According to the hypothesis of Wood and Graybiel (7), motion sickness occurred when activation of the central cholinergic system disturbed the balance of vestibular reactions, and protection would be achieved by utilizing anticholinergic drugs. Diphenidol (1, 1-diphenil-4-piperidine-1-butanol) which is related chemically to trihexylphenidil and chlorphenianol has been found effective in the treatment of motion sickness (8-11). Leonard et al. (12) have shown that diphenidol is equal in anti-emetic potency to chlorpromazine and that diphenidol has a greater selectivity of pharmacological action in experimental animals. The present experiments using cats were designed to study the effects of diphenidol on evoked responses in the central vestibular and visual systems.
Denervation itself produces a striking alteration in the surface membrane of muscle fiber in which the region of acetvicholine sensitivity spreads out from the endplates to the whole of the fiber membrane in the rat (1, 2) and in the frog (3). In addition, changes in the characteristics of the sarcoplasmic reticulum may be considered as a possible mechanism for the occurrence of the supersensitivity in the denervated muscle: preservation and proliferation of the sarcoplasmic reticulum demonstrated by electron microscopy (4), the rise in susceptibility to caffeine that appears to exert direct action on the sarcoplasmic reticulum (5) and the marked increase in calcium uptake by the isolated sarcoplasmic reticulum (6, 7). More recently the marked increase in contractures induced by drugs replacing calcium ions by strontium ions was also reported by Taga, Takayanagi and Takagi (8). The aim in this paper was to study non-specific potentiation (non-specific supersensitivity) with views of the contractile activity and the potentiation of drug-contracttires in substituting strontium ions for calcium ions in the denervated muscle. For this purpose changes in function of the sarcoplasmic reticulum after denervation were further investigated.
There have been few reports on monoamine oxidase (MAO) [EC 126.96.36.199. monoamine: oxygen oxidoreductase (deaminating)] activators and at present it is only known that reserpine (1-3), in vivo and 4-diazo-imidazole-5-carboxamide (4), in vitro cause increase in MAO activity. A previous report from this laboratory showed that sodium nitrite (NaNO2) activated MAO with certain substrates (5). Namely, using benzylamine, butylamine, amylamine, hexylamine or β-phenylethylamine as substrate, MAO activity in rat liver mitochondria was increased by NaNO2, while when using tyramine or serotonin it was inhibited. In rat brain mitochondria, MAO activity was increased by NaNO2 when tyramine or butylamine were used as substrates, however, it was inhibited when other substrates were used. These results suggested the presence of multiple forms of MAO in mitochondria. This paper describes the effects of NaNO2 on the substrate specificities, pS maxima, pH optima and Michaelis constants of MAO in rat liver mitochondria.
It is well known that in the cardiac muscle the amount of uptake of Ca ions depends on external Ca concentration and on the electrically driven rate of the preparation (1-5). These Ca ions taken up are considered to play an important role as a direct or indirect activator of the contractile system of the muscle (6, 7). According to Lüttgau and Niedergerke (8) and Niedergerke (2, 3), the external Ca ions may be carried into the heart cells in combination with a hypothetical receptor site or molecule, R. This RCa complex, which may be in close equilibrium with external Ca concentration, appears to move inward, when the membrane is depolarized, so as to initiate the contraction. In the present report, the relationship between external Ca concentration and contractile force in guinea-pig atria driven electrically was analyzed with the formulation of the above scheme in the kinetic equations originated by Michaelis and Menten (9). Furthermore, the mode of the modification of the above relationship by Mn ions was analyzed in terms of the same kinetic models.
Chemical compounds which are used as coronary vasodilators in the clinic may be divided into specific and non-specific groups. Dipyridamole (1), carbochromen (2) and lidoflazine (3) belong to the former, while nitroglycerin and papaverine derivatives are typical drugs belonging to the latter. Since Bretschneider (4) discovered in 1962 that dipyridamole potentiated hypotensive response to adenosine, extensive studies have been published as to the effect of dipyridamole on adenosine metabolism. Miura et al. (5) observed a marked potentiation of adenosineinduced coronary vasodilation after dipyridamole treatment. On the other hand, Hashimoto et al. (6) described that dipyridamole induced a vasoconstriction in the renal artery similar to the effects of AMP or adenosine. Sakai et al. (7) found that in the renal artery dipyridamole potentiated vasoconstrictor response not only to adenosine and AMP but also to norepinephrine. Recently, the authors (8) confirmed a potentiation of coronary vasodilator response to norepinephrine after dipyridamole treatment. In this paper, the effects of dipyridamole, carbochromen and lidoflazine on the renal and the coronary vessels have been compared. A constant volume perfusion was arranged and the change in perfusion pressure was recorded. Drug solution, 0.1 ml was injected intra-arterially in a period of 10 sec.. The continuous administration of drug solution was performed using a Harvard infusion pump (Model 600/900). Dipyridamole was infused at a rate of 0.01 and 0.1 μg/min and carbochromen or lidoflazine was infused at the rate of 0.1 and 1.0 μg/min.