Effects of cholinergic and adrenergic drugs on the transmurally stimulated mouse vas deferens were investigated as a basis for further understanding of the innervation of the mouse vas deferens. Particular attention was paid to the cholinergic mechanism in the vas deferens. Results were summarized as follows. 1) Ganglion cells are considerd to exsist in the vicinity of the vas deferens. 2) Transmural stimulation at 0.5 msec pulse duration acts on the postganglionic nerves and at 2 msec on the muscle itself. 3) Since cholinergic drugs were more effective at low than high frequency stimulation, low frequency stimulation are considerd to act on the cholinergic mechanism predominantly. 4) In the mouse vas deferens, adrenergic nerves innervate predominantly over cholinergic nerves. 5) Cholinergic and adrenergic nerves are seemed to act independently on the contractile mechanism. 6) There exsist possibilities that cholinergic nerves are resistant to atropine and therefore cholinergic receptor (J. R.) is nicotinic.
B-64114-Ca was synthesized by BYK Gulden Lonbark Co. in Germany and has chemical structure that open the pyrazolidinering of pheny lbutazone. The anti-inflammatory effects of B-64114-Ca were examined in comparison with that of phenylbutazone and oxyphenbutazone. It was found that B-64114-Ca has potent inhibitory effects against acceleration of capillary permeability and similarly potent anti-edematous effect against experimental edema (rat paw edema test). The compound has also proven to have inhibitory activity against proliferation of granulation tissue (cotton pellet test, granuloma pouch test and wound healing test), against ultraviolet-erythema and adjuvant arthritis and appears to have uricosuric effect from activity that delay the excretion of PSP. These activities of B-64114-Ca were almost similar to those of phenylbutazone and stronger than that of oxphenbutazone. From the above results, B-64114-Ca may be considered to be similar clinically useful to phenylbutazone as a nonsteroid antiinflammatory agent.
In the previous report, B-64114 derivatives were proven to have similar potent antiinflammatory activity to that of phenylbutazone. In this paper, the general pharmacological activities of B-64114-Ca were examined in comparison with phenylbutazone. The acute toxicity of B-64114-Ca was weaker than that of phenylbutazone. Toxic action of phenylbutazone was inhibition on the heart function, but on the other hand, B-64114-Ca did not hinder the heart function and showed mainly inhibitory action on the respiration. It was found that B-64114-Ca was almost similar or less to phenylbutazone in such activities as analgesic, hypothermic and antipyretic effects and lack hypnotic potentiation and anti-convulsive effects. It may be, therefore, considered to be extremely low in the effects on the central nervous system. B-64114-Na showed temporary hypotensive effect and it was also found to only slightly affect the cardiac movement and capillary vessels. It was free of any effects on the blood sodium and potassium levels, urinary sodium and potassium outputs, and urine volume and blood coagulation times. It did not affect the intestinal movement and did not show the antagonistic effects on such mediators as histamine, acetylcholine, serotonin and so on. It was found that B-64114-Na has the local irritation and B-64114-Ca caused the stomach ulcer, but these activities were similar or weaker to those of phenylbutazone. From the above results, it may be thought that B-64114-Ca is valuable of clinical usage as nonsteroid anti-inflammatory agent which is lower in toxicity and in side effects than phenylbutazone.
Comparative studies on lethal dose of digitoxin and post-mortem concentration of the drug in heart muscle were made in cat, guinea pig and rat. It was found that relative ratios of lethal dose for these animals were 1: 2.5: 60 and that relative concentration ratios of digitoxin were 1: 9: 70. When atria was prepared for recording twitch tension, digitoxin (2.2 × 10-7 g/ml) initially increased and then reduced the tension. In the rat, the time for 50 % decline in peak tension was four times longer than that in the guinea pig, whereas uptake of 3H-digitoxin by atria was almost the same in both animals. From the results obtained, it could be concluded that the in vivo sensitivity to digitoxin might be in parallel with sensitivity of heart muscle to the drug.
In order to know the reason for the species difference in the in vivo sensitivity to ouabain, the (Na+-K+)-activated adenosine triphosphatase (ATPase) activity of prepared cell membrane from heart and skeletal muscles was observed in several animals. The ratio of ouabain concentration which caused 50 % inhibition of activity of the enzyme from hearts of cat, guinea pig, rat and bufo was obtained in 1: 4: 80: 660, which was approximately the same as the ratio of lethal dose in these animals (1 : 3 : 150: 1000). In the course of this study, a stage was found that (Na+-K+)-activated ATPase activity was not inhibited in presence of manifest positive inotropic effect of ouabain, using ouabain-infused cat heart.
Substrate specificity, pS maxima and pH optima of mitochondrial MAO in rabbit brain and liver were studied using tyramine, phenylethylamine, dopamine, tryptamine, serotonin, noradrenaline and adrenaline as substrates. Both enzymes in brain and liver did not oxidize adrenaline and serotonin. The enzyme in brain did not oxidize noradrenaline. The pS maxima and Qo2 values of brain enzyme differed from that of liver's when tyramine, phenylethylamine tryptamine were used as substrates. The pS maxima of the enzyme in brain mitochondria was found at lower concentrations than that in liver mitochondria with various substrates examined. The enzyme solubilized with Emulgen 810 from liver mitochondria showed almost the same pS maxima as that in liver mitochondria, but did not oxidize noradrenaline. The optimal pH of the enzyme in brain was also found to be differed from that of liver's to the substrates except phenylethylamine. In case of serotonin used as substrate, the optimal pH's of the enzymes in brain and liver were observed at pH 8.1 and 8.9 respectively. From the experimental results obtained in this work, it may be concluded that the enzyme in brain differes in enzymic properties from that in liver. In situ, MAO may more actively oxidize tyramine, phenyle t hylamine and tryptamine which are biosynthesized as precusors for the active amines and consequently, it may control the metabolism of the biogenic amines such as adrenaline, noradrenaline or serotonin in mammalian tissues.
Pharmacological properties of 6, 6, 9-trimethyl-9-[3, 3, 1]non-3β-yl α, α-di(2-thienyl)glycolate hydrochloride monohydrate (PG-501) were examined as an anti-parkinsonian agent. PG-501 was found to have pronounced anti-acetylcholine, anti-tremorine-induced tremor, anti-physostigmine-induced death, anti-haloperidol-induced parkinsonism and anti-EEG arousal activities. PG-501 was also found to have greater dissociation between contral and peripheral anticholinergic activities. These results suggest that PG-501 has great benefit in the treatment of parkinsonism, especially in the prevention of undesirable side-effects.
Animals were dead by hemorrhage due to large dosage of Dicumarol which is known as an anti-vitamin K substance. The protective effects of Menaquinone-4 (K2) and Phytonadione (K1) on the death of animals caused by Dicumarol were studied in mice. K2, K1 (5-10 mg/kg/day) or vehicle with Dicumarol (50 mg/kg/day) were orally given to three groups of mice for 10 days. The K2 or K1 treated groups significantly survived longer compared with the control group. K2 had statistically more potent protective effect than K1.
Menaquinone-4 (K2) or Phytonadione (K1) was given to rabbits with hypoprothrombinemia caused by 2-4 mg/kg orally administered Warfarin potassium, the coagulation time was measured every 3 hours for first 12 hours then every 6 hours for 18 hours. The group orally given 1-2 mg/kg of K2 was more rapidly improved in pr o thrombin time compared with the group given same dosage of K1, as well as intramuscular administration of 0.2-2 mg/kg of the drugs.
Menaquinone-4 (K2), Phytonadione (K1) or vehicle, with Dicumarol and Neomycin, was given to rabbits for 10 days. During this term, prothrombin time and thrombelastogram were observed daily and every other day respectively. Hypoprothrombinemia was definitly caused in rabbits by daily administration of 0.4 mg/kg of Dicumarol intravenously and 200 mg/kg of Neomycin orally, and several deaths due to hemorrhage were observed. In all carcasses, hemorrhage was observed in caecalpart. Under these conditions, the experiments showed that oral administration of K2 or K1 significantly suppressed prolongation of the prothrombin time, and prevented bleeding death of animals. K2 had more potent preventive effect than K1. Both r and k values of the thrombelastogram in rabbits were prolonged after Dicumarol and Neomycin were continuously given, while the groups given K2 or K1 showed no marked effect on the prolongation of r value but apparent suppresive effect on the prolongation of k value until 6 days after the administration. In this case, K2 had significantly more potent suppressive effect than K1.