We evaluated antiarrhythmic effects of N-696 using canine digitalis ventricular arrhythmia models and electrophysiological actions of N-696 using canine ventricular muscles and isolated blood perfused A-V node preparations and compared the effects with those of proranolol. 1) N-696 at 30 mg/kg, i.v. was not effective on digitalis arrhythmia, but reduced the total heart rate and atrial rate for 60 min and transiently decreased the blood pressure. Propranolol at 3 mg/kg, i.v. transiently suppressed digitalis ventricular arrhythmia and decreased the total heart rate, atrial rate and blood pressure. The minimum effective plasma concentration of propranolol was 1.7±0.4μg/ml. 2) Ten to 100μg/ml N-696 and 3 to 10μg/ml propranolol did not affect the resting potential and the action potential duration at 75%, repolarization of the canine ventricular muscle, but decreased the maximum rate of rise of the action potential in a dose-dependent fashion, and 100μg/ml N-696 decreased significantly the action potential amplitude. The minimum effective durg concentration of N-696 was 60μg/ml, and that of propranolol was 6μg/ml. 3) N-696 (30μg-3mg) dose-dependently delayed the A-V conduction time of the isolated blood perfused A-V node preparation when it was administered into the posterior septal artery (PSA) and the anterior septal artery (ASA). Propranolol(10-600μg) also had similar effects, but the doses of N-696 delaying the A-V conduction time by 15% was about 8 to 21 times higher than those of propranolol.

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The drugs used were pargyrine, methamphetamine, reserpine, norepinephrine, epinephrine, propranolol, chlorpromazine, 6-hydroxydopamine, haloperidol, pilocarpine, neostigmine and atropine. The body weight gain of pups receiving reserpine, chlorpromazine, 6-hydroxydopamine and pilocarpine was significantly inhibited. The mortality of pups given reserpine was significantly increased. The behavioral development of righting reflex, cliff drop avoidance and negative geotaxis of rats given reserpine, propranolol, 6-hydroxydopamine and haloperidol was significantly retarded in comparison with that of control pups. Spontaneous motor activity measured by Animex was increased in pups receiving norepinephrine, epinephrine, chlorpromazine, reserpine, propranolol and atropine. Furthermore, pharmacological challenge by the injection of methamphetamine exhibited an accentuated response to an increase in spontaneous motor activity in pups exposed to chlorpromazine, reserpine, propranolol, 6-hydroxydopamine and atropine. These findings suggest that an increase in spontaneous motor activity may be induced by the developmental impairment of central catecholamine mechanisms, especially the noradrenaline nervous system. Delayed latency, decreased rearing and preening of pups receiving propranolol were observed on the open field test. The conditioned avoidance responses using the shuttle box revealed deficits in acquisition of avoidance learning of rats given haloperidol, 6-hydroxydopamine and propranolol, suggesting that the learning deficits may be due to the developmental impairment of catecholamine mechanisms, especially the dopamine nervous system.

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The influence of taurine on neutrophil phagocytic and bactericidal capacities and lysosomal enzyme-releasing ability was evaluated in the present study using neutrophils obtained from casein-elicited rat peritoneal exudates. Taurine was dissolved in drinking water at a concentration of 0.3%, and the solution was given to rats for 1-21 days (460 mg/kg/day). Taurine concentration in the serum increased with the term of its administration, wihle in the neutrophils, it increased significantly after adimnistration for 1 or 3 days. When administered for 7 or 10 days, however, no difference was noted from the control group, but then the concentration remarkably increased after 21 days of administration. The bactericidal capacity of the neutrophils against Escherichia coli was strengthened as their concentration of taurine increased; phagocytic capacity was also strengthened. The release of myeloperoxidase following phagocytosis of yeasts increased with administration, while the release of P-glucuronidase, lysozyme and lactate dehydrogenase, which are induced by N-formylmethionyl-leucyl-phenylalanine, were inhibited. The hypotonic hemolysis of erythrocytes was also inhibited. Taurine decreased the fluorescence depolarization of diphenylhexatriene, indicating an increase in membrane fluidity. These results suggested that taurine strengthens both phagocytic and bactericidal capacities of neutrophils by increasing the fluidity of neutrophil membrane and membrane stability and thus plays an important role in the mechanism of host defense.

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Effects of catecholamines on plasma uric acid and allantoin levels were studied in oxonate-treated rats and nontreated rats. 1) In non-treated rats, epinephrine, isoproterenol and phenylephrine, which were injected intraveneously, clearly increased plasma uric acid and allantoin, and norepinephrine had only a slight effect. The orders of potency to increase plasma uric acid and allantoin were epinephrine>isoproterenol>phenylephrine> norepinephrine. β-adrenoceptor agonists also increased plasma uric acid and allantoin in non-treated rats. The order of potency to increase plasma uric acid was isoproterenol≈=salbutamol≈trimetoquinol>terbutaline, and that of potency to increase plasma allantoin was isoproterenol≈salbutamol ?? trimetoquinol>terbutaline. 2) In oxonate-treated rats, the four P-adrenoceptor agonists (50μg/kg, i.v.) markedly potentiated the hyperuricemic effect of oxonate. These effects of β-adrenoceptor agonists were inhibited by propranolol (2.0 mg/kg. i.v.). In addition, the effect of isoproterenol was inhibited by butoxamine (1.0 mg/kg, i.v.), but not by atenolol (1.0 mg/kg, i.v.). These results suggest that hyperuricemia induced by catecholamines is closely related to β₂-adrenoceptor action.

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Improvement of energy metabolism in ischemic cerebral tissue benefits the therapy of occlusive cerebrovascular lesions. In the present study, the effects of 6-(10-hydroxydecyl)-2, 3-dimethoxy-5-methyl-1, 4-benzoquinone (idebenone, CV-2619) on neurological signs, local cerebral blood flow, and cerebral energy metabolism were assessed in stroke-prone spontaneously hypertensive rats (SHRSP) with bilateral carotid artery occlusion (BCAO). Pretreatment with CV-2619 (10-100 mg/kg, p.o.) for three or ten successive days delayed the onset of ischemic seizure (acute stroke) and prolonged survival time in the SHRSP. When the compound (100 mg/kg, i.p.) was given once 30 min after BCAO, it exerted similar ameliorating effects on the neurological deficits. When CV-2619 (100 mg/kg for 3 days) was given orally, it did not inhibit a decrease in regional cerebral blood flow induced by the carotid artery occlusion. However, the same treatment markedly inhibited increases in lactate content and lactate/pyruvate ratio and a decrease in ATP content in the cerebral cortex. In addition, the compound showed no effect on cerebral blood flow in normal rats. These results suggest that CV-2619 has an ameliorating effect on neurological deficits related with cerebral ischemia, and this effect is mediated by improved cerebral energy metabolism.

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Pharmacological effects of ritodrine hydrochloride (ritodrine), a, β₂-adrenoceptor agonist, were investigated in comparison with that of isoxsuprine hydrochloride (isoxsuprine) on the motor nervous system and the central nervous system. Ritodrine (1-30 mg/kg, i.v.) suppressed spontaneous movements in mice, rats and dogs. The animals became slightly sedative and immobile. Ritodrine caused an increase of water intake and vomitting in dogs. These fingings were recovered in 3-5 hr. Isoxsuprine showed similar effects on general behaviour, but the depressive action was more potent than that of ritodrine. Ritodrine slightly suppressed exploratory behaviour in high dose, but had little effect on emotinal behaviour. Ritodrine had no effects on conditioned avoidance response, tremor, motor coordination, thiopental induced sleeping time and few types of convulsions. Ritodrine showed no analgetic effects or muscle relaxant actions. Isoxsuprine, in high dose, suppressed motor coordination and showed ataxia. Ritodrine slightly raised body temparature and dose-dependently suppressed hypothermia and ptosis induced by reserpine. Ritodrine (1-10 mg/kg, i.v.) caused a slight resting pattern of spontaneous EEG in rabbits. On the other hand, arousal responses evoked by auditory stimulation, photic stimulation or electrical stimulation of mesencephalic reticular formation were unaffected by ritodrine at any doses used. These results suggest that ritodrine shows little effect on the motor nervous system and central nervous system, and its effects may be nonspecific.

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