piperidines and pantogab

A method for measuring the organic infarct focus induced by arachidonate infusion into rat brain was devised, and the statistical relationship between the measured values and stroke signs in the rat was studied. By the infusion of arachidonate, a high incidence of cerebral infarction was found in the live rats with uniformly necrotized foci. The size of these foci (infarction rate) were measured by transcripting them to a graduated brain sheet. The relationship between the independent parameter of the infarction rate and the dependent parameter of stroke signs was fully analyzed by multidimensional quantification. Many animals showed no stroke signs despite having lesions (false negative). By contract, no animal without any lesion showed stroke signs (false positive). When each parameter of these signs were quantified and normalized, the stumbling and abnormal posture signs showed a wide range of values, relatively accurately reflecting the infarction degree. Moreover, the highest partial correlation ratio between the various parameters was found to be that between the stumbling and abnormal posture stroke signs. Thus, it may be said that the stumbling and the abnormal posture stroke signs can be considered relatively good parameters for evaluating the degree of an infarction. These parameters should be useful for the testing of anti-infarction drugs.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Brain; Cerebral Infarction; Cerebrovascular Disorders; Drug Evaluation; gamma-Aminobutyric Acid; Male; Pantothenic Acid; Piperidines; Rats; Rats, Inbred Strains

Recently, it has been proposed that the combined administration of ifenprodil tartrate and calcium hopantenate might produce a beneficial synergistic effect in the treatment of cerebrovascular diseases. To further examine this clinical phenomena, the blood flow in the internal carotid arteries of the rat and the isometric tension of canine internal carotid arteries were measured with a transit-time ultrasonic volume flowmeter and a force transducer, respectively. Ifenprodil tartrate produced a sustained increase in the internal carotid arterial blood flow of rats, while calcium hopantenate had no effect. However, the increase in the internal carotid arterial blood flow induced by ifenprodil tartrate was significantly enhanced by calcium hopantenate. Ifenprodil tartrate caused a dose-related relaxation of K+-induced contractions in the isolated canine internal carotid arteries, while calcium hopantenate had no effect. The dose-response curve of ifenprodil tartrate was shifted to the left by pre-incubation in calcium hopantenate. Ifenprodil tartrate inhibited the K+-induced Ca2+ uptake in the canine internal carotid arteries, and the inhibition induced by ifenprodil tartrate was significantly enhanced by calcium hopantenate. These results suggest that the observed enhancement by calcium hopantenate of the ifenprodil tartrate effect on the internal carotid arterial blood flow was due to increased vascular myorelaxation resulting from the influence of calcium hopantenate on the Ca2+ movement.

Topics: Animals; Blood Flow Velocity; Calcium; Carotid Artery, Internal; Cerebrovascular Disorders; Dogs; Drug Synergism; Drug Therapy, Combination; gamma-Aminobutyric Acid; In Vitro Techniques; Muscle Relaxation; Muscle, Smooth, Vascular; Pantothenic Acid; Piperidines; Rats; Rats, Inbred Strains; Vascular Resistance

In our earlier report [Shibuya et al. in press], we demonstrated the partial mechanism of the synergism between ifenprodil tartrate and calcium hopantenate on cardiovascular diseases. The mechanisms of the synergistic effects in the basilar and vertebral arteries were further studied in this paper using our described methods. Ifenprodil tartrate produced a sustained increase in the vertebral arterial blood flow of rats, while calcium hopantenate. Ifenprodil tartrate caused dose-related relaxation of K+-induced contractions in by ifenprodil tartrate was significantly enhanced by the coadministration of calcium hopantenate. Ifenprodil tartrate caused dose-related relaxation of K+-induced contractions in isolated canine basilar arteries, while calcium hopantenate had no effect. The dose-relaxation curve of ifenprodil tartrate was shifted to the left by pre-incubation in calcium hopantenate. In K+-depolarized basilar arteries, ifenprodil competitively antagonized the response to Ca2+, and this was enhanced by pre-incubation in calcium hopantenate. Ifenprodil tartrate inhibited K+-induced Ca2+ uptake in canine cerebral arteries and this was enhanced by pre-incubation in calcium hopantenate. These results suggest that the enhancement by calcium hopantenate of the ifenprodil tartrate effect on the vertebral blood flow is due to increased vascular relaxation through the inhibition of Ca2+ influx.

Topics: Animals; Basilar Artery; Blood Flow Velocity; Calcium; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Female; gamma-Aminobutyric Acid; Male; Pantothenic Acid; Piperidines; Rats; Vertebral Artery

Cerebral protective effect of MCI-2016 and influence of age on survival time in the cerebral ischemic model induced by bilateral-carotid-arterial ligation in male Mongolian gerbils were studied. Of all animals (6 to 40 weeks old), the mean survival time of the immature group (6 to 7 weeks) was long (3.6 hr), but variable, and that of the 10 to 40 weeks group was relatively stable (1.9-2.4 hr), but that of the older group (30-40 weeks) inclined to be reduced. Effects of drugs on this model were studied in 10 to 15 weeks old male Mongolian gerbils. The mean survival time in the control groups was 2.3-2.4 hr. After a single administration of MCI-2016 at doses of 25 mg/kg, i.p., and 100 mg/kg, p.o., the mean survival time were 8.1 and 6.4 hr, respectively. In these cases, some animals survived over 12 hr, while no animals surviving over 12 hr were observed in the control group. In this model, animals showed severe neurological symptoms. This, however, tended to be depressed by the administration of MCI-2016 at a dose of 25 mg/kg, i.p., which was observed early after ligation. A cerebral metabolic activator, Ca-hopantenate, slightly increased the survival time at a dose of 100 mg/kg, i.p., and a cerebral vasodilator, ifenprodil, was not effective. Subsequently, consecutive administration of MCI-2016 at a dose of 25 and 50 mg/kg, p.o., was more effective than a single administration of MCI-2016 at each dose. The mechanism for the cerebral protective effect of MCI-2016 was discussed.

Topics: Administration, Oral; Age Factors; Animals; Benzhydryl Compounds; Brain Ischemia; Carotid Artery Diseases; Constriction, Pathologic; gamma-Aminobutyric Acid; Gerbillinae; Male; Pantothenic Acid; Piperidines

The anti-anoxic effect of sufoxazine was investigated in various cerebral anoxia models with mice, in comparison with those of various cerebroactive drugs. Sufoxazine reduced dose-dependently the duration of coma induced by a sublethal dose of KCN (1.8 mg/kg, i.v.), significantly stimulating recovery from the coma at 5 mg/kg, i.p. and 30 mg/kg, p.o. It also protected against a lethal dose of KCN (2.5 mg/kg, i.v.). Sufoxazine prolonged the survival time of mice subjected to hypobaric and normobaric hypoxia. Dihydroergotoxin and ifenprodil gave similar protection in the KCN-induced anoxia models, but produced adverse effects in the hypoxia models. Calcium hopantenate exerted similar but weak protection only at a dose as high as 300 mg/kg, i.p. These findings suggest that sufoxazine has an anti-anoxic action superior to those of the other cerebroactive drugs used.

Topics: Animals; Atmospheric Pressure; Coma; Dihydroergotoxine; Drug Therapy, Combination; gamma-Aminobutyric Acid; Hypoxia, Brain; Mice; Morpholines; Pantothenic Acid; Physostigmine; Piperidines; Potassium Cyanide