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The central effects of endothelin-1 (ET-1) and their modification by the calcium entry blocker cinnarizine have been investigated using CNS and hypoxia/ischemia tests. CNS tests comprised behavior, horizontal and vertical motor activity and hot plate test. Hypoxia/ischemia tests used were hypobaric hypoxia and complete ischemia by decapitation. ET-1 was injected intracerebroventricularly (i.c.v.) in a volume of 0.01 ml at doses of 1.25, 2.5 and 5 pmol/mouse 15 min before the tests. Cinnarizine (10 mg/kg, i.p.) was administered 60 min prior to ET-1. The i.c.v. ET-1 at all the doses used decreased horizontal and vertical motor activity and produced barrel-rolling. Survival/gasping time of mice subjected to hypoxia/ischemia increased dose-dependently. ET-1 showed an antinociceptive effect. Cinnarizine attenuated the appearance of barrel-rolling, did not antagonize disturbances in motor activity and reversed the antinociceptive effect of ET-1. In hypobaric hypoxia and decapitation cinnarizine antagonized the effects of 5 pmol/mouse ET-1 and potentiated that of 1.25 pmol/mouse. The pharmacological modification of the ET-1 effects by cinnarizine strongly suggests that the CNS actions of ET-1 might be due to multiple mechanisms triggered by an increased influx of extracellular Ca2+ into the brain cells.

In acute experiments on cats under urethan anaesthesia and on dogs under chloralose-urethan narcosis the effect of the cinnarizine analogue Aligeron on local cortical cerebral blood flow (local CBF) and internal carotid blood flow was studied. The local CBF was recorded by means of a thermoclearance method using thermistor transducers. In addition the cortical pH and the arterial blood pressure were registered. For determination of internal carotid flow the flowmetric method was used accompanied by a simultaneous registering of heart rate and arterial blood pressure. Cinnarizine and papaverine were used as reference compounds. The results obtained show that Aligeron increases both the internal carotid flow (with 64% in a dose of 5 mg/kg) and the local CBF (with 30% in a dose of 1 mg/kg and 40% at 5 mg/kg). This effect is higher and longer-lasting than those of cinnarizine and papaverine.

The antagonistic action of aligeron as compared to that of papaverine against different smooth muscle stimuli was studied in experiments in vitro. Three series of experiments were conducted: study of the antagonistic action against experimental spasms of isolated organs caused by different spasmogens; determination of the type of antagonism to adrenaline in isolated vas deferens preparation; and study of the antagonistic action against vasoconstrictor effects of noradrenaline and adrenaline in isolated perfused rabbit renal artery. Aligeron showed a broad spectrum of antagonistic action against different spasmogens in different isolated organs. Its effect was more pronounced than that of papaverine. The antagonism was of the non-competitive type. The experiments on isolated perfused rabbit artery showed the antagonistic action of aligeron against the vasoconstrictor effects of noradrenaline and adrenaline. The results suggest the clinical use of aligeron in conditions associated with increased release of these vasoactive substances.

The interaction of aligeron and piracetam with the effects of prostaglandin F2 alpha (PGF2 alpha) E2 (PGE2) was studied using in vitro and in vivo tests for evaluation of PG antagonistic activity. Aligeron was found to be a non-selective PG antagonist in isolated guinea-pig stomach smooth muscle preparations. It antagonized the PGF2 alpha and PGE2-induced fall in blood pressure in cats prevented diarrhoea induced by PGF2 alpha in mice, inhibited rat paw oedema induced by PGE2 in rats, but did not modify the PGF2 alpha induced bronchoconstriction in guinea-pigs. Piracetam did not antagonize the smooth muscle contractile effects of PGF2 alpha and PGE2 and in the in vivo tests it inhibited only the rat paw oedema induced by PGE2. It is concluded that aligeron is active in vitro and in vivo as an antagonist of some of the actions of PGs studied. Its effect in vitro lacks selectivity and is probably due to interference with the action of Ca2+. The probable clinical implication of these results will be discussed. Piracetam can not be considered a PG antagonist.

The effect of As2 and Cinnarizin on cerebral circulation is studied on rabbits using the method of local cerebral rheography. Rheoencephalograms (REG) are recorded from the following brain structures; sensomotor cortex, substantia alba, poseterior hippocampus amygdala; nucleus caudatus and coliculus superior. Arterial blood pressure and ECG are studied simultaneously. Qualitative and quantitative analysis of the REG wave is made. Quantitative analysis involves the calculation of the following parameters: amplitude, anacrotic section of the curve and its relative part, spreading time and dicrotic index. The complex of REG-changes under the effect of the two drugs is very similar and suggests dilatation of the cerebral blood vessels. The difference is in the time of occurrence of the maximum effect: 5th min for As2 and 45th min for Cinnarizine.

The anti-hypoxic effect of cinnarizine was studied using the following experimental methods: hypobaric and anoxic hypoxia in mice, complete ischemia by decapitation in mice and hemic hypoxia in rats. Papaverine, xanthinol nicotinate and naftidrofuryl were used as reference drugs. In hypobaric and anoxic hypoxia the interaction of cinnarizine with the effect of prostacyclin (PGI2) was investigated. Cinnarizine showed an anti-hypoxic effect in all the methods used. It was more effective in hypobaric and anoxic hypoxia, in incomplete ischemia by decapitation, and less effective in hemic hypoxia. Cinnarizine potentiated the effect of PGI2 shifting the anti-hypoxic dose-response curve of PGI2 to the left. Suggestions as to the possible mechanism of anti-hypoxic action of cinnarizine are made.

The effect of Aligeron (1-benzhydril-4-allyl-piperazine dihydrochloride) on the cranial circulation was studied in dogs under chloralose-urethan anaesthesia. The parameters followed were: venous outflow from the confluence of the cerebral sinusses (CVO), cerebrospinal fluid pressure in cysterna magna (CSFP), systemic arterial blood pressure (BP) and pulse rate (PR). CVP was measured using the technique of Rapela and Green (1964). Aligeron was applied at doses of 5 and 10 mg/kg i.v. Papaverine hydrochloride was used as a reference compound. aligeron administration at a dose of 5 mg/kg led to quick increase of the CVO with a duration of the effect approximately 30 min. CSFP also increased in a similar way. BP and PR showed insignificant changes. The administration of 10 mg/kg did not lead to an increase of its effect on CVO. Papaverine (1 mg/kg i.v.) had a weaker effect than that of Aligeron. According to the classical concepts the changes observed in our experiments were due to the cerebral vasodilator effect of Aligeron which caused a fall in cerebrovascular resistance and an increase of the intracranial blood volume. Our experiments suggest that Aligeron influenced the resistance vessels more than the capacitance ones.

The following methods were used: neuropharmacologic study according to the a modified method of Nikolova, Daleva, orientation reaction according to Boissier and Simon, "open field" according to Fontenay et al. and actographic study. The data from "the free" observation suggested clearly a manifested central stimulating effect of aligeron. The data from the actographic study were similar, which showed an increased motor activity in mice and rats, given doses of 1/100-1/4 of LD50. The stimulating action of the preparation was observed in doses of 1/8-1/6 of LD50 during the experimental procedure "open field". The preparation inhibited orientation reaction in mice. Cinnarizine inhibited the examined indices, obtained by all tests. The complex of the used methods allowed to make an inference that aligeron had central stimulating effect, weaker in smaller therapeutic doses and more manifested in higher doses. Cinnarizine had weak depressive effect.

In rats with streptozotocin-induced diabetes antioxidant protection of diabetic angiopathy was performed by flunarizine (10 mg/kg/day) and aligeron (10 mg/kg/day), applied intraperitoneally during 2.5 months of diabetes. Diabetic vascular complications were assessed by morphologic determination of PAS-positive mucopolysaccharides and measurement of vascular wall thickness in addition to quantitative estimation of lipid hydroperoxides, thromboxane A2/prostacyclin disbalance and plasma beta-thromboglobulin changes. Both drugs prevented development of diabetic angiopathy in rats by inhibition of lipid peroxidation, prostanoid synthesis and platelet activity, but the effect of flunarizine was more pronounced, which could be explained by its additional blocking effect of abnormal calcium flux into vascular cells. The free radical scavenging action of flunarizine and aligeron was investigated.

The effect of the compound AS2 (N'-benzhydryl, N''-allylpiperazine dihydrochloride) on the central and peripheral mechanisms of vascular tone regulation is studied. Six series of experiments on cats are carried out. The effect of the compound is tested on a model of central-hypertensive reaction, on the spontaneous bioelectrical activity of the renal nerve, on the transmission of excitation to the upper cervical ganglion and the ganglia of the solar plexus. Experiments are made to study its adrenolytic a-d myotropic properties. Cinnarizine is tested as control. The results show that the compound AS2, similar to Cinnarizine, affects the central and peripheral mechanisms of vascular tone regulation. In small doses (1-5 mg/kg) AS2 manifests poor myotropic properties. Administration of the drug in doses of 10-20 mg/kg results in considerable inhibition of the vasomotor centres, brief disturbances in the excitation transmission in the sympathetic ganglia and slight inhibition of adrenergic transmission.

The effect of aligeron (5 mg/kg i.v.) and cinnarizine (10 mg/kg i.v.) on general and local depression of cortical bioelectrical activity was studied in acute experiments on cats. Asphyxic anoxia and hypoventilation hypoxia were used as models of general depression. Local depressions were caused by topical application of potassium chloride (KCl) and adenosine-5'-monophosphate (AMP) on the cortex. In hypoventilation hypoxia aligeron and cinnarizine increased cortical resistance to hypoxia and accelerated the recovery of cortical bioelectrical activity. In KCl- and AMP-induced depressions the drugs showed a protective effect manifested in a decrease of the degree and duration of the depression. In asphyxic anoxia their effect was insignificant.

The effect of the cinnarizine analogue Aligeron on the resistance of cerebral and peripheral blood vessels was studied in acute experiments on cats and dogs. The resistance of the cerebral vessels was determined directly and indirectly. For direct determination the method of autoperfusion was used. The resistance was calculated indirectly as a quotient of mean arterial blood pressure and internal carotid blood flow. For evaluation of Aligeron effect on the resistance of the peripheral blood vessels and method of autoperfusion of the femoral artery was used. Aligeron was administered i. v. and i. a. In some of the experiments the compound was applied on the background of previously injected dihydroergotamine. Cinnarizine and papaverine were used as reference compounds. The results show that Aligeron decreases considerably the cerebral and peripheral resistance vessels tone, and its effect is higher than those of cinnarizine. For the realization of this effect most probably its direct myotropic action plays the main role. The reduction of its effect after alpha-adrenergic blockade suggests an involvement of some adrenergic blocking properties in its mechanism of vascular action.

Various well-known agents with a favourable influence on cerebral circulation were used as a basis for creating new methods to asses the effects on this vascular region in experimental animals. A technique was worked out for radiocirculography and simultaneous radiometry, as well as for scanning and simultaneous radiometry of cat brain. Radiocirculography, followed by scintigraphy, proved to be among the best methods used for assessment of the effect of As2 on cerebral circulation. Simultaneous radiometry with the methods mentioned above had only orientational value. Radiocirculographic and scanning data after application of As2 in a dose of 10 mg/kg are close to those for nicotinic acid in a dose of 1 mg/kg. Similar to the data of the isotopic methods after application of As2 in a dose of 5 mg/kg are the results obtained with 5 mg/kg cinnarizin, which suggests a similar machanism of action.