Mitigating Effect of Nitrates (Monizol) on Pharmacodynamic Shifts in the Cardiovascular System Caused by Radioprotector Indralin.

We studied the effect of radioprotector indralin (B-190) alone or in combination with monizol on BP and HR in rabbits, reduction of blood supply and spleen weight in rats and (CBA×C57Bl/6)F1 hybrids mice, and on blood loss from a wound on tip of the tail in mice. Being an α1-adrenomimetic, indralin caused hypertensive reaction with the development of bradycardia, reduced blood supply and spleen weight, and sharply reduced blood loss from the wound. Monizol as nitrate reduced BP without affecting HR and reduced blood loss from the wound. Monizol administered prior to indralin eliminated radioprotector-induced hypertensive reaction, reduced bradycardia by more than 2 times, and attenuated the effect of indralin on spleen weight and blood loss from the wound by 1.6-1.8 times. Monizol administered after indralin had no effect on shifts in peripheral blood supply caused by the radioprotector.

[PECULIARITIES OF THE CEREBROVASCULAR EFFECTS OF GLUTAMIC ACID].

Experiments on nonlinear rats subjected to global transient cerebral ischemia revealed the ability of glutamic acid to improve cerebral circulation. Consequently, the excitatory amino acid can produce adverse (neurotoxic) and positive (anti-ischemic) effects in cerebral ischemia. The cerebrovascular effect of glutamic acid in cerebral ischemia is attenuated on the background action of the MNDA receptor blocker MK-801 (0.5 mg/kg intravenously) and eliminated by bicuculline. When glutamic acid is combined with the non-competitive MNDA receptor antagonist MK-801, neither one nor another drug shows its vasodilator effect. The results are indicative of the interaction between excitatory and inhibitory systems on the level of cerebral vessels and once again confirm our previous conclusion about the decisive role of GABA(A) receptors in brain vessels in the implementation of anti-ischemic activity of endogenous compounds (melatonin) and well-known pharmacological substances (mexidol, afobazole), and new chemical compounds based on GABA-containing lipid derivatives.

[ANTIPLATELET AND ANTI-ISCHEMIC EFFECTS OF MEMANTINE AND 5-HYDROXYADAMANTAN-2-ONE IN PATIENTS WITH CEREBROVASCULAR PATHOLOGY AND IN EXPERIMENTS].

It was investigated the effect of two adamantane derivatives, memantine and 5-hydroxyadamantan-2-one (5-HA), in patients with cerebrovascular disorders. In vitro studies showed that 5-HA, unlike memantine, exhibited antiplatelet activity. Experiments showed that memantine reduced cerebral blood flow in the brain cortex of intact rats and those under conditions of transient global ischemia, whereas 5-HA only selectively improved blood flow in ischemic brain and was superior to the reference drug nimodipine. The obtained data indicate the leading role of the GABA-ergic (rather than glutamatergic mechanisms) in implementation of the anti-ischemic cerebrovascular activity.

[NEUROCHEMICAL STUDY OF TROPOXIN EFFECTS ON THE CONTENT OF MONOAMINES AND ITS METABOLITES IN WISTAR RAT BRAIN STRUCTURES].

The influence of perspective anti-migraine drug tropoxin on the content of monoamines and related metabolites in Wistar rat brain structures, including frontal cortex (FC), hypothalamus, nucleus accumbens (NA), striatum, and hippocampus, has been studied using HPLC/ED technique. Tropoxin (10 mg/kg) induced a 30% decrease (p < 0.05) in dopamine (DA) level in FC as well as norepinephrine content in NA, while the concentrations of DA metabolites DOPAC and HVA in the hypothalamus were found to increase. The injection of tropoxin in a dose of 20 mg/kg led to an increase in HVA level in hypothalamus as well as seroto- nin metabolite 5-HIAA content in NA. The obtained data provide evidence that tropoxin predominantly influenced the activity of dopaminergic system while the drug effects on the parameters of serotoninergic link seem to be rather mild.

[ANTIARRHYTHMIC EFFECTS OF 2-ETHYL-6-METHYL-3-HYDROXYPYRIDINE HEMISUCCINATE IN COMPARISON TO MEXIDOL.]

Based on the results of experiments on nonlinear white awake male rats it is established that 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate and mexidol exhibit a pronounced antiarrhythmic (antifibrillatory) activity on the calcium chloride arrhythmia model. The maximum effect was observed for hemisuccinate 2-ethyl-6-methyl-3-hydroxypyridine. This substaned; unlike mexidol, also showed high activity on the model of aconitine arrhythmia, which is typical of class I antiarrhytmics. Mexidol did not show this activity. Consequently, 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate possesses a wider therapeutic spectrum than the well-known antiarrhythmic drugs of class I (lidocaine, procainamide) and is comparable in this respect with class IV drug verapamil.

[GABA-ergic mechanism of cerebrovascular and antiischemic effects of docosahexaenoic acid].

In experiments on rats, measurements of the local blood flow in the cortex of cerebrum with the aid of a laser Doppler flow meter showed that docosahexaenoic acid (DHA) enhanced the local cerebral circulation in animals with global transient cerebral ischemia, while not influencing that in intact animals. This vasodilatory effect of DHA in ischemized rats is blocked by bicuculline (specific GABA(A) receptor blocker), which is indicative of a GABA-ergic mechanisms of the vascular tone regulation. The results of radioligand binding assay in vitro showed the possibility of direct DHA interaction with cerebrovascular GABA(A) receptors.

[Effect of S-amlodipine nicotinate on the cerebral circulation in rats under conditions of ischemic and hemorrhagic brain injury].

We have performed a comparative study of the effects of S-amlodipine nicotinate and nimodipine on the local cerebral blood flow were studied in intact rats and those with model ischemic and hemorrhagic brain injury. It is established that S-amlodipine nicotinate produces a somewhat more pronounced enhancement of cerebral blood flow in rats with ischemic and hemorrhagic brain injury than in intact animals. In addition, S-amlodipine nicotinate significantly exceed nimodipine with respect to cerebrovascular activity in rats with brain pathology of both ischemic and hemorrhagic nature.

[Comparative study of the effect of S-amlodipine nicotinate and amlodipine benzylate on the arterial pressure of awake rats].

We have performed a comparative study of the effects of two calcium channel blockers, S-amlodipine nicotinate and amnlodipine benzylate, on the arterial pressure (AP) of awake rats measured in the tail artery. The results of experiments showed that both preparations produce a statistically significant long-term decrease in the AP of animals. In respect of both strength and duration of the hypotensive effect, S-amlodipine nicotinate somewhat exceeds amnlodipine benzylate.

[GABAergic mechanism of cerebrovascular effect of the NMDA receptor antagonist MK-801].

NMDA receptor antagonist MK-801 (dizocilpine) increases the local blood flow in the cerebral cortex in rats under transient global ischemia (TGI) conditions to a greater degree than in intact animals. The GABA receptor blocker bicuculline in most experiments eliminates or reduces the MK-801 induced increase in the blood flow after TGI, which is indicative of the participation of GABAergic mechanism of cerebrovascular tone control in the observed MK-801 activity.

[Cerebrovascular pharmacology of separate and combined vascular pathology of brain and heart].

The effect of nimodipine, mexidol, melatonin, afobazole, 5-hydroxy-adanamtan-2-one, and GABA conjugates with arachidonic acid and docosahexaenoyl dopamine on the cerebral circulation has been studied in intact rats and those with global transient cerebral ischemia, experimental myocardial infarction, and combined vascular pathology of brain and heart. The most pronounced vasodilation activity in rats with global transient cerebral ischemia is exhibited by nimodipine, mexidol, melatonin, afobazole, 5-hydroxy-adanamtan-2-one, and GABA-containing lipid derivatives. This effect of all these drugs (except for nimodipine) is not manifested on the background of GABA receptor blocker bicuculline. In rats with experimental myocardial infarction and combined vascular pathology of brain and heart not all of the compounds mentioned acbove with GABA-ergic mechanism of action stimulate the cerebral blood flow. Thus, both similarity and differences in cerebrovascular effects of these compounds have been found, which depend on the initial state of organism and the vascular pathology of brain and/or heart. The obtained results show good prospects for this direction of research.

[Cerebrovascular effects of GABA-prostaglandin E2 conjugate in comparison with prostaglandin E2].

Experiments have shown that GABA conjugate with prostaglandin E2 enhances cerebral blood flow in rats after global transient ischemia, while not affecting the cerebral hemoperfusion in intact animals. It is established that cerebrovascular activity of the GABA conjugate with prostaglandin E2 under conditions of cerebral ischemia is based on GABAergic mechanisms of vascular tone regulation, since it is removed by GABA(A)-receptor blocker bicuculline. At the same time, cerebral blood flow of intact rats and rats after global transient ischemia of brain is equally enhanced by prostaglandin E2 alone. This effect is not neutralized by bicuculline.

[Search for new drugs with antiarrhythmic properties among derivatives of adamant-2-ylamides of alkylamidocarbonic acids].

The experiments on white outbred awaken male rats have shown that derivatives of adamant-2-ylamides of alkylamidocarbonic acids exhibit prominent antiarrhythmic (antifibrillatory) effect on the model of calcium chloride arrhythmia. The most pronounced effect was demonstrated by N-[2(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide. This compound was also active on the model of aconitine arrhythmia, which is characteristic of class-I antiarrhythmic agents. It is established that N-[2-(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide has prominent antiarrhythmic activity and is more safe than other antiarrhythmic drugs of class I (lidocaine, ethmosine, novocainamide), class IV (verapamil), and class III (cardiocyclide).

[Peculiarities of cerebrovascular effects of GABA conjugate with docosahexaenoyl dopamine under conditions of separate and combined vascular pathology of brain and heart].

A GABA conjugate with docosahexaenoyl dophamine (DHED) enhanced local cerebral blood flow in rats under conditions of global transient cerebral ischemia, experimental myocardial infarction, and combined vascular pathology of brain and heart. At the same time, the GABA-DHED conjugate did not influence brain hemoperfusion in intact animals. The cerebrovascular effect of this conjugate is determined by its direct action on the vascular tone, since no changes in blood pressure have been observed. Under conditions of the combined vascular pathology of brain and heart, the cerebrovascular effect of GABA-DHED conjugate is inhibited by bicuculline, which is evidence for the involvement of GABAergic mechanisms in the drug action upon cerebrovascular tone.

[Adamantane derivate enhances cerebral blood flow under conditions of ischemic brain damage].

Experiments have shown that adamantane derivate - 5-hydroxyadamantan-2-on (100 mg/kg, i.v.) enhances the local blood flow in the cerebral cortex of rats under global transient brain ischemia conditions, while not influencing the brain blood flow in intact rats. In the same dose, adamantane derivate significantly decreases mortality in rats under conditions of hypergravity ischemia. The cerebrovascular effect of adamantane derivate is abolished by bicuculline (GABA-A receptor blocker), which is evidence for a GABAergic component in the mechanism of the cerebrovascular action ofadamantane derivate.

[GABAergic mechanism of the cerebrovascular effect of melatonin].

In most experiments on rats under conditions of cerebral global transient ischemia, melatonin substantially enhanced local blood flow and decreased arterial blood pressure. In intact rats, the effect of melatonin on brain perfusion was much less pronounced and the arterial pressure was not influenced at all. The mechanism of melatonin action has been studied with the aid of bicuculline. It is established that the cerebrovascular activity of the epiphyseal hormone is mediated by GABA-A receptors of cerebral vessels. Melatonin (in doses of 1.0 and 5.0 mg/kg) significantly increased survival of rats under conditions of hypergravity ischemia.

[Effect of mexidol on combined vascular pathology of brain and heart].

The effect of mexidol on cerebral blood flow under conditions of experimental myocardial infarction and combined disturbances of cerebral and coronary perfusion in comparison with intact and false-operated rats and rats after global transient ischemia of brain was studied. It is established that mexidol (200 mg/kg) more prominently enhances the blood flow in the parietal region of brain cortex of rats with combined ischemia of brain and heart as compared to intact rats and rats after experimental myocardial infarction. Under conditions of combined pathology, mexidol produces the same cerebrovascular effect as that in animals with cerebral ischemia.

[Influence of 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate on cerebral blood perfusion in rats under experimental pathology conditions].

Experiments on rats showed that 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate increases cerebral blood flow in the system of carotid arteries both in intact animals and under conditions of global transient ischemia. In combination with tropoxin, 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate enhances the blood flow in the inner carotid artery of intact rats and the local blood flow under conditions of global transient ischemia. A combination of 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate and tropoxin increases baseline cerebral blood flow and decreases the constrictor reaction of cerebral blood vessels to 5HT(2B/2C) receptor agonist meta-chlorophenylpiperazine.

[Cerebrovascular and antiserotoninergic activity of the combination of tropoxin and mexidol].

The results of experiments on narcotized rats showed that tropoxin substantially reduces the constrictor reactions of cerebral blood vessels to meta-chlorophenylpiperazine, while not increasing the blood flow in the carotid system of either intact rats or animals with model ischemic damage of brain. In contrast, mexidol increases the cerebral blood flow in rats under conditions of global transient ischemia of brain. A combination of tropoxin and mexidol retains both the anti-serotoninergic activity of tropoxin and the vasodilating effect of mexidol.

[Cerebrovascular effects of GABA conjugate with arachidonic acid under conditions of separate and combined vascular pathology of brain and heart].

Experiments on rats showed that, under conditions of global transient ischemia, a conjugate of GABA with arachidonic acid enhances the local cerebral blood flow due to a decrease in the vascular tone. In intact rats, the examined neurolipin did not show unidirectional changes in the cerebral perfusion. Under conditions of experimental myocardial infarction and combined vascular pathology of brain and heart, the GABA conjugate with arachidonic acid increased the blood flow in the parietal region of brain cortex in most experiments, while decreasing the level of blood pressure.

[Effect of tropoxin on cerebrovascular effects of meta-chlorophenylpiperazine and serotonin].

Experiments on rats showed that meta-chlorophenylpiperazine, as well as serotonin, decreases cerebral blood flow registered in internal carotid artery of narcotized animals. Therefore, this agonist of postsynaptic 5HT(2B/2C) receptors can be used for directed search of new antimigraine drugs. Tropoxin (10 mg/kg) substantially reduces constrictor reactions of cerebral blood vessels induced by meta-chlorophenylpiperazine. The effect was observed during both prophylaxis and treatment of the model disorder with this drug.