The use of 2-component myocardial contraction for assessing the mechanism of action of inotropic substances

The possibility of using two-component contraction of the myocardium to evaluate the mechanisms of action of cardiotropic pharmacological agents was studied. Caffeine, ouabain, low-natrium solution, varapamil, nifedipine and BAY K-8644 were used. It was concluded that the analysis of contraction component amplitude dynamics makes it possible to determine the effect of the pharmacological agents on the interrelated mechanisms of the delivery of Ca2+ into the myoplasm of cardiomyocytes from sarcoplasmic reticulum and through sarcolemma during a single cardiac cycle.     

Humic substances: pharmacological properties, mechanisms of action, and prospects for use in medicine

In recent years, the group of natural compounds called humic substances has drawn increasing interest of researchers both in, Russia and abroad. The properties of humic substances were studied and attempts of creating related medical preparations were undertaken. The article summarizes and reviews information about the pharmacological properties of humic substances and their possible mechanisms of action, analyzes relationships and separates the primary and secondary factors, and assesses prospects of using humic substances in medicine.     

Psychotropic properties of nootropic substances with a cholinergic action component in single and long-term use

Long-term administration of centrophenoxine and cleregil was found to exert on rats the antiamnestic and anxiogenic-like effects, to increase emotional reactivity and aggressiveness, to reduce motor activity and readiness to contact. The withdrawal of centrophenoxine and especially cleregil was followed by still greater enhancement of emotional reactivity and the appearance of spontaneous aggressiveness.     

The mechanisms of the anti-ulcer action of plant drug agents]

The mechanisms of the gastroprotective effect of well-known drugs (plantaglucid, befungin, plantain juice), extractions of birch bark (Betula pendula Roth,) and burdock seeds (Arctium tomentosum Mill.) on various links of gastric ulcer pathogenesis were compared. Phytopreparations were found to have a variety of effects on gastric secretion in rats. Differences in their action on the smooth muscles of the stomach and intestine were detected.     

The efficacy of substances with antihypoxic action in experimental hyperlipidemia]

Experiments on rats, guinea pigs and rabbits with hyperlipidemia induced by high-cholesterol diet have revealed that the specific antihypoxic drug oliphen has hypolipidemic effect which is least pronounced in oral GABA. Oliphen causes a significant increase in alpha-cholesterol (antiatherogenic lipoprotein cholesterol) decreased by hyperlipidemia. It is suggested that oliphen improves hepatic receptor-dependent uptake and atherogenic lipoprotein degradation.     

The mechanism of the antiarrhythmic action of dalargin in experimental myocardial ischemia]

It has been found that injection of dalargin before the occlusion of the left anterior coronary artery prevents an increase of cAMP content in the myocardium and blood plasma. In the myocardium of rats given dalargin before acute myocardial ischemia, the content of cGMP was increased and the level of somatostatin was reduced. It is assumed that the increase of the content of cGMP and the reduction of cAMP and somatostatin levels in the myocardium play an important role in antiarrhythmic action of dalargin.     

The action of morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum

Morphine depresses the twitch and tetanus of stimulated guinea-pig ileum by reducing acetylcholine released from cholinergic nerve endings. Acetylcholine output per shock falls to roughly the same residual amount at varying stimulation rates. Since normal output per shock declines with increasing stimulus frequency, the proportionate effect of morphine diminishes as stimulus frequency rises. Acute “tolerance” to morphine and a state of “morphinedependence” can be produced. Phenadoxone, dihydromorphinone, metopon, methadone, and heroin are more active, codeine and pethidine less active, than morphine. Nalorphine also depresses the twitch and can desensitize the gut both to itself and to morphine.     

Neurophysiological mechanisms of the action of stimulators on the memory]

Aethimizol - and strychnine-induced improvement of the short-term memory in dogs is attened by a rising level of excitability of the mesencephalic reticular formation, ventral hippocampus and of the frontal region of the neocrotex. And, conversely, with the stimulats producing a facilitating effect on the memory the excitability of the dorsal hippocampus, mamillary bodies and the dorso-medial amygdala becomes less intensive. At the same time, the function of the anterio-ventral thalamus, basolateral amygdala and also of the primary visual and accoustic regions of the neocortex remains unchanged. Aethimizol exerts an inhibitory effect on the lateral and ventro-medial hypothalamus whereas strychnine raises the excitability of the later and does not change the function of the ventro-medial hypothalamus. The lack of stimulating effect of caffeine on the memory is due to a different organization of the brain.     

The cytogenetic effects of antitumor preparations with different mechanisms of action]

The cytogenetic effects of antitumor drugs with different action mechanism on the genetic structure of bone marrow hemopoietic cells were studied in experiments on CBA mice. It has been shown that single injections of doxorubicin (6 mg/kg), vinblastin (2.2 mg/kg), cyclophosphamide (250 mg/kg) and continuous administration of doxorubicin (0.95 mg/kg), vinblastin (0.24 mg/kg), cyclophosphamide (27 mg/kg) in 1/10 LD50 x 10 induce the formation of bone marrow cells with cytogenetic damage and peripheral red blood cells with micronuclei. The cytogenetic damage of hemopoietic tissue may be detectable 1-3 months after cytostatic influence.     

The neurotropic and cardiotropic properties of new amino acid derivatives of isonicotinic acid]

Different derivatives of isonicotinic acid are used widely enough as antimicrobial and antituberculous agents. However, their neurotropic and cardiotropic effects have been studied little. The paper is concerned with investigations of these types of the activity of the new derivatives of isonicotinic acid: beta-phenyl-beta-alanine, l-proline, DL-valine, beta-alanine and DL-threonine synthesized for the first time at the Institute of Fine Organic Chemistry, Academy of Sciences of Armenia.     

The serotonin- and dopaminergic mechanisms in the action of 1-pyrimidinyl piperazine derivatives]

It has been established in experiments on spinal ganglia neurons of rats that 1-pyrimidinyl-piperazine derivatives show the properties of partial agonists of 5-HT1A-receptors. Some of them were discovered to be capable of blocking D2-dopamine receptors. Comparison of neuronal and behavioral activity of the substances tested has demonstrated that their anxiolytic activity detectable under the conditions of the conflict situation method significantly correlates with 5-HT1A-mimetic and anti-dopamine activity. The latter one correlates well with the influence of the substances tested on the time of immobilization in the forced swimming test.     

Chemical chaperones: mechanisms of action and potential use

An increasing number of studies indicate that low-molecular-weight compounds can help correct conformational diseases by inhibiting the aggregation or enable the mutant proteins to escape the quality control systems, and thus their function can be rescued. The small molecules were named chemical chaperones and it is thought that they nonselectively stabilize the mutant proteins and facilitate their folding. Chemical chaperones are usually osmotically active, such as DMSO, glycerol, or deuterated water, but other compounds, such as 4-phenylbutiric acid, are also members of the chemical chaperone group. More recently, compounds such as receptor ligands or enzyme inhibitors, which selectively recognize the mutant proteins, were also found to rescue conformational mutants and were termed pharmacological chaperones. An increasing amount of evidence suggests that the action of pharmacological chaperones could be generalized to a large number of misfolded proteins, representing new therapeutic possibilities for the treatment of conformational diseases. A new and exciting strategy has recently been developed, leading to the new chemical group called folding agonist. These small molecules are designed to bind proteins and thus restore their native conformation.     

The cardioprotective action of 18-dehydroglycyrrhetic acid in experimental myocardial damage]

Experiments on rats with isadrine damage to the myocardium showed that when used for preventive-therapeutic purposes 18-dehydroglycyrrhizic acid (glyderinine preparation) causes statistically significant prevention of a rise in the serum level of marker enzymes (creatine phosphokinase, lactate dehydrogenase, aspartate aminotranspherase), prevents activation of lipid peroxidation, decrease of blood serum antioxidation activity and pathological changes in the content of glycogen and total lipids in the heart, it also improves the electrocardiographic parameters, reduces myocardial inflammatory edema. The results of the study show that glyderinine possesses a marked cardioprotective effect.     

The use of recombinant inbred strains to study mechanisms of drug action.

Long-sleep (LS) and short-sleep (SS) mice which were selectively bred for sensitivity to the sedative-hypnotic effects of ethanol have been used extensively in the examination of sensitivity to ethanol as well as to other CNS depressants. Understanding the relationship between sensitivity to ethanol and other depressants using LS and SS mice has been limited to a two mouse line comparison because these mice do not exist as replicate lines. To circumvent this problem, DeFries et al. have bred LSXSS recombinant inbred strains (LSXSS RIs) from a cross of LS and SS mice. These mice are being characterized on their responses to a variety of CNS depressants and agents that interact with the GABAergic system. Preliminary results are presented here on the sensitivity of these LSXSS RIs to pentobarbital, phenobarbital, and flurazepam as measured by sleep times. Additionally, analyses of seizure susceptibility to the GABAergic antagonist, bicuculline, in 24 LSXSS RIs indicate that there is no significant relationship between this measure of GABAergic function and sensitivity to ethanol as measured by the sleep-time response. These results are presented in the context of questions that can be resolved using RIs in drug-abuse research.